Máté E. Maros

Correlations of Differentially Expressed Gap Junction Connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with Breast Cancer Progression and Prognosis

Background and Aims Connexins and their cell membrane channels contribute to the control of cell proliferation and compartmental functions in breast glands and their deregulation is linked to breast carcinogenesis. Our aim was to correlate connexin expression with tumor progression and prognosis in primary breast cancers. Materials and Methods Meta-analysis of connexin isotype expression data of 1809 and 1899 breast cancers from the Affymetrix and Illumina array platforms, respectively, was performed. Expressed connexins were also monitored at the protein level in tissue microarrays of 127 patients equally representing all tumor grades, using immunofluorescence and multilayer, multichannel digital microscopy. Prognostic correlations were plotted in Kaplan-Meier curves and tested using the log-rank test and cox-regression analysis in univariate and multivariate models. Results The expression of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and, for the first time, GJA6/Cx30 and GJB1/Cx32 was revealed both in normal human mammary glands and breast carcinomas. Within their subfamilies these connexins can form homo- and heterocellular epithelial channels. In cancer, the array datasets cross-validated each other’s prognostic results. In line with the significant correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker stronger than vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming mitotic index and necrosis. Elevated versus low Cx43 protein levels allowed the stratification of grade 2 tumors into good and poor relapse free survival subgroups, respectively. Also, elevated versus low Cx30 levels stratified grade 3 patients into poor and good overall survival subgroups, respectively. Conclusion Differential expression of Cx43 and Cx30 may serve as potential positive and negative prognostic markers, respectively, for a clinically relevant stratification of breast cancers.

Incidence, Locations, and Longitudinal Course of Cerebral Microbleeds in European Moyamoya

Background and Purpose— Cerebral microbleeds (cMBs) have previously been linked with especially high incidence in Asian patients with moyamoya together with high tendency to bleed. This, presumably, is characteristic of patients with moyamoya. Herein, we, therefore, investigate retrospectively the frequency, location, and longitudinal course of cMBs in a large German cohort. Methods— We included all patients with moyamoya who underwent standard magnetic resonance imaging, including T2*-weighted images, in our department between 1998 and 2015. Two independent readers evaluated magnetic resonance imaging scans to determine the occurrence of cMBs according to the Brain Observer Microbleed Scale. Demographics, initial symptoms leading to hospitalization, and associated diseases were obtained by chart review. Results— Overall, there was a total of 242 T2* studies of 101 included moyamoya patients available with a strong female predominance (69.3%). Eight patients (7.9%) were ⩽18 years of age. We detected 25 cMBs within 13 patients (12.9%). One patient <18 of age was presented with a cMB; 2 of 3 patients with an intracranial hemorrhage as initial event demonstrated cMB(s). In 72 of 101 cases, there were 1719 person months of follow-up, with 3 adult patients showing 3 de novo cMBs in the course. The majority of cMBs (64.0%) were located at the cortex/gray–white junction. Conclusions— Although the frequency of cMBs herein is much higher than the expected age-specific incidence, it is still much lower compared with previous reports on cMBs in moyamoya patients of Asian descent. These results might reflect another ethnic-specific difference in patients diagnosed with moyamoya.

Image Quality of 3rd Generation Spiral Cranial Dual-Source CT in Combination with an Advanced Model Iterative Reconstruction Technique: A Prospective Intra-Individual Comparison Study to Standard Sequential Cranial CT Using Identical Radiation Dose

Objectives To prospectively intra-individually compare image quality of a 3rd generation Dual-Source-CT (DSCT) spiral cranial CT (cCT) to a sequential 4-slice Multi-Slice-CT (MSCT) while maintaining identical intra-individual radiation dose levels. Methods 35 patients, who had a non-contrast enhanced sequential cCT examination on a 4-slice MDCT within the past 12 months, underwent a spiral cCT scan on a 3rd generation DSCT. CTDIvol identical to initial 4-slice MDCT was applied. Data was reconstructed using filtered backward projection (FBP) and 3rd-generation iterative reconstruction (IR) algorithm at 5 different IR strength levels. Two neuroradiologists independently evaluated subjective image quality using a 4-point Likert-scale and objective image quality was assessed in white matter and nucleus caudatus with signal-to-noise ratios (SNR) being subsequently calculated. Results Subjective image quality of all spiral cCT datasets was rated significantly higher compared to the 4-slice MDCT sequential acquisitions (p<0.05). Mean SNR was significantly higher in all spiral compared to sequential cCT datasets with mean SNR improvement of 61.65% (p*Bonferroni0.05<0.0024). Subjective image quality improved with increasing IR levels. Conclusion Combination of 3rd-generation DSCT spiral cCT with an advanced model IR technique significantly improves subjective and objective image quality compared to a standard sequential cCT acquisition acquired at identical dose levels.

Signal changes of the alar ligament in a healthy population: a dispositional or degenerative consequence?

OBJECT The alar ligaments (ALs) are vital for stabilizing the craniocervical junction. In terms of morphology, their appearance varies and is visible on MRI. Dark signal of the AL on proton-density (PD)-weighted images is generally considered the norm, but the etiology of frequently observed signal hyperintensities is poorly understood. Using spectral fat suppression, signal hyperintensities can be differentiated into fat- and nonfat-related hyperintensities (NFH). Although signal hyperintensities have no evident association with whiplash-associated disorder, age-related degeneration has often been theorized. Therefore, this study investigates the signal intensities of the ALs on 3.0-T MRI with special reference to age. Expanding thereon, the authors investigated the relationship between signal hyperintensities and patient characteristics, such as height, weight, and sex. METHODS Sixty-six healthy volunteers were scanned using 3.0-T PD-weighted MRI, including spectral fat suppression of the craniocervical junction. The study population was separated into 2 groups (old vs young) using 2 approaches: dichotomization at the median age (40.0 years) and the calculated threshold (28.5 years) using receiver operating characteristics (ROC). The AL was independently characterized with respect to continuity, course, shape, signal intensity, and graduation of homogeneity by 2 experienced neuroradiologists. Signal intensity was differentiated into fat-related hyperintensity and NFH. Univariate and multivariate logistic regression models were employed to investigate the relationship between patient characteristics and signal intensities. RESULTS Two different AL patterns were observed: inhomogeneous (33.3%) and homogeneous (66.7%). The latter pattern was mostly surrounded by a small dark rim (56.8%). Fat could be identified in 15.9% of all ALs (21 of 132 patients), and NFH was identified in 17.4% of all ALs (23 of 132 patients). Here, 28.5 years was the preferred threshold, demonstrating a relatively high sensitivity for dichotomizing the population based on the ROC of NFH. The most relevant factor for having NFH was being older than the calculated threshold (odds ratio [OR] 3.420, p = 0.051). Fat-related hyperintensities occurred significantly more frequently in men than women (OR 0.110 and p = 0.007 for women; OR 9.075 and p = 0.007 for men). Height was the second most significant factor: for every 1-cm increase, the odds of having fat lesions increased by approximately 10% (OR 1.102; p = 0.017). CONCLUSIONS This study shows that AL signal hyperintensities are substantially influenced by age, sex, and height in healthy individuals. Regarding fat-related hyperintensities, the most relevant factors proved to be sex and height. The odds of detecting NFH increased almost significantly after a relatively young age (> 28.5 years) and were remarkably more frequent in individuals older than 28.5 years. The authors caution presumptions equating signal alterations with age-related deterioration. Instead, they suggest that dispositional factors such as sex and height are more relevant in the AL constitution. Signal alterations in ALs naturally occur in healthy symptom-free individuals, underscoring the importance of cautiously interpreting such lesions on posttraumatic MRI scans.

Contrast-enhanced fat-suppressed FLAIR for the characterization of leptomeningeal inflammation in optic neuritis

Background: Leptomeningeal contrast enhancement on fluid-attenuated inversion recovery (FLAIR) images has been reported in patients with multiple sclerosis and interpreted as a biomarker of inflammation. In this study, we sought to evaluate this phenomenon in patients with optic neuritis (ON). Methods: A total of 42 patients with suspected ON were included in this prospective study and underwent a dedicated study magnetic resonance imaging (MRI) protocol including native and contrast-enhanced fat-suppressed thin-section axial and coronal FLAIR images on an 1.5 T magnetic resonance (MR) system. Results: After diagnostic workup, 34 patients with final diagnosis of ON were analyzed in detail. On contrast-enhanced fat-suppressed FLAIR images, 25 (73.5%) patients with ON demonstrated perioptic leptomeningeal enhancement, and in 3 (8.8%) patients, this was even the only pathological MRI finding. In comparison, patients with perioptic leptomeningeal enhancement on contrast-enhanced fat-suppressed FLAIR images had a higher prevalence of additional hyperintense brain lesions (p = 0.022) as well as cerebrospinal fluid (CSF)-specific oligoclonal bands (p = 0.013) than patients without. Conclusion: Perioptic leptomeningeal contrast enhancement on fat-suppressed FLAIR images is a novel marker in ON and possibly reflects a leptomeningeal inflammatory process preceding or accompanying ON. Thin-section contrast-enhanced fat-suppressed FLAIR images might be a useful addition in MRI protocols for patients with suspected ON.

Intra-individual diagnostic image quality and organ-specific-radiation dose comparison between spiral cCT with iterative image reconstruction and z-axis automated tube current modulation and sequential cCT.

Highlights • Superiority of spiral versus sequential cCT in image quality and organ-specific-radiation dose.• Spiral cCT: lower organ-specific-radiation-dose in eye lense compared to tilted sequential cCT.• State-of-the-art IR spiral cCT techniques has significant advantages over sequential cCT techniques.

Prognostic impact of reduced connexin43 expression and gap junction coupling of neoplastic stromal cells in giant cell tumor of bone.

Missense mutations of the GJA1 gene encoding the gap junction channel protein connexin43 (Cx43) cause bone malformations resulting in oculodentodigital dysplasia (ODDD), while GJA1 null and ODDD mutant mice develop osteopenia. In this study we investigated Cx43 expression and channel functions in giant cell tumor of bone (GCTB), a locally aggressive osteolytic lesion with uncertain progression. Cx43 protein levels assessed by immunohistochemistry were correlated with GCTB cell types, clinico-radiological stages and progression free survival in tissue microarrays of 89 primary and 34 recurrent GCTB cases. Cx43 expression, phosphorylation, subcellular distribution and gap junction coupling was also investigated and compared between cultured neoplastic GCTB stromal cells and bone marow stromal cells or HDFa fibroblasts as a control. In GCTB tissues, most Cx43 was produced by CD163 negative neoplastic stromal cells and less by CD163 positive reactive monocytes/macrophages or by giant cells. Significantly less Cx43 was detected in α-smooth muscle actin positive than α-smooth muscle actin negative stromal cells and in osteoclast-rich tumor nests than in the adjacent reactive stroma. Progressively reduced Cx43 production in GCTB was significantly linked to advanced clinico-radiological stages and worse progression free survival. In neoplastic GCTB stromal cell cultures most Cx43 protein was localized in the paranuclear-Golgi region, while it was concentrated in the cell membranes both in bone marrow stromal cells and HDFa fibroblasts. In Western blots, alkaline phosphatase sensitive bands, linked to serine residues (Ser369, Ser372 or Ser373) detected in control cells, were missing in GCTB stromal cells. Defective cell membrane localization of Cx43 channels was in line with the significantly reduced transfer of the 622 Da fluorescing calcein dye between GCTB stromal cells. Our results show that significant downregulation of Cx43 expression and gap junction coupling in neoplastic stromal cells are associated with the clinical progression and worse prognosis in GCTB.

Objective Comparison Using Guideline-based Query of Conventional Radiological Reports and Structured Reports

Background: This feasibility study of text-mining-based scoring algorithm provides an objective comparison of structured reports (SR) and conventional free-text reports (cFTR) by means of guideline-based key terms. Furthermore, an open-source online version of this ranking algorithm was provided with multilingual text-retrieval pipeline, customizable query and real-time-scoring. Materials and Methods: Twenty-five patients with suspected stroke and magnetic resonance imaging were re-assessed by two independent/blinded readers [inexperienced: 3 years; experienced >6 years/Board-certified). SR and cFTR were compared with guideline-query using the cosine similarity score (CSS) and Wilcoxon signed-rank test. Results: All pathological findings (18/18) were identified by SR and cFTR. The impressions section of the SRs of the inexperienced reader had the highest median (0.145) and maximal (0.214) CSS and were rated significantly higher (p=2.21×10−5 and p=1.4×10−4, respectively) than cFTR (median=0.102). CSS was robust to variations of query. Conclusion: Objective guideline-based comparison of SRs and cFTRs using the CSS is feasible and provides a scalable quality measure that can facilitate the adoption of structured reports in all fields of radiology.

Susceptibility Vessel Sign on T2*-Weighted Gradient Echo Imaging in Lacunar Infarction

Background/Aim: In stroke due to large vessel occlusion, thrombotic material can be demonstrated by the susceptibility vessel sign (SVS), a hypointense signal on T2*-weighted gradient echo magnetic resonance (GRE) images. In the present study, we evaluated the value of GRE for the detection of perforating artery occlusion in hyperacute lacunar infarction (LI). Materials and Methods: The presence of SVS on GRE in 58 patients with LI who underwent magnetic resonance imaging within 24 hours after symptom onset was analyzed. Results: On diffusion-weighted images (DWI), LI was found in the basal ganglia in 17.2%, internal capsule in 25.9%, corona radiata in 19.0%, thalamus in 32.8%, and brainstem in 5.2%. On GRE a subtle circumscribed hypointense signal at the lower edge of the LI consistent with SVS was detected in 11/58 (19%) patients. Patients with SVS had larger ischemic lesions on DWI (p=0.045). Conclusion: SVS on GRE may be useful for detection of perforating artery occlusion in a subset of patients with hyperacute LI.

Anatomical distribution of cerebral microbleeds and intracerebral hemorrhage in vertebrobasilar dolichoectasia

Objectives Vertebrobasilar dolichoectasia (VBD) is a dilatative arteriopathy associated with intracerebral hemorrhage. In the present study, we sought to evaluate the frequency and anatomical distribution of cerebral microbleeds (cMBs) and intracerebral hemorrhage (ICH) in VBD. Methods From a MRI database 94 VBD patients were identified and analyzed with special emphasis on cMBs and ICH on T2*-weighted gradient echo images (GRE) in relation to the established diagnostic MRI criteria of VBD (diameter, height, and lateral position). cMBs/ICH location was categorized into anterior/posterior circulation. Clinical information like demographic details, clinical symptoms, and comorbidities were abstracted from the case records. An extensive modelling approach using generalized linear mixed-effects models was used. Results Overall, 79 (84.0%) patients (mean age 72.1±10.0 years, 74.7% male) with a standard stroke MRI protocol including T2*-weighted images were included in the analysis. cMBs were observed in 38/79 (48.1%) patients, ranging from 1 to 84 cMBs per patient. In the posterior circulation cMBs were observed more frequently (34/38 (89.5%)) in comparison to the anterior circulation (24/38 (63.2%)). cMBs were observed in the thalamus in 20/38 (52.6%), hippocampus in 1/38 (2.6%), occipital lobe in 18/38 (47.4%), pons in 6/38 (15.8%), medulla oblongata in 2/38 (5.2%), and cerebellum in 14/38 (36.8%) patients. ICH was observed in only 6/79 (7.6%) patients. There were significantly more cMBs in the posterior- (NCMBs-PC = 1.717, 95%CI: 1.336–2.208, p = 0.0315) than in the anterior circulation. Logistic regression model showed a significant positive effect of clinical symptoms such as ischemic, TIA and hemorrhagic stroke on the presence of cMBs (OR = 3.34, 95%CI [2.0–5.57], p = 0.0184; ndf = 78, AIC = 107.51). General linear model showed that clinical symptoms have a highly significant effect on the number of cMBs (N = 2.78, 95%CI [2.51–3.07], p<2*10–16; ndf = 78, AIC = 1218). Conclusion cMBs and ICH may be observed in the anterior and posterior circulation in VBD but they occur more frequently in the posterior circulation. Most common anatomical locations of cMBs in VBD were the thalamus, occipital lobe and cerebellum. This posterior dominance of cMBs and ICH in VBD might reflect a specific underlying vascular pathology.