Mediterranean isolation preconditioning the Earth System for late Miocene climate cooling.

A global Neogene cooling trend culminated ~7 million years ago with the onset of Greenland glaciation. Increased ocean-atmosphere interaction and low- to high-latitude circulation are thought to be key factors in reorganizing late Miocene global temperature and precipitation patterns, but the drivers of this reorganization have yet to be identified. Here, we present new information about the evolution of the Atlantic-Mediterranean gateway that generated Mediterranean overflow. We use sedimentary and palaeogeographic evidence to constrain the timing and dimensions of this gateway and document the initiation of a saline plume of water within the North Atlantic. Today, this saline jet entrains and transports Eastern North Atlantic water and its dissolved inorganic carbon into the interior of the ocean, contributing to the drawdown of CO2 and the sensitivity of the ocean to atmospheric changes. We show that during the Miocene this transport emerged simultaneously with gateway restriction and propose that the resulting interaction of ocean-surface and ocean-interior carbon inventories would have greatly enhanced ocean-atmosphere exchange, preconditioning the Earth System for late Miocene cooling.

Lessons on Climate Sensitivity From Past Climate Changes.

Over the last decade, our understanding of climate sensitivity has improved considerably. The climate system shows variability on many timescales, is subject to non-stationary forcing and it is most likely out of equilibrium with the changes in the radiative forcing. Slow and fast feedbacks complicate the interpretation of geological records as feedback strengths vary over time. In the geological past, the forcing timescales were different than at present, suggesting that the response may have behaved differently. Do these insights constrain the climate sensitivity relevant for the present day? In this paper, we review the progress made in theoretical understanding of climate sensitivity and on the estimation of climate sensitivity from proxy records. Particular focus lies on the background state dependence of feedback processes and on the impact of tipping points on the climate system. We suggest how to further use palaeo data to advance our understanding of the currently ongoing climate change.

Characterization and therapy monitoring of head and neck carcinomas using diffusion-imaging-based intravoxel incoherent motion parameters-preliminary results.

INTRODUCTION: Using the intravoxel incoherent motion (IVIM) model, diffusion-related coefficient (D) and perfusion-related parameter (f) can be measured. Here, we used IVIM imaging to characterize squamous cell carcinomas of head and neck (HNSCC) and evaluated its application in follow-up after nonsurgical organ preserving therapy. METHODS: Twenty-two patients with locally advanced HNSCC (clinical stage III to IVb) were examined before treatment using eight different b values (b = 0, 50, 100, 150, 200, 250, 700, 800 s/mm(2)). All patients were followed for at least 7.5 months after conclusion of therapy. In 16 of these patients, follow-up MRI was available. Using the IVIM approach, f and D were extracted using a bi-exponential fit. For comparison, ADC maps were calculated. RESULTS: The initial values of f before therapy were located between 5.9 % and 12.9 % (mean: 9.4 ± 2.4 %) except for two outliers (f = 17.9 % and 18.2 %). These two patients exclusively displayed poor initial treatment response. Overall, high initial f (13.1 ± 4.1 % vs. 9.1 ± 2.4 %) and ADC (1.17 ± 0.08 × 10(-3) mm(2)/s vs. 0.98 ± 0.19 × 10(-3) mm(2)/s) were associated with poor short term outcome (n = 6) after 7.5 months follow-up. D values before treatment were 0.98 × 10(-3) ± 0.18 mm(2)/s and ADC values were 1.03 × 10(-3) ± 0.18 mm(2)/s. At follow-up, in all primary responders, D (69 ± 52 %), f (65 ± 46 %), and ADC (68 ± 49%) increased. CONCLUSIONS: Our preliminary evaluation indicates that an initial high f may predict poor prognosis in HNSCC. In responders, a significant increase of all IVIM parameters after therapy was demonstrated.

Fibrosis and pancreatic lesions: counterintuitive behavior of the diffusion imaging-derived structural diffusion coefficient d.

INTRODUCTION: Stroma reaction leading to fibrosis is the most characteristic histopathological feature of both pancreatic carcinoma and chronic pancreatitis with increased fibrosis compared with healthy pancreatic tissue and further increased fibrosis during radiochemotherapy. Recent studies using intravoxel incoherent motion-derived parameters did not show differences for structural diffusion constant D between these 2 diseases. The aim of this study was to verify the hypothesis that D correlates with the histopathological grade of fibrosis in pancreatic lesions. MATERIALS AND METHODS: We included 15 patients with histopathologically proven pancreatic carcinoma and 9 patients with histopathologically proven focal chronic pancreatitis. Diffusion-weighted magnetic resonance imaging was performed using 10 b values between 25 and 800 s/mm² before surgery. We calculated the apparent diffusion coefficient and the intravoxel incoherent motion-derived parameters D and f within tumors and focal chronic pancreatitis. The resected tissue was evaluated with regard to the grade of fibrosis. RESULTS: Fourteen patients were found to have moderate fibrosis and 10 patients had severe fibrosis. The difference between the D values for the moderate and severe fibrosis was significant with mean (SD) D value of 1.02 × 10⁻³ (0.48 × 10⁻³ mm/s) and mean (SD) D of 1.22 × 10⁻³ (0.76 × 10⁻³) mm²/s. There were no significant differences for the f and ADC values. CONCLUSIONS: Contrary to our hypothesis, D rises from moderate to severe fibrosis. It seems that cellular complexes surrounded by fibrosis provide more structural limitations than does fibrosis alone. Our data suggest that D is not intuitively related to the degree of fibrosis. Compared with healthy tissue, D is reduced in moderate fibrosis but increases when severe fibrosis is present.

Toward a non-invasive screening tool for differentiation of pancreatic lesions based on intra-voxel incoherent motion derived parameters.

Early recognition of and differential diagnosis between pancreatic cancer and chronic pancreatitis is an important step in successful therapy. Parameters of the IVIM (intra-voxel incoherent motion) theory can be used to differentiate between those lesions. The objective of this work is to evaluate the effects of rigid image registration on IVIM derived parameters for differentiation of pancreatic lesions such as pancreatic cancer and solid mass forming pancreatitis. The effects of linear image registration methods on reproducibility and accuracy of IVIM derived parameters were quantified on MR images of ten volunteers. For this purpose, they were evaluated statistically by comparison of registered and unregistered parameter data. Further, the perfusion fraction f was used to differentiate pancreatic lesions on eleven previously diagnosed patient data sets. Its diagnostic power with and without rigid registration was evaluated using receiver operating curves (ROC) analysis. The pancreas was segmented manually on MR data sets of healthy volunteers as well as the patients showing solid pancreatic lesions. Diffusion weighted imaging was performed in 10 blocks of breath-hold phases. Linear registration of the weighted image stack leads to a 3.7% decrease in variability of the IVIM derived parameter f due to an improved anatomical overlap of 5%. Consequently, after registration the area under the curve in the ROC-analysis for the differentiation approach increased by 2.7%. In conclusion, rigid registration improves the differentiation process based on f-values.

Diffusion-weighted imaging-based probabilistic segmentation of high- and low-proliferative areas in high-grade gliomas.

The apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) correlates inversely with tumor proliferation rates. High-grade gliomas are typically heterogeneous and the delineation of areas of high and low proliferation is impeded by partial volume effects and blurred borders. Commonly used manual delineation is further impeded by potential overlap with cerebrospinal fluid and necrosis. Here we present an algorithm to reproducibly delineate and probabilistically quantify the ADC in areas of high and low proliferation in heterogeneous gliomas, resulting in a reproducible quantification in regions of tissue inhomogeneity. We used an expectation maximization (EM) clustering algorithm, applied on a Gaussian mixture model, consisting of pure superpositions of Gaussian distributions. Soundness and reproducibility of this approach were evaluated in 10 patients with glioma. High- and low-proliferating areas found using the clustering correspond well with conservative regions of interest drawn using all available imaging data. Systematic placement of model initialization seeds shows good reproducibility of the method. Moreover, we illustrate an automatic initialization approach that completely removes user-induced variability. In conclusion, we present a rapid, reproducible and automatic method to separate and quantify heterogeneous regions in gliomas.

Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype.

AIMS: The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca(2+), Na(+), K(+)) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes. METHODS AND RESULTS: Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis. CONCLUSION: The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014. Clinicaltrials.gov identifier: NCT01209494.

Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology.

Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging-technique that may mirror tissue cellularity by measuring random movements of water molecules. To investigate if DWI is capable of assessing bone marrow cellularity in monoclonal plasma cell disease, we investigated 56 patients with multiple myeloma or monoclonal gammopathy of undetermined significance, and 30 healthy controls using DWI of the pelvis and/or the lumbar spine. In 25 of 30 patients who underwent biopsy, bone marrow trephine and DWI could be compared. Of the patients with symptomatic disease 15 could be evaluated after systemic treatment. There was a positive correlation between the DWI-parameter apparent diffusion coefficient (ADC) and bone marrow cellularity as well as micro-vessel density (P<0·001 respectively). ADC was significantly different between patients and controls (P<0·01) and before and after systemic therapy (P<0·001). In conclusion, DWI enabled bone marrow infiltration to be monitored in a non-invasive, quantitative way, suggesting that after further investigations on larger patient groups this might become an useful tool in the clinical work-up to assess tumour burden.

Enhancing pancreatic adenocarcinoma delineation in diffusion derived intravoxel incoherent motion f-maps through automatic vessel and duct segmentation.

Diffusion-based intravoxel incoherent motion imaging has recently gained interest as a method to detect and characterize pancreatic lesions, especially as it could provide a radiation- and contrast agent-free alternative to existing diagnostic methods. However, tumor delineation on intravoxel incoherent motion-derived parameter maps is impeded by poor lesion-to-pancreatic duct contrast in the f-maps and poor lesion-to-vessel contrast in the D-maps. The distribution of the diffusion and perfusion parameters within vessels, ducts, and tumors were extracted from a group of 42 patients with pancreatic adenocarcinoma. Clearly separable combinations of f and D were observed, and receiver operating characteristic analysis was used to determine the optimal cutoff values for an automated segmentation of vessels and ducts to improve lesion detection and delineation on the individual intravoxel incoherent motion-derived maps. Receiver operating characteristic analysis identified f = 0.28 as the cutoff for vessels (Area under the curve (AUC) = 0.901) versus tumor/duct and D = 1.85 µm(2) /ms for separating duct from tumor tissue (AUC = 0.988). These values were incorporated in an automatic segmentation algorithm and then applied to 42 patients. This yielded clearly improved tumor delineation compared to individual intravoxel incoherent motion-derived maps. Furthermore, previous findings that indicated that the f value in pancreatic cancer is strongly reduced compared to healthy pancreatic tissue were reconfirmed.

Intravoxel incoherent motion MRI for the differentiation between mass forming chronic pancreatitis and pancreatic carcinoma.

PURPOSE: To determine which of the quantitative parameters obtained from intravoxel incoherent motion diffusion weighted imaging (DWI) is the most significant for the differentiation between pancreatic carcinoma and mass-forming chronic pancreatitis. MATERIALS AND METHODS: Twenty-nine patients with pancreatic masses were included, 9 proved to have a mass-forming pancreatitis and 20 had a pancreatic carcinoma. The patients were studied using intravoxel incoherent motion DWI with 11 b-values and the apparent diffusion coefficient (ADC), the true diffusion constant (D) and the perfusion fraction (f) were calculated. The diagnostic strength of the parameters was evaluated using receiver operating characteristic analysis. RESULTS: The ADC in chronic pancreatitis was higher than in pancreatic carcinoma with significant differences at b = 50, 75, 100, 150, 200, 300 s/mm (ADC50 = 3.17 ± 0.67 vs. 2.55 ± 1.09, ADC75 = 2.46 ± 0.4 vs. 1.93 ± 0.52, ADC100 = 2.28 ± 0.48 vs. 1.73 ± 0.45, ADC150 = 1.97 ± 0.26 vs. 1.63 ± 0.40, ADC200 = 1.98 ± 0.24 vs. 1.53 ± 0.28, and ADC300 = 1.76 ± 0.19 vs. 1.46 ± 0.31 × 10(-3) mm2/s). No significant differences were found at b = 25, 400, 600, and 800 s/mm (ADC25 = 4.69 ± 0.65 vs. 4.04 ± 1.35, ADC400 = 1.57 ± 0.21 vs. 1.37 ± 0.30, ADC600 = 1.38 ± 0.18 vs. 1.24 ± 0.25, and ADC800 = 1.27 ± 0.10 vs. 1.18 ± 0.19 × 10(-3) mm2/s) nor using ADCtot (1.42 ± 0.23 vs. 1.28 ± 0.12 × 10(-3) mm2/s). The perfusion fraction f was significantly higher in pancreatitis compared with pancreatic carcinoma (16.3% ± 5.30% vs. 8.2% ± 4.00%, P = 0.0001). There was no significant difference between groups for D (1.07 ± 0.224 × 10(-3) mm2/s for chronic pancreatitis and 1.09 ± 0.3 × 10(-3) mm2/s for pancreatic carcinoma, P = 0.66). For f, the highest area under the curve (0.894) and combined sensitivity (80%) and specificity (89.9%) were found. CONCLUSIONS: There were significant differences in ADC50-300 between chronic pancreatitis and pancreatic carcinoma. Because D is not significantly different between groups, differences in ADC can be attributed mainly to differences in perfusion. The perfusion fraction f proved to be the superior DWI-derived parameter for differentiation of mass-forming pancreatitis and pancreatic carcinoma.

An in vivo verification of the intravoxel incoherent motion effect in diffusion-weighted imaging of the abdomen.

To investigate the vascular contribution to the measured apparent diffusion coefficient and to validate the Intra Voxel Incoherent Motion theory, the signal as a function of the b-value was measured in the healthy pancreas with and without suppression of the vascular component and under varying echo times (TE = 50, 70, and 100 msec). The perfusion fraction f and the diffusion coefficient D were extracted from the measured DW-data using the original Intra Voxel Incoherent Motion-equation and a modified version of this equation incorporating relaxation effects. First, the perfusion fraction f in the blood suppressed pancreatic tissue decreased significantly (P = 0.03), whereas the diffusion coefficient D did not change with suppression (P = 0.43). Second, the perfusion fraction f increased significantly with increasing echo time (P = 0.0025), whereas the relaxation time compensated perfusion fraction f' showed no significant dependence on TE (P = 0.31). These results verify a vascular contribution to the diffusion weighted imaging measurement at low b values and support the Intra Voxel Incoherent Motion-theory.

Differentiation of pancreas carcinoma from healthy pancreatic tissue using multiple b-values: comparison of apparent diffusion coefficient and intravoxel incoherent motion derived parameters.

OBJECTIVES: To evaluate in detail the diagnostic performance of diffusion-weighted imaging (DWI) to differentiate pancreas carcinoma from healthy pancreas using the apparent diffusion coefficient (ADC) and parameters derived from the intravoxel incoherent motion (IVIM) theory. MATERIALS AND METHODS: Twenty-three patients with pancreas carcinoma and 14 volunteers with healthy pancreas were examined at 1.5 Tesla using a single-shot echo-planar imaging DWI pulse sequence. Eleven b-values ranging from 0 to 800 s/mm2 were used. The acquisition was separated into blocks (b0, b25), (b0, b50),...(b0, b800) and each block was acquired in a single expirational breath-hold (TA = 26 seconds) to avoid motion artifacts. The ADC was calculated for all b-values using linear regression yielding ADC(tot). By applying the IVIM model, which allows for the estimation of perfusion effects in DWI, the perfusion fraction f and the perfusion free diffusion parameter D were calculated. The diagnostic performance of ADC, f and D as a measure for the differentiation between healthy pancreas and pancreatic carcinoma was evaluated with receiver operating characteristics analysis. RESULTS: In the healthy control group, the ADC(tot) ranged from 1.53 to 2.01 microm2/ms with a mean value of 1.71 +/- 0.19 microm2/ms, the perfusion fraction f ranged from 18.5% to 40.4% with a mean value of 25.0 +/- 6.2%, and the diffusion coefficient D from 0.94 to 1.28 microm2/ms with a mean value of 1.13 +/- 0.15 microm2/ms. In patients with pancreas carcinoma, the ADC(tot) ranged from 0.98 to 1.81 microm2/ms with a mean value of 1.31 +/- 0.24 microm2/ms, the perfusion fraction f ranged from 0% to 20.4% with a mean value of 8.59 +/- 4.6% and the diffusion coefficient D from 0.74 to 1.60 microm2/ms with a mean value of 1.15 +/- 0.22 microm2/ms. In comparison to healthy pancreatic tissue, a significant reduction of the perfusion fraction f and of ADC(tot) was found in pancreatic carcinoma (P < 0.00001, 0.0002, respectively). The f value showed more than a 10-fold higher significance level in distinguishing cancerous from normal tissue when compared with the ADC(tot) value. No significant difference in the diffusion coefficient D was observed between the 2 groups (P > 0.5). In the receiver operating characteristic-analyses, the area under curve for f was 0.991 and significantly larger than ADC(tot) (P < 0.05). f had the highest sensitivity, specificity, negative predictive value, and positive predictive value with 95.7%, 100%, 93.3%, and 100%, respectively. CONCLUSIONS: Using the IVIM-approach, the f value proved to be the best parameter for the differentiation between healthy pancreas and pancreatic cancer. The acquisition of several b-values strongly improved the stability of the parameter estimation thus increasing the sensitivity and specificity to 95.7% and 100% respectively. The proposed method may hold great promise for the non invasive, noncontrast-enhanced imaging of pancreas lesions and may eventually become a screening tool for pancreatic cancer.