MRI intensity inhomogeneity correction by combining intensity and spatial information

We propose a novel fully automated method for retrospective correction of intensity inhomogeneity, which is an undesired phenomenon in many automatic image analysis tasks, especially if quantitative analysis is the final goal. Besides most commonly used intensity features, additional spatial image features are incorporated to improve inhomogeneity correction and to make it more dynamic, so that local intensity variations can be corrected more efficiently. The proposed method is a four-step iterative procedure in which a non-parametric inhomogeneity correction is conducted. First, the probability distribution of image intensities and corresponding second derivatives is obtained. Second, intensity correction forces, condensing the probability distribution along the intensity feature, are computed for each voxel. Third, the inhomogeneity correction field is estimated by regularization of all voxel forces, and fourth, the corresponding partial inhomogeneity correction is performed. The degree of inhomogeneity correction dynamics is determined by the size of regularization kernel. The method was qualitatively and quantitatively evaluated on simulated and real MR brain images. The obtained results show that the proposed method does not corrupt inhomogeneity-free images and successfully corrects intensity inhomogeneity artefacts even if these are more dynamic.     

Telomerase reactivation is an early event in laryngeal carcinogenesis.

The exact role and timing of reactivation of telomerase, a key enzyme implicated in cellular immortalization and transformation in the multistep process of laryngeal carcinogenesis, is still unknown. We attempted to (1) determine that quantitative differences exist in the levels of telomerase catalytic subunit (hTERT) mRNA expression among different grades of laryngeal epithelial abnormalities classified according to the Ljubljana classification; (2) determine that telomerase reactivation is an important, most probably early event in laryngeal carcinogenesis; and (3) analyze whether the relative quantity of hTERT mRNA can be used as a molecular biomarker in the early detection of precancerous lesions. The relative quantity of hTERT mRNA, expressed as an hTERT index, was analyzed in 140 frozen laryngeal tissue specimens representing different morphological stages of laryngeal carcinogenesis by using a commercially available LightCycler Telo TAGGG hTERT Quantification kit. The presence and relative quantity of hTERT mRNA in laryngeal epithelium increases progressively with the degree of epithelial abnormalities. hTERT mRNA was detectable in 1/15 normal laryngeal epithelia (7%, mean hTERT index 0.02), 3/15 simple hyperplasias (20%, mean hTERT index 0.09), 10/27 abnormal hyperplasias (37%, mean hTERT index 0.18), 9/12 atypical hyperplasias (75%, mean hTERT index 0.74), 8/9 intraepithelial carcinomas (89%, mean hTERT index 1.82), and 53/62 invasive laryngeal squamous cell carcinomas (85%, mean hTERT index 2.51). Statistical analysis revealed two groups of laryngeal epithelial changes with significant differences in the levels of hTERT mRNA expression (P <.0033): (1) normal and reactive hyperplastic laryngeal epithelium (simple and abnormal hyperplasia) and (2) atypical hyperplasia (precancerous lesion), intraepithelial and invasive laryngeal squamous cell carcinoma. The results of the present study suggest that telomerase reactivation is an early event in laryngeal carcinogenesis, detectable already at the stage of precancerous laryngeal epithelial changes. Nevertheless, other genetic abnormalities appear to be necessary for progression of these epithelial abnormalities toward invasive laryngeal squamous cell carcinoma.     

Genomic diversity of human papillomavirus genotype 53 in an ethnogeographically closed cohort of white European women

Human papillomavirus (HPV) genotype 53 is classified taxonomically in alpha HPV genus-species 6, together with HPV-30, HPV-56, and HPV-66 and is considered to be one of three "probable high-risk" HPV genotypes. Recent worldwide comparison of 44 isolates of HPV-53 showed the existence of nine long control region (LCR) genomic variants, which formed a phylogenetic tree with two deep dichotomic branches. In order to investigate further the genomic diversity of HPV-53, a total of 94 isolates of HPV-53 obtained from an ethnogeographically closed cohort of 70 white European women was analyzed. The identification and characterization of HPV-53 genomic variants was based on analysis of three different HPV genomic regions: LCR, E6 and E7. A higher genomic diversity of HPV-53 was identified in the ethnogeographically closed cohort of white European women than has been reported previously on isolates collected worldwide. Altogether, 19 HPV-53 genomic variants, composed of 13 LCR, 13 E6, and 5 E7 genomic variants, were identified. Eleven out of 13 LCR, all E6, and four out of five E7 genomic variants were described for the first time. The present study confirmed dichotomic phylogeny of HPV-53 described previously and, in addition, showed for the first time that after a dichotomic split, both groups of HPV-53 genomic variants formed star-like phylogenetic clusters. In women with persistent HPV-53 infection, HPV-53 genomic variants remained unchanged for up to 51 months. In rare cases, infection with multiple HPV-53 genomic variants is possible. Taking into account the results of this and previous studies, at least 26 different HPV-53 genomic variants exist today.     

Structural basis and prediction of substrate specificity in protein serine/threonine kinases

The large number of protein kinases makes it impractical to determine their specificities and substrates experimentally. Using the available crystal structures, molecular modeling, and sequence analyses of kinases and substrates, we developed a set of rules governing the binding of a heptapeptide substrate motif (surrounding the phosphorylation site) to the kinase and implemented these rules in a web-interfaced program for automated prediction of optimal substrate peptides, taking only the amino acid sequence of a protein kinase as input. We show the utility of the method by analyzing yeast cell cycle control and DNA damage checkpoint pathways. Our method is the only available predictive method generally applicable for identifying possible substrate proteins for protein serinethreonine kinases and helps in silico construction of signaling pathways. The accuracy of prediction is comparable to the accuracy of data from systematic large-scale experimental approaches.     

Endovascular treatment of intracranial artery aneurysms in the posterior cerebral circulation

The purpose of the study was to determine the safety and effectiveness of electrolytically detachable platinum coils in the endovascular treatment of ruptured and unruptured aneurysms in the posterior cerebral circulation. The aneurysms were occluded with electrolytically detachable platinum coils. Six patients with posterior cerebral circulation aneurysms were treated. Four patients suffered a subarachnoid hemorrhage, in two patients the aneurysms were detected incidentally, in one due to mass effect. In all six patients, the diameters of the aneurysms were less than 12 mm and were therefore classified as small aneurysms. Complete occlusion (100%) was achieved in 4 patients, the rate of occlusion in the other two patients was estimated at 75% in one case and at 90% in the other. The clinical outcome in five patients was excellent, without any additional neurological deficit. One patient died five weeks after the procedure due to respiratory complications. At the time of endovascular treatment, she had been graded clinically as grade 5 according to Hunt and Hesse. None of the patients experienced any recurrence of hemorrhage during the follow up period of 12 months. Endovascular occlusion of posterior cerebral artery aneurysms with detachable coil system is an effective alternative therapy to established surgical treatment and could become the treatment of choice. The method is minimally invasive and there is no need for skull trepanation.     

Cytochrome P450 2D6 and outcomes of adjuvant tamoxifen therapy: results of a meta-analysis

Pharmacological evidence shows that cytochrome P450 2D6 (CYP2D6) function is important in the conversion of tamoxifen to its active metabolites. Many retrospective analyses have assessed the role of both CYP2D6 genotype and concurrent administration of drug inhibitors of CYP2D6 on outcome of tamoxifen therapy. These studies have frequently been of small size and their data highly variable. A published data meta-analysis of trials evaluating outcomes of tamoxifen therapy in early breast cancer was undertaken. Hazard ratios (HRs) were extracted for disease-free survival (DFS) and overall survival (OS). Pooled estimates were computed using inverse-variance and random-effect modeling. Data from 10 studies assessing CYP2D6 genotype were included in a meta-analysis. There was significant heterogeneity in the definition of comparison groups between studies. When compared to reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR 2.07, 95% CI 0.96–4.49, P = 0.06) but not OS (HR 1.36, 95% CI 0.73–2.52, P = 0.34). Pooling of data from two studies evaluating CYP2D6 drug inhibitors showed that concomitant administration of these with tamoxifen was associated with a non-significant association with DFS (HR 1.37, 95% CI 0.69–2.73, P = 0.37). Analysis of the effect of CYP2D6 drug inhibitors on OS was not possible. The effect of CYP2D6 genotype on breast cancer seems to be relatively small and may not warrant testing of CYP2D6 genotype in all women with hormone receptor positive breast cancer. The effect of CYP2D6 genotype on outcome in low-risk patients may not be clinically relevant, while the upfront use of aromatase inhibitors is a reasonable alternative to tamoxifen in high-risk post-menopausal women, irrespective of CYP2D6 genotype. There are limited data supporting the association of potent inhibitors of CYP2D6 and detrimental outcome, but avoidance of such drugs seems reasonable.     

Solitary fibrous tumor of the parapharyngeal space

Solitary fibrous tumors are rare tumors originating from the mesenchymal tissue. In most cases they arise from the subpleural tissue but have also been described in other locations in the body. Most such tumors in the head and neck region occur in the orbit. Although malignant tumors can occur, benign tumors are far more common. The therapy is surgical excision. For a conclusive diagnosis, a typical morphology and immunohistochemistry are required. The tumor is strongly positive for CD34 and vimentin. This report describes the clinical appearance and treatment of a solitary fibrous tumor of the parapharyngeal space in a female patient. The symptoms were similar to those in a peritonsillar abscess, one of the more common ear-nose-throat dysfunctions. Fewer than 10 cases of a solitary fibrous tumor of the parapharyngeal space have been described in the literature.