Perfusion Studies Research Articles

Contrast-agent-based perfusion MRI code repository and testing framework: ISMRM Open Science Initiative for Perfusion Imaging (OSIPI).

Software has a substantial impact on quantitative perfusion MRI values. The lack of generally accepted implementations, code sharing and transparent testing reduces reproducibility, hindering the use of perfusion MRI in clinical trials. To address these issues, the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI) aimed to establish a community-led, centralized repository for sharing open-source code for processing contrast-based perfusion imaging, incorporating an open-source testing framework. A repository was established on the OSIPI GitHub website. Python was chosen as the target software language. Calls for code contributions were made to OSIPI members, the ISMRM Perfusion Study Group, and publicly via OSIPI websites. An automated unit-testing framework was implemented to evaluate the output of code contributions, including visual representation of the results. The repository hosts 86 implementations of perfusion processing steps contributed by 12 individuals or teams. These cover all core aspects of DCE- and DSC-MRI processing, including multiple implementations of the same functionality. Tests were developed for 52 implementations, covering five analysis steps. For T1 mapping, signal-to-concentration conversion and population AIF functions, different implementations resulted in near-identical output values. For the five pharmacokinetic models tested (Tofts, extended Tofts-Kety, Patlak, two-compartment exchange, and two-compartment uptake), differences in output parameters were observed between contributions. The OSIPI DCE-DSC code repository represents a novel community-led model for code sharing and testing. The repository facilitates the re-use of existing code and the benchmarking of new code, promoting enhanced reproducibility in quantitative perfusion imaging.

Sporadic Hemiplegic Migraine: Hypoperfusion Demonstrated by Susceptibility-Weighted Magnetic Resonance Imaging and Computed Tomography Perfusion Study

Sporadic Hemiplegic Migraine: Hypoperfusion Demonstrated by Susceptibility-Weighted Magnetic Resonance Imaging and Computed Tomography Perfusion Study

Characterization of a human placental clearance system to regulate serotonin levels in the fetoplacental unit

BackgroundSerotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels. We hypothesized that placental 5-HT clearance is important for maintaining 5-HT levels in the fetoplacental unit. We therefore investigated placental 5-HT uptake from the umbilical circulation at physiological and supraphysiological levels as well as placental metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA efflux from trophoblast cells.MethodsWe employed a systematic approach using advanced organ-, tissue-, and cellular-level models of the human placenta to investigate the transport and metabolism of 5-HT in the fetoplacental unit. Human placentas from uncomplicated term pregnancies were used for perfusion studies, culturing explants, and isolating primary trophoblast cells.ResultsUsing the dually perfused placenta, we observed a high and concentration-dependent placental extraction of 5-HT from the fetal circulation. Subsequently, within the placenta, 5-HT was metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which was then unidirectionally excreted to the maternal circulation. In the explant cultures and primary trophoblast cells, we show concentration- and inhibitor-dependent 5-HT uptake and metabolism and subsequent 5-HIAA release into the media. Droplet digital PCR revealed that the dominant gene in all models was MAO-A, supporting the crucial role of 5-HT metabolism in placental 5-HT clearance.ConclusionsTaken together, we present transcriptional and functional evidence that the human placenta has an efficient 5-HT clearance system involving (1) removal of 5-HT from the fetal circulation by OCT3, (2) metabolism to 5-HIAA by MAO-A, and (3) selective 5-HIAA excretion to the maternal circulation via the MRP2 transporter. This synchronized mechanism is critical for regulating 5-HT in the fetoplacental unit; however, it can be compromised by external insults such as antidepressant drugs.

In vitro studies on the dependence of drug deposition in dentin on drug concentration, contact time, and the physicochemical properties of the drugs

The chemical analysis of dental hard tissues can provide information on previous drug use due to the deposition of drugs into this tissue. For the interpretation of analytical results in, e.g., postmortem toxicology or regarding archeological samples, the influence of drug dosing, consumption frequency, duration of intake and type of drug on analyte concentrations in teeth has to be characterized. To approximate these correlations, in vitro models were applied to investigate the time dependency of drug deposition via and against pulp pressure (perfusion studies) and the concentration dependency of drug deposition via oral cavity (incubation study) as well as the influence of de- and remineralization (pH cycling) on the incorporation of drugs in bovine dentin pellets. Some of the drugs of abuse most relevant in forensic case work (amphetamines, opiates, cocaine and benzoylecgonine) were applied. Concentrations in dentin samples were analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) after pulverization and extraction via ultrasonication with methanol. The studies showed that drug deposition in dentin likely depends on the physicochemical properties of the drug molecules as well as on the duration of contact with drugs via the blood stream and on drug concentrations present in the oral cavity. Higher drug concentrations in teeth can result from a more frequent or longer drug use. In addition, intake of higher doses or oral/inhalative consumption can also be expected to lead to higher drug concentrations. These findings can be helpful for the interpretation of postmortem cases.

Perfusion-weighted software written in Python for DSC-MRI analysis.

Dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion studies in magnetic resonance imaging (MRI) provide valuable data for studying vascular cerebral pathophysiology in different rodent models of brain diseases (stroke, tumor grading, and neurodegenerative models). The extraction of these hemodynamic parameters via DSC-MRI is based on tracer kinetic modeling, which can be solved using deconvolution-based methods, among others. Most of the post-processing software used in preclinical studies is home-built and custom-designed. Its use being, in most cases, limited to the institution responsible for the development. In this study, we designed a tool that performs the hemodynamic quantification process quickly and in a reliable way for research purposes. The DSC-MRI quantification tool, developed as a Python project, performs the basic mathematical steps to generate the parametric maps: cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), signal recovery (SR), and percentage signal recovery (PSR). For the validation process, a data set composed of MRI rat brain scans was evaluated: i) healthy animals, ii) temporal blood-brain barrier (BBB) dysfunction, iii) cerebral chronic hypoperfusion (CCH), iv) ischemic stroke, and v) glioblastoma multiforme (GBM) models. The resulting perfusion parameters were then compared with data retrieved from the literature. A total of 30 animals were evaluated with our DSC-MRI quantification tool. In all the models, the hemodynamic parameters reported from the literature are reproduced and they are in the same range as our results. The Bland-Altman plot used to describe the agreement between our perfusion quantitative analyses and literature data regarding healthy rats, stroke, and GBM models, determined that the agreement for CBV and MTT is higher than for CBF. An open-source, Python-based DSC post-processing software package that performs key quantitative perfusion parameters has been developed. Regarding the different animal models used, the results obtained are consistent and in good agreement with the physiological patterns and values reported in the literature. Our development has been built in a modular framework to allow code customization or the addition of alternative algorithms not yet implemented.

Combined Right and Left Ventricular Reperfusion Injury following Percutaneous Coronary Intervention: Role of Myocardial Contrast Echocardiography

Right ventricular myocardial infarction (RVMI) occurs in up to half of the patients of inferior wall myocardial infarction. RVMI results in edema and increased right ventricular (RV) mass, and hence, it should be possible to visualize microvascular obstruction as a manifestation of reperfusion injury. Reperfusion injury of the RV myocardium following primary percutaneous coronary intervention has been rarely reported. This report describes a patient with the left ventricular inferior and RVMI who showed echocardiographically detected reperfusion injury of the RV-free wall and left ventricular basal inferolateral wall and conformed by myocardial contrast perfusion study despite successful percutaneous revascularization of the right coronary artery.

A Teleradiology System for Early Ischemic and Hemorrhagic Stroke Evaluation and Management

Abstract Purpose Stroke is a cardinal cause of death and disability globally. It is an emergency condition where the rapidity of diagnosis is directly linked to the outcome. “Imaging is Brain” is, therefore, an important concept. The early diagnosis of stroke is crucial not only in guiding its effective treatment but also in estimating prognosis. This study aims to provide perspective on the implementation of international teleradiology in stroke evaluation, management, and care. Methods A dedicated international teleradiology stroke network has been evaluated in our study between March 2019 and July 2022 where the interpretation and analysis of the computed tomography (CT) scans of the patients from distant hospitals in United States were performed by teleradiologists via high-quality Digital Imaging and Communications in Medicine (DICOM)-image transfer through a cloud-based radiology information system/picture archival and communication system platform RADspa. Results Over a period of three and a half years, starting from March 2019, a total of 30,406 CT scans of 19,342 patients from 96 hospitals of 15 states in the United States were interpreted and reported by board-certified radiologists empaneled by Teleradiology Solutions. The mean report turnaround time for all noncontrast CT studies was 9.97 minutes at 95% confidence interval (CI: 9.89–10.05); for CT angiogram studies, it was 20.57 minutes 95% CI (20.38–20.77); and for CT perfusion studies, it was 13.72 minutes 95% CI (13.42–14.03). Conclusion A dedicated international teleradiology stroke network designed in our study allowed for transmission, prioritization, evaluation, and management of CT cases performed in the setting of acute stroke in the study population. The results of our investigation indicate that teleradiology provides an effective solution for early diagnosis/interpretation of CT examinations performed internationally in the setting of acute stroke. This may further be used as a model or template for the development of a nationwide stroke network within our own country.

Pancreatic CT perfusion: quantitative meta-analysis of disease discrimination, protocol development, and effect of CT parameters

BackgroundThis study provides a quantitative meta-analysis of pancreatic CT perfusion studies, investigating choice of study parameters, ability for quantitative discrimination of pancreatic diseases, and influence of acquisition and reconstruction parameters on reported results.MethodsBased on a PubMed search with key terms ‘pancreas’ or ‘pancreatic,’ ‘dynamic’ or ‘perfusion,’ and ‘computed tomography’ or ‘CT,’ 491 articles published between 1982 and 2020 were screened for inclusion in the study. Inclusion criteria were: reported original data, human subjects, five or more datasets, measurements of pancreas or pancreatic pathologies, and reported quantitative perfusion parameters. Study parameters and reported quantitative measurements were extracted, and heterogeneity of study parameters and trends over time are analyzed. Pooled data were tested with weighted ANOVA and ANCOVA models for differences in perfusion results between normal pancreas, pancreatitis, PDAC (pancreatic ductal adenocarcinoma), and non-PDAC (e.g., neuroendocrine tumors, insulinomas) and based on study parameters.ResultsReported acquisition parameters were heterogeneous, except for contrast agent amount and injection rate. Tube potential and slice thickness decreased, whereas tube current time product and scan coverage increased over time. Blood flow and blood volume showed significant differences between pathologies (both p < 0.001), unlike permeability (p = 0.11). Study parameters showed a significant effect on reported quantitative measurements (p < 0.05).ConclusionsSignificant differences in perfusion measurements between pathologies could be shown for pooled data despite observed heterogeneity in study parameters. Statistical analysis indicates most influential parameters for future optimization and standardization of acquisition protocols.Critical relevance statementQuantitative CT perfusion enables differentiation of pancreatic pathologies despite the heterogeneity of study parameters in current clinical practice.Graphical abstract

Quantitative Analysis of Brain CT Perfusion in Healthy Beagle Dogs: A Pilot Study.

Brain computed tomography (CT) perfusion is a technique that allows for the fast evaluation of cerebral hemodynamics. However, quantitative studies of brain CT perfusion in veterinary medicine are lacking. The purpose of this study was to investigate the normal range of perfusion determined via CT in brains of healthy dogs and to compare values between white matter and gray matter, differences in aging, and each hemisphere. Nine intact male beagle dogs were prospectively examined using dynamic CT scanning and post-processing for brain perfusion. Regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), mean transit time, and time to peak were calculated. Tissue ROIs were drawn in the gray matter and white matter of the frontal, temporal, parietal, and occipital lobes; caudate nucleus; thalamus; piriform lobe; hippocampus; and cerebellum. Significant differences were observed between the white matter regions and gray matter regions for rCBV and rCBF (p < 0.05). However, no significant differences were identified between hemispheres and between young and old groups in brain regions. The findings obtained in this study involving healthy beagle dogs might serve as a reference for regional CT perfusion values in specific brain regions. These results may aid in the characterization of various brain diseases in dogs.

SUSCEPTIBILITY WEIGHTED IMAGING TECHNIQUE UTILITY IN DIVERSE NEUROLOGICAL ENTITIES

Background: Susceptibility Weighted Imaging (SWI) is a novel modality based upon GE (Gradient Echo) sequences that employ differences in susceptibility of various paramagnetic as well as diamagnetic substances that aid in the better diagnosis of various neurological entities such as intracranial tumors, vascular malformations, arterial stroke, venous hemorrhagic infarcts. Objective:To assess utility of SWI in various neurological diseases. Methods: The retrospective observational study was held in a tertiary care medical center in India in 2021. Multiple neurological diseases on SWI were analyzed in 100 patients with neurological complaints. The inclusion criteria included patient of all age group who presented with neurological signs and symptoms. The exclusion criteria included presence of post-operative non-compatible orthopedic hardware and patients with cardiac pacemakers, cochlear implants in situ. Results: The majority were males and &gt; 60 years (23%) in age. Among 100 patients, most had tumors (18%), followed by trauma (16%), arterial stroke (15%), and hemorrhage (14%). Most of 14 patients with hemorrhage have intraparenchymal hemorrhage 9 (64.29%). There were10 patients with venous sinuses thrombosis and 15 cases with arterial stroke amongst whom most had middle cerebral artery thrombosis (46.66%). Most 13 patients with vascular pathologies had amyloid angiopathy 4 (30.77%). The majority of tumors were primary 15 (83.33%) with 10 (66.67%) newly diagnosed tumors, 11 (61.11%) tumors had a hemorrhage, 3 (16.67%) presented with calcification, and 4 (22.22%) had both hemorrhage and calcification. According to SWI grading of the tumor by intratumoral susceptibility score (ITSS), the majority were in grade III. On the correlation of SWI grading with MR Spectroscopy (MRS) and MR perfusion (MRP) study, 6 (100%) grade III patients showed hyperperfusion on MRP with raised choline/Creatinine ratio. SWI was better than CT (P&lt;0.05) in detecting trauma, hemorrhage, cerebral venous sinus thrombosis, vascular pathologies, and tumors. Conclusion: SWI is a helpful imaging tool in neuroradiological practice and should be incorporated into standard procedures. It is beneficial in identifying hemorrhages, low-flow vascular abnormalities, diffuse axonal injury, and neurodegenerative illnesses. In addition, it is a supplementary sequence in the stroke by distinguishing calcium from hemorrhage in the brain and categorizing brain tumors.

Transplacental transfer of Remdesivir and GS‐441524: An ex vivo perfusion study

Transplacental transfer of Remdesivir and GS‐441524: An ex vivo perfusion study

Correlation of magnetic resonance angiography and transcranial doppler ultrasound in acute stroke patients

The incidence of cerebrovascular diseases increases with age, and the number of strokes is projected to increase as the elderly population grows. Most cerebrovascular diseases are manifest by the abrupt onset of a focal neurologic deficit. Computed Tomography images identify or exclude hemorrhage as the cause of stroke, and they identify extra-parenchymal hemorrhages, neoplasms, abscesses, and other conditions masquerading as stroke. Non-contrast CT brain is the 1st imaging investigation usually performed in acute stroke patients. Magnetic Resonance Imaging (MRI) reliably documents the extent and location of infarction in all areas of the brain, including the posterior fossa and cortical surface. It also identifies intracranial hemorrhage and other abnormalities but is less sensitive than CT for detecting acute blood. Diffusion-weighted imaging is more sensitive for early brain infarction than standard MR sequences or CT, as is fluid-attenuated inversion recovery (FLAIR) imaging. Using IV administration of gadolinium contrast, MR perfusion studies can be performed. Thus it is evident that both TCD and MRA are promising modalities in the evaluation of acute stroke. This dissertation aims to compare and correlate the findings of MRA and TCD and their advantages and disadvantages in the practical hospital set-up. Total 50 patients – 30 Male and 20 Females – with a clinical diagnosis of stroke (Acute or Chronic) were evaluated with MRI and MR Angiography and Transcranial Doppler(TCD) with TCD being performed prior to MRI/MRA in all patients. Time interval between these two examinations was 2 to 8 hours. Out of 50 patients studied, 10 patients were excluded due to inadequate insonation windows. Of the 40 patients, 24 patients showed abnormality on MRA. Of the MRA abnormal 24 patients, 20 were abnormal on TCD (True positive on TCD), while 4 were normal on TCD (False negative on TCD). Also of the 16 MRA normal patients, 9 were normal on TCD (True negative) while 7 were abnormal on TCD (False positive). Analysis of above findings revealed, Sensitivity 83.33 %, Specificity 56.25%, Positive predictive value 74.07 %, Negative predictive value 69.23 % for TCD compared to MRA in Assessment of the Anterior circulation.

Expanding the Horizons of Pre-Transplant Renal Vascular Assessment Using Ex Vivo Perfusion.

Recently, immense efforts have focused on improving the preservation of (sub)optimal donor organs by means of ex vivo perfusion, which enables the opportunity for organ reconditioning and viability assessment. However, there is still no biomarker that correlates with renal viability. Therefore, it is essential to explore new techniques for pre-transplant assessment of organ quality to guarantee successful long-term transplantation outcomes. The renal vascular compartment has received little attention in machine perfusion studies. In vivo, proper renal vascular and endothelial function is essential for maintaining homeostasis and long-term graft survival. In an ex vivo setting, little is known about vascular viability and its implications for an organ's suitability for transplant. Seeing that endothelial damage is the first step in a cascade of disruptions and maintaining homeostasis is crucial for positive post-transplant outcomes, further research is key to clarifying the (patho)physiology of the renal vasculature during machine perfusion. In this review, we aim to summarize key aspects of renal vascular physiology, describe the role of the renal vasculature in pathophysiological settings, and explain how ex vivo perfusion plays a role in either unveiling or targeting such processes. Additionally, we discuss potentially new vascular assessment tools during ex vivo renal perfusion.

Synthetic Attenuation Correction Maps for SPECT Imaging Using Deep Learning: A Study on Myocardial Perfusion Imaging.

(1) Background: The CT-based attenuation correction of SPECT images is essential for obtaining accurate quantitative images in cardiovascular imaging. However, there are still many SPECT cameras without associated CT scanners throughout the world, especially in developing countries. Performing additional CT scans implies troublesome planning logistics and larger radiation doses for patients, making it a suboptimal solution. Deep learning (DL) offers a revolutionary way to generate complementary images for individual patients at a large scale. Hence, we aimed to generate linear attenuation coefficient maps from SPECT emission images reconstructed without attenuation correction using deep learning. (2) Methods: A total of 384 SPECT myocardial perfusion studies that used 99mTc-sestamibi were included. A DL model based on a 2D U-Net architecture was trained using information from 312 patients. The quality of the generated synthetic attenuation correction maps (ACMs) and reconstructed emission values were evaluated using three metrics and compared to standard-of-care data using Bland-Altman plots. Finally, a quantitative evaluation of myocardial uptake was performed, followed by a semi-quantitative evaluation of myocardial perfusion. (3) Results: In a test set of 66 test patients, the ACM quality metrics were MSSIM = 0.97 ± 0.001 and NMAE = 3.08 ± 1.26 (%), and the reconstructed emission quality metrics were MSSIM = 0.99 ± 0.003 and NMAE = 0.23 ± 0.13 (%). The 95% limits of agreement (LoAs) at the voxel level for reconstructed SPECT images were: [-9.04; 9.00]%, and for the segment level, they were [-11; 10]%. The 95% LoAs for the Summed Stress Score values between the images reconstructed were [-2.8, 3.0]. When global perfusion scores were assessed, only 2 out of 66 patients showed changes in perfusion categories. (4) Conclusion: Deep learning can generate accurate attenuation correction maps from non-attenuation-corrected cardiac SPECT images. These high-quality attenuation maps are suitable for attenuation correction in myocardial perfusion SPECT imaging and could obviate the need for additional imaging in standalone SPECT scanners.

Prevalence of Stroke in Patient Presenting to Emergency Department (ED) With Dizziness Base on Brain Computed Tomography (CT)

Objectives: Dizziness is a common acute emergency complain which can present in isolation. Diagnosing a stroke in patient complains of dizziness only is major challenge to the practicing emergency physician as this symptom nor sensitive neither specific. The purpose of this study was to measure the prevalence of stroke as a diagnosis in patient who present to the emergency department with dizziness base on brain CT. Methods: This is Retrospective, Cross sectional study was carried out at the Armed Force Hospital (adult ED) in Muscat, Oman, from between August 2019 -August 2020. All patients who underwent head CT during this period where review both indication and the CT finding. Result: out of 1000 CT brain request, 115 patients meet the inclusion criteria, and 13 patients from the inclusion criteria have stroke with isolated dizziness. 80% of brain CT was normal, while 11% showed acute stroke. Conclusion: patient present with dizziness carry the risk to have stroke and head CT brain can help in diagnosis. Adding further imaging, such as, brain perfusion study and MRI can lower the chance of missing stroke case in isolated dizziness presentation.

P.089 A literature search using titles and key terms was conducted for articles containing brain death ancillary testing diagnosis, and CTP as primary focus

Background: Ancillary testing assist in the diagnosis of brain death. While traditionally, lack of blood flow (BF) in the intracranial arteries constitutes conclusive evidence that the brain is dead, there is apparent discrepancy between the BF, and sufficient cerebral perfusion; In 15% of patients with confirmed clinical diagnosis of brain death, BF is still preserved. In these patients, cerebral perfusion is significantly impaired suggesting that cerebral perfusion rather than BF more accurately assesses brain function. We aim to present a history of brain death, its pathophysiology, and ancillary tests utilized for its diagnosis- specifically CT Perfusion studies. Methods: A literature search using titles and key terms was conducted for articles containing brain death ancillary testing diagnosis, and CTP as primary focus. Results: Across selected studies, CTP diagnosed brain death with 100% positive predictive value, as none of the patients were proven not-dead on follow-up. The early prediction of mortality outcome in these patients with proven high mortality rate may help decisions for withdrawal of life support. It may also facilitate procurement of organs for transplants. Conclusions: Although clinical assessment is the gold standard method of brain death determination, CTP has shown promising results that could alter our current clinical approach.

Automated dynamic motion correction improves repeatability and reproducibility of myocardial blood flow quantification with rubidium-82 PET imaging

BackgroundPatient motion reduces the accuracy of PET myocardial blood flow (MBF) measurements. This study evaluated the effect of automatic motion correction on test-retest repeatability and inter-observer variability in a clinically relevant population. MethodsPatients with known or suspected CAD underwent repeat rest 82Rb PET scans within minutes as part of their scheduled rest-stress perfusion study. Two trained observers evaluated the presence of heart motion in each scan. Global LV and per-vessel MBF were computed from the dynamic rest images before and after automatic motion correction. Test-retest and inter-observer variability were assessed using intra-class correlation and Bland-Altman analysis. Results140 pairs of test-retest scans were included, with visual motion noted in 18%. Motion correction decreased the global MBF values by 3.5% (0.80 ± 0.24 vs 0.82 ± 0.25 mL⋅min−1⋅g−1; P < 0.001) suggesting that the blood input function was underestimated in cases with patient motion. Test-retest repeatability of global MBF improved by 9.7% (0.25 vs 0.28 mL⋅min−1⋅g−1; P < 0.001) and inter-observer repeatability was improved by 7.1% (0.073 vs 0.079 mL⋅min−1⋅g−1; P = 0.012). There was a marked impact on both test-retest repeatability as well as inter-observer repeatability in the LCX territory, with improvements of 16.5% (0.30 vs 0.36 mL⋅min−1⋅g−1; P < 0.0000) and 18.4% (0.13 vs 0.16 mL⋅min−1⋅g−1; P < 0.001), respectively. ConclusionAutomatic motion correction improved test-retest repeatability and reduced differences between observers.

Phase I and pharmacodynamic study of arsenic trioxide plus radiotherapy for newly diagnosed glioblastoma.

2061 Background: Arsenic Trioxide (ATO) demonstrated prolonged survival in a transplanted rodent glioblastoma (GBM) model. Given the lack of effective therapies before temozolomide was available, the NCI funded NABTT Brain Tumor Consortium initiated a Phase I study of ATO with radiation in patients with newly diagnosed glioblastoma. Dose escalations using two different schedules of ATO were studied. Methods: Patients with newly diagnosed GBM (MGMT and IDH mutation status unknown) were assigned to receive ATO once or twice weekly during the 6-week course of radiation. The starting ATO dose was 0.25 mg/kg. This was escalated by 0.05 mg/kg until an MTD was reached. Patients did not receive ATO or other adjuvant therapy once the radiation was completed. As ATO affected tumor vasculature and blood flow in experimental imaging studies, perfusion MRIs were obtained before ATO administration and one and six weeks later. Survival was a secondary endpoint. Results: Thirty-one patients were enrolled: median age 54.9 years, 68% male, 77% patients KPS &gt;90, 77% had tumor resection. The MTD was determined to be 0.4mg/kg on the weekly schedule and 0.3mg/kg on the biweekly schedule. ATO was well tolerated with 81% of patients completing the 6 weeks combined treatment. Major dose limiting toxicities were increased aspartate and alanine aminotransferases and one case of hyperkalemia. For all patients the median overall survival (mOS) was 17.7 months and the median progression-free survival (mPFS) was 5.4 months. However, there was a significant survival difference between the two ATO dose schedules across all doses with a mOS of 22.8 months in the biweekly schedule, vs 12.1 months in the weekly schedule (P = 0.039). There was a similar difference in mPFS (10.2 months vs 3.2 months, respectively, P = 0.004). Similarly, there were significant differences in perfusion imaging between the two ATO dose schedules with relative cerebral blood flow showing a significant decrease after one week of ATO treatment on the biweekly schedule (p = 0.007). Conclusions: TheMTDs of ATO in patients with GBM administered once or twice weekly for six weeks with standard radiation were determined. This regimen was well tolerated. Survival in patients on the biweekly schedule was much better (22.8 months) than expected in patients not receiving temozolomide. In addition, patients on biweekly ATO also had significant changes on MRI perfusion studies suggesting a pharmacodynamic effect of this agent. These finding should be explored further in patients with newly diagnosed MGMT unmethylated GBM where temozolomide has very limited activity. Clinical trial information: NCT00045565 .

The assessment of moderate acne vulgaris face skin using blood perfusion and hyperspectral imaging-A pilot study.

Microcirculation is the flow of blood through the smallest vessels in the circulatory system. Capillaries respond to various pathologies much earlier than arteries and veins, the changes which indicate that the disease is already developing. Careful monitoring of the functioning of the capillary system often allows the detection of in vivo disorders at an early stage. The aim of the study was to evaluate the microcirculation within acne lesions. A noninvasive method of semi-quantitative blood perfusion measurement based on laser speckle contrast analysis (LASCA) and a quantitative assessment of the acne severity using the hyperspectral imaging method supported by image analysis and processing methods were used. The acne lesion perfusion was compared to the healthy skin perfusion of the control group. The reflectance in the range from 400 to 1000 nm was also compared for acne lesions and healthy skin. A dedicated version of the algorithm based on the gray-level co-occurrence matrix was used to compare differences between acne lesions and healthy skin. Blood perfusion in acne lesions is on average 117% higher than in healthy skin. The reflectance of acne lesions was lower in the range of 400-600 nm compared to the healthy skin. A statistically significant decrease in the reflectance of acne lesions was demonstrated for wavelengths: 434, 549, and 588 nm. Increased blood perfusion in acne lesions compared to healthy skin suggests increased chemotaxis of inflammatory cells and wound healing. Decrease points in skin reflectance resemble the absorption peaks for hemoglobin and coproporphyrin III produced by Cutibacterium acnes. Thus, the proposed methods may serve not only for the early detection of acne lesions, before they manifest themselves clinically for the naked eye, but may also be a tool for quantifying the effectiveness of acne treatment.

E-selectin Gene Modified Mesenchymal Stem Cell Therapy Reverses Impairments in Wound Healing in Ischemic Limbs

Tissue loss is a major source of morbidity and substantially worsens the risk of extremity amputation in patients with chronic limb-threatening ischemia (CLTI). Although cell-based therapies utilizing mesenchymal stem cells (MSC) hold significant promise to augment wound healing and therapeutic angiogenesis, unmodified MSCs have demonstrated only minor benefits for CLTI in previous clinical trials. Here we report the effects of MSCs engineered to overexpress E-selectin (E-sel), a cell adhesion molecule capable of inducing neovascularization, on a translational murine model recapitulating hindlimb ischemia with cutaneous tissue loss. MSCs were harvested from bone marrow of 8- to 10-week-old FVB/Rosa26SormTmG donor mice and cultured in MesenCult medium. MSCs were verified as CD44+/CD73+/CD105+/CD29+/Sca-1+ by flow cytometry. MSCs underwent viral transduction with E-sel-GFP/AAV or GFP/AAV. Femoral artery ligation was performed in 12- to 14-week-old recipient FVB mice followed by a 4-mm acute cutaneous wound in the ipsilateral limb and local injection of PBS or 1 × 106 donor GFP+/MSCs or E-sel+/MSCs (E-sel+/MSC). Wounds were monitored daily for 7 days, at which point tissue specimens were harvested for microscopy and whole-body DiI perfusion studies. Unmodified MSCs do not express basal levels of E-sel, and E-sel+/MSCs retained MSC phenotype and trilineage differentiation capability. Mice receiving E-sel+/MSC treatment (n = 10) demonstrated accelerated wound closure rates compared to both GFP+/MSCs (n = 10) and phosphate-buffered saline (PBS) (n = 10)-treated mice at each postoperative day (POD) with the highest degree of difference observed at POD 5 (94 ± 3% vs 79 ± 10% GFP vs 72 ± 9% PBS; P < .001) and 7 (98 ± 2% vs 86 ± 8% GFP vs 87 ± 6% PBS; P < .010). Collagen deposition was more abundant in wounds treated with E-sel+/MSCs (21 ± 4% vs 5 ± 1% GFP vs 9 ± 1% PBS). DiI perfusion at POD 10 demonstrated greater vessel density in wounds treated with E-sel+/MSCs (76 ± 15% vs 29 ± 7% GFP vs 9 ± 5% PBS relative vascular density). Wound healing focused polymerase chain reaction array identified upregulation of target genes in wound tissue responding to E-sel+/MSCs. E-sel+/MSCs demonstrated enhanced viability more mTmG+-E-sel+/MSCs (13 ± 3 cells/high powered field [HPF] vs GFP+/MSCs 3 ± 2 cells/HPF vs PBS 0 ± 0 cells/HPF; P < .010) observed at POD 7 on microscopy. Cell-based therapy using E-sel-overexpressing MSCs reverses impairments in wound healing of ischemic limbs. These data exhibit the potential role for E-sel-modified MSCs as a novel therapeutic alternative in future clinical applications for delayed and nonhealing wounds associated with CLTI.