Pseudo‐extravasation rate constant of dynamic susceptibility contrast‐MRI determined from pharmacokinetic first principles

Dynamic susceptibility contrast‐magnetic resonance imaging (DSC‐MRI) is widely used to obtain informative perfusion imaging biomarkers, such as the relative cerebral blood volume (rCBV). The related post‐processing software packages for DSC‐MRI are available from major MRI instrument manufacturers and third‐party vendors. One unique aspect of DSC‐MRI with low‐molecular‐weight gadolinium (Gd)‐based contrast reagent (CR) is that CR molecules leak into the interstitium space and therefore confound the DSC signal detected. Several approaches to correct this leakage effect have been proposed throughout the years. Amongst the most popular is the Boxerman–Schmainda–Weisskoff (BSW) K₂ leakage correction approach, in which the K₂ pseudo‐first‐order rate constant quantifies the leakage. In this work, we propose a new method for the BSW leakage correction approach. Based on the pharmacokinetic interpretation of the data, the commonly adopted R₂* expression accounting for contributions from both intravascular and extravasating CR components is transformed using a method mathematically similar to Gjedde–Patlak linearization. Then, the leakage rate constant (K_L) can be determined as the slope of the linear portion of a plot of the transformed data. Using the DSC data of high‐molecular‐weight (~750 kDa), iron‐based, intravascular Ferumoxytol (FeO), the pharmacokinetic interpretation of the new paradigm is empirically validated. The primary objective of this work is to empirically demonstrate that a linear portion often exists in the graph of the transformed data. This linear portion provides a clear definition of the Gd CR pseudo‐leakage rate constant, which equals the slope derived from the linear segment. A secondary objective is to demonstrate that transformed points from the initial transient period during the CR wash‐in often deviate from the linear trend of the linearized graph. The inclusion of these points will have a negative impact on the accuracy of the leakage rate constant, and even make it time dependent.     

Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model

Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-α(V) integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5?min before infusion without further treatment; (3) intetumumab intravenously 4?h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7?days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett's test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median?=?14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median?=?2, p?=?0.0055), including 30?% of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52?days, p?=?0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.     

First clinical experience with the novel cold storage SherpaPak™ system for donor heart transportation

BackgroundThe current gold standard for donor heart preservation is a three-bag-technique and storage in a cooler filled with slush ice. This technique can cause freezing injury with protein denaturation. We report our early experience with a single-use disposable device (SherpaPak™, Paragonix Technologies, MA, USA) specifically designed for sterile permanent temperature-controlled transportation of donor hearts.MethodsIn this case control study with 2:1 matching we identified 21 patients after heart transplantation depending on type of organ transport (standard three-bag-technique vs. SherpaPak™). The outcome after donor heart storage in the SherpaPak™ was compared with donor heart transportation with the standard technique.ResultsSince July 2018 seven patients (5 males; mean age 50.3±13.2years) underwent heart transplantation with the SherpaPak™ system. Cold ischemic time was longer in the SherpaPak™ group (207.7±23.3 vs. 181.6±21.9, P=0.027). SherpaPak™ kept the organ temperature at 5.1±0.8 °C, with an average outside temperature of 21.4±3.6 °C. Among all 21 transplanted patients four developed fatal early graft failure (28.6% vs. 21.4%, P=0.432). Over the first hours we noticed no difference in hemodynamic parameters, CK-MB levels or vasoactive-inotropic score. During first follow-up we noticed slightly better right heart function in the SherpaPak™ group (TAPSE 17.83±2.71 vs. 14.52±2.61 mm, P=0.020). We identified no positive blood cultures in the SherpaPak™ group within the first 30 days after heart transplantation.ConclusionsThe SherpaPak™ provides a constant temperature during transportation with permanent monitoring, never dropping below 4 °C. Organs transported with this novel device showed a normal perioperative function.     

Ferumoxytol-enhanced MRI differentiation of meningioma from dural metastases: a pilot study with immunohistochemical observations

Malignant dural neoplasms are not reliably distinguished from benign dural neoplasms with contrast-enhanced magnetic resonance imaging (MRI). MRI enhancement in central nervous system (CNS) diseases imaged with ferumoxytol has been attributed to intracellular uptake in macrophages rather than vascular leakage. We compared imaging to histopathology and immunohistochemistry in meningiomas and dural metastases having ferumoxytol-enhanced MRI (FeMRI) and gadolinium-enhanced MRI (GdMRI) in order to correlate enhancement patterns to macrophage presence and vascular state. All patients having extraaxial CNS tumors were retrospectively selected from one of two ongoing FeMRI studies. Enhancement was compared between GdMRI and FeMRI. Diagnoses were confirmed histologically and/or by characteristic imaging. Tumor and vascular histology was reviewed. Immunohistochemical staining for CD68 (a macrophage marker), Connexin-43 (Cx43) (a marker of normal gap junctions), and smooth muscle actin (SMA) as a marker of vascularity, was performed in seven study cases with available tissue. Immunohistochemistry was performed on archival material from 33 subjects outside of the current study as controls: 20 WHO grade I cases of meningioma and 13 metastatic tumors. Metastases displayed marked delayed enhancement on FeMRI, similar to GdMRI. Four patients with dural metastases and one patient with meningioma showed similar enhancement on FeMRI and GdMRI. Five meningiomas with typical enhancement on GdMRI lacked enhancement on FeMRI. Enhancement on FeMRI was better associated with decreased Cx43 expression than intralesional macrophages. These pilot data suggest that FeMRI may better differentiate metastatic disease from meningiomas than GdMRI, and that differences in tumor vasculature rather than macrophage presence could underlie differences in contrast enhancement.     

Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models

We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting α(V)-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4-6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting α(V)-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.