Fluctuations in tumor blood perfusion assessed by dynamic contrast-enhanced MRI.

Temporal heterogeneity in blood perfusion is a common phenomenon in tumors, but data characterizing the nature of the blood flow fluctuations are sparse. This study investigated the occurrence of blood flow fluctuations in A-07 melanoma xenografts by using gadopentetate dimeglumine (Gd-DTPA)-based dynamic contrast-enhanced MRI (DCE-MRI). Each tumor was subjected to two DCE-MRI acquisitions separated by 1 hour. The data were processed by Kety analysis and resulted in two E.F images (E is the initial extraction fraction of Gd-DTPA and F is the perfusion) and two lambda images (lambda is the partition coefficient of Gd-DTPA) for each tumor. The E . F images were used to determine the changes in blood perfusion arising in the time between the two imaging sequences. The lambda images were used to control the reproducibility of the experimental procedure. The study showed that DCE-MRI with subsequent Kety analysis is a useful method for detection of blood flow fluctuations in A-07 tumors, and strongly suggested that the peripheral regions of A-07 tumors are more exposed to temporal changes in blood perfusion than are the central regions.     

Regulation of tissue-degrading factors and in vitro invasiveness in progression of breast cancer cells

Hormone-independent growth and invasiveness represent phenotypic properties acquired during early progression of breast cancer. We compared human mammary adenocarcinoma cells, MCF-7, which are estrogen-dependent and poorly metastatic, with the estrogen-independent and highly metastatic subline, MCF7/LCC1, with regard to expression of tissue-degrading factors of the matrix metalloproteinase (MMP)-and urokinase (uPA)-dependent degradative pathways, as well as for their in vitro invasive properties. Both cell lines showed low constitutive mRNA expression of the MMP inhibitor TIMP-1. Baseline expression of TIMP-2 mRNA was also very low in MCF-7 cells, whereas the MCF7/LCC1 level was much higher (~10- fold). Furthermore, both cell lines revealed low constitutive capacity to migrate in an in vitro invasion assay. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM) induced the mRNAs for TIMP-1 as well as for MMP-1, MMP-9, the uPA receptor, and the uPA inhibitor PAI-1, am ongst which only the responses of MMP-9 and PAI-1 were cell-specific. The mRNA levels of MMP-9 and PAI-1 were ~10-fold and ~15-fold higher in MCF7/LCC1 cells compared to MCF-7 cells. The secretion of immuno-reactive PAI-1 was considerably elevated (. 20-fold) in TPA-treated MCF7/LCC1 cells, whereas the TPA-dependent level of 92-kDa MMP-9 was only ~2-fold higher in MCF7/LCC1 cells than in MCF-7 cells. In both cell lines treatment with TPA was associated with an increase (~10-fold) in in vitro migration, which in the MCF7/LCC1 cells was significantly attenuated by a reconstituted basement membrane extract (Matrigel). These data suggest that TPA-responsive in vitro invasive properties that are probably associ-ated with PAI-1 expression may co-vary with progression from hormone-dependent to -independent breast cancer. © Rapid Science 1998     

Dynamic path analysis – a useful tool to investigate mediation processes in clinical survival trials

When it comes to clinical survival trials, regulatory restrictions usually require the application of methods that solely utilize baseline covariates and the intention‐to‐treat principle. Thereby, much potentially useful information is lost, as collection of time‐to‐event data often goes hand in hand with collection of information on biomarkers and other internal time‐dependent covariates. However, there are tools to incorporate information from repeated measurements in a useful manner that can help to shed more light on the underlying treatment mechanisms. We consider dynamic path analysis, a model for mediation analysis in the presence of a time‐to‐event outcome and time‐dependent covariates to investigate direct and indirect effects in a study of different lipid‐lowering treatments in patients with previous myocardial infarctions. Further, we address the question whether survival in itself may produce associations between the treatment and the mediator in dynamic path analysis and give an argument that because of linearity of the assumed additive hazard model, this is not the case. We further elaborate on our view that, when studying mediation, we are actually dealing with underlying processes rather than single variables measured only once during the study period. This becomes apparent in results from various models applied to the study of lipid‐lowering treatments as well as our additionally conducted simulation study, where we clearly observe that discarding information on repeated measurements can lead to potentially erroneous conclusions. Copyright © 2015 John Wiley & Sons, Ltd.     

Right ventricular and pulmonary arterial dimensions in adults with osteogenesis imperfecta

We examined right ventricular (RV) and ascending pulmonary artery (PA1) dimensions in adults with osteogenesis imperfecta (OI). The survey included 99 adults with OI divided in 3 clinical types (I, III, and IV) and 52 controls. RV and PA1 dimensions were measured by echocardiography and indexed for body surface area. Scoliosis was registered, and spirometry was performed in 75 patients with OI. All RV dimensions indexed by body surface area were significantly larger in the OI group compared to controls (RV basal dimension 1.9 ± 0.5 vs 1.7 ± 0.3 cm/m(2), p <0.05; RV midcavity dimension 1.7 ± 0.5 vs 1.5 ± 0.3 cm/m(2), p <0.05; RV longitudinal dimension 4.3 ± 1.1 vs 4.0 ± 0.9 cm/m(2), p <0.05). RV outflow tract (RVOT) proximal diameter (1.8 ± 0.4 vs 1.5 ± 0.2 cm/m(2), p <0.05), RVOT distal diameter (1.2 ± 0.2 vs 1.0 ± 0.1 cm/m(2), p <0.05), and PA1 (1.2 ± 0.3 vs 1.0 ± 0.2 cm/m(2), p <0.05) were also significantly larger in the OI group. Furthermore, all RV dimensions and PA1 were significantly larger in patients with OI type III compared to patients with OI types I and IV and controls. There were no differences in RV, RVOT, or PA1 dimensions between patients presenting a restrictive ventilatory pattern (n = 11) and patients a normal ventilatory pattern. Scoliosis was registered in 42 patients. Patients with OI type III had greater RV and PA1 dimensions compared to controls and patients with OI types I and IV. Impaired ventilatory patterns and scoliosis did not have any impact on RV dimensions in these patients. In conclusion, patients with OI had increased RV and PA1 dimensions compared to the control group.     

Cannabis use and premorbid functioning as predictors of poorer neurocognition in schizophrenia spectrum disorder

BackgroundEvidence of associations between neurocognitive function and cannabis use in schizophrenia is inconclusive. However, direct measures of cannabis intake and premorbid function are rarely explored in this context. We investigated the relation between cannabis use, determined by its presence in urine, and neurocognitive functioning in schizophrenia controlling for the potential bias of premorbid functioning.MethodsNaturalistic study of 364 patients with schizophrenia spectrum disorder from catchment areas in Oslo, Norway. Hierarchical multiple regression analyses were used to assess the relationship between cannabis in urine and measures of neurocognitive functioning, with adjustment for confounders, including premorbid functioning.ResultsCannabis was detected in the urine of 21 patients, who had significant dysfunction in several neurocognitive domains independent of a current diagnosis of cannabis abuse. However, level of premorbid functioning explained the associations for all measures.ConclusionDifferences in premorbid functioning may explain apparent differences in neurocognitive function between schizophrenia spectrum patients using cannabis or not. The findings suggest that illness-related traits present early in life can affect both later cannabis use and neurocognition, probably by complex mechanisms.