The relative distribution of membranous and cytoplasmic met is a prognostic indicator in stage I and II colon cancer

PURPOSE: The association hepatocyte growth factor receptor (Met) tyrosine kinase with prognosis and survival in colon cancer is unclear, due in part to the limitation of detection methods used. In particular, conventional chromagenic immunohistochemistry (IHC) has several limitations including the inability to separate compartmental measurements. Measurement of membrane, cytoplasm, and nuclear levels of Met could offer a superior approach to traditional IHC. EXPERIMENTAL DESIGN: Fluorescent-based IHC for Met was done in 583 colon cancer patients in a tissue microarray format. Using curvature and intensity-based image analysis, the membrane, nuclear, and cytoplasm were segmented. Probability distributions of Met within each compartment were determined, and an automated scoring algorithm was generated. An optimal score cutpoint was calculated using 500-fold crossvalidation of a training and test data set. For comparison with conventional IHC, a second array from the same tissue microarray block was 3,3'-diaminobenzidine immunostained for Met. RESULTS: In crossvalidated and univariate Cox analysis, the membrane relative to cytoplasm Met score was a significant predictor of survival in stage I (hazard ratio, 0.16; P = 0.006) and in stage II patients (hazard ratio, 0.34; P < or = 0.0005). Similar results were found with multivariate analysis. Met in the membrane alone was not a significant predictor of outcome in all patients or within stage. In the 3,3'-diaminobenzidine-stained array, no associations were found with Met expression and survival. CONCLUSIONS: These data indicate that the relative subcellular distribution of Met, as measured by novel automated image analysis, may be a valuable biomarker for estimating colon cancer prognosis.     

Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee.

BACKGROUND AND METHOD: A randomised controlled trial in locally advanced non-small cell lung cancer (NSCLC), compared CHART which employs 36 fractions of 1.5 Gy 3 times per day to give 54 Gy in 12 consecutive days with conventional radiotherapy-30 fractions of 2 Gy to a total dose of 60 Gy in 6 weeks. A total of 563 patients were entered between April 1990 and April 1995. This report is based upon the data updated to 1 April 1998. RESULTS: The analysis of the mature data shows that the benefits previously reported have been maintained. Overall there was a 22% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 9% from 20 to 29% (P = 0.008) and a 21% reduction in the relative risk of local progression (P = 0.033). In the large subgroup of patients with squamous cell cancer which accounted for 81% of the cases, there was a 30% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 13% from 20 to 33% (P = 0.0007) and a 27% reduction in the relative risk of local progression (P = 0.012). Furthermore, in squamous carcinoma there was a 25% reduction in the relative risk of local and/or distant progression (P = 0.025) and 24% reduction in the relative risk of metastasis (P = 0.043). There was no evidence that CHART gave more or less benefit in any other subgroup. CONCLUSION: This analysis of mature data confirms that CHART is superior to conventional radiotherapy in achieving local tumour control and survival in locally advanced NSCLC. This demonstrates the importance of cellular repopulation as a cause of failure in the radiotherapy of NSCLC. The reduction in the risk of metastasis confirms that improved local tumour control, even in lung cancer, can reduce the incidence of metastasis. This trial shows that control of local tumour can lead to an improvement in long term survival.     

Juvenile nasopharyngeal angiofibroma: evaluation and surgical management of advanced disease.

OBJECTIVE: Evaluate preoperative imaging in predicting operative stage. Describe the outcomes in surgically treated juvenile nasopharyngeal angiofibroma (JNA) with the influence of middle cranial fossa, carotid, or dural involvement on recurrence. STUDY DESIGN: Retrospective cohort of surgically treated patients with JNA. SUBJECTS AND METHODS: Eighty-five patients from a regional Italian referral center were assessed for recurrence, radiologic, and operative staging. High risk areas involved were recorded at surgery. RESULTS: Recurrence for advanced disease (IIIb+) was 18.2% (6 of 33) and 15.3% (13 of 85) overall. Preoperative staging poorly correlated with operative stage (P = 0.15). No single high risk area was predictive for recurrence, but the absence of any risk factor was associated with a favorable outcome (P < 0.01). CONCLUSION: Dural involvement by tumor is rare and imaging may overstage disease. Anterior access, endoscopic or open, is sufficient to address intracranial involvement. When an open approach is used, a midface degloving technique affords excellent exposure even for advanced disease. Lateral approaches with their associated morbidity can be reserved for selected recurrent disease.     

The role of chronic infection in children with otitis media with effusion: Evidence for intracellular persistence of bacteria

OBJECTIVE: Demonstrate mucosal bacterial infection in children with otitis media with effusion (OME). STUDY DESIGN AND SETTING: Middle ear mucosal biopsies from 11 children with OME were examined for bacteria utilizing transmission electron microscopy. This was correlated with standard culture and polymerase chain reaction (PCR) of middle ear effusions. RESULTS: Gram-positive coccal bacteria were demonstrated in middle ear mucosal epithelial cells of 4 of 11 (36%) children. Morphological appearance of bacteria and detection of pneumolysin DNA by PCR in middle ear fluid suggests a role for persistent intracellular infection with Streptococcus pneumoniae and other gram-positive cocci in some cases of OME. CONCLUSION: Intracellular bacterial infection of middle ear mucosal epithelial cells in children with OME may be an important mechanism for bacterial persistence, and contribute to inflammation and mucus production in the pathogenesis of this condition. SIGNIFICANCE: Persistent intracellular infection is a novel paradigm for OME pathogenesis in children and may influence antibiotic effectiveness in treatment of this condition.     

Viral vectors for neurotrophic factor delivery: A gene therapy approach for neurodegenerative diseases of the CNS

The clinical manifestation of most diseases of the central nervous system results from neuronal dysfunction or loss. Diseases such as stroke, epilepsy and neurodegeneration (e.g. Alzheimer's disease and Parkinson's disease) share common cellular and molecular mechanisms (e.g. oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction) that contribute to the loss of neuronal function. Neurotrophic factors (NTFs) are secreted proteins that regulate multiple aspects of neuronal development including neuronal maintenance, survival, axonal growth and synaptic plasticity. These properties of NTFs make them likely candidates for preventing neurodegeneration and promoting neuroregeneration. One approach to delivering NTFs to diseased cells is through viral vector-mediated gene delivery. Viral vectors are now routinely used as tools for studying gene function as well as developing gene-based therapies for a variety of diseases. Currently, many clinical trials using viral vectors in the nervous system are underway or completed, and seven of these trials involve NTFs for neurodegeneration. In this review, we discuss viral vector-mediated gene transfer of NTFs to treat neurodegenerative diseases of the central nervous system.     

General practitioners' use of computers during the consultation.

This study documents the extent of reported computer use by general practitioners (GPs) in consultations with patients, and identifies barriers to their use. There was a 65% response rate from a random sample of 600 GPs in the South and West National Health Service (NHS) region who were sent a questionnaire. Ninety-one per cent (357) had a desktop computer terminal in their consulting rooms. Of these, 98% used the computer to look up information or prescribe medication, 75% entered details about selected problems presented by patients, and 36% entered information about the patient's presenting problem at every consultation. Only 18% used computers to access reference information. Use of the computer for anything other than looking up patient information or prescribing was positively associated with fundholding status and use of a personal computer at home, and was independent of number of years in practice. Sixty-five per cent of responders had positive attitudes to the inclusion of management guidelines on the computer software, and 45% of responders held positive views towards the idea of integrating management guidelines with the patient's personal computerized medical record. Consideration should be given to targeting training at those GPs who appear to be reluctant to use computers during the consultation.