Serial Imaging Studies Research Articles

Radiolabeled, Antibody-Conjugated Manganese Oxide Nanoparticles for Tumor Vasculature Targeted Positron Emission Tomography and Magnetic Resonance Imaging.

Manganese oxide nanoparticles (Mn3O4 NPs) have attracted a great deal of attention in the field of biomedical imaging because of their ability to create an enhanced imaging signal in MRI as novel potent T1 contrast agents. In this study, we present tumor vasculature-targeted imaging in mice using Mn3O4 NPs through conjugation to the anti-CD105 antibody TRC105 and radionuclide copper-64 (64Cu, t1/2: 12.7 h). The Mn3O4 conjugated NPs, 64Cu-NOTA-Mn3O4@PEG-TRC105, exhibited sufficient stability in vitro and in vivo. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies evaluated the pharmacokinetics and demonstrated targeting of 64Cu-NOTA-Mn3O4@PEG-TRC105 to 4T1 murine breast tumors in vivo, compared to 64Cu-NOTA-Mn3O4@PEG. The specificity of 64Cu-NOTA-Mn3O4@PEG-TRC105 for the vascular marker CD105 was confirmed through in vivo, in vitro, and ex vivo experiments. Since Mn3O4 conjugated NPs exhibited desirable properties for T1 enhanced imaging and low toxicity, the tumor-specific Mn3O4 conjugated NPs reported in this study may serve as promising multifunctional nanoplatforms for precise cancer imaging and diagnosis.

Predictors of late aortic intervention in patients with medically treated type B aortic dissection

BackgroundPatients with medically managed type B aortic dissection (TBAD) have a high incidence of aorta-related complications over time. Whereas early thoracic endovascular aortic repair (TEVAR) to seal the entry tear can promote aortic remodeling and prevent late aneurysm formation, there are sparse data as to which patients will benefit from such therapy. The goal of this study was to identify clinical and anatomic factors that are associated with the need for subsequent aortic intervention in patients who present with uncomplicated TBAD. These factors could guide the selection of patients who will benefit from TEVAR in the subacute phase. MethodsPatients who presented with acute uncomplicated TBAD and were initially managed medically from January 2000 to December 2013 were included in the study. Timing of intervention was stratified into early (within 180 days of initial presentation) and late (181 days and later) cohorts. All patients had follow-up axial imaging studies. These imaging studies were reviewed for anatomic criteria in a retrospective fashion. Predictors of aortic intervention were determined using Cox regression analyses. ResultsThere were 254 patients (65% men) with medically managed acute TBAD. The average age at presentation was 66.3 years, and 82.5% had a history of hypertension. Mean follow-up was 6.8 years (range, 0.1-13.6 years). There were a total of 97 (38%) patients who required an aortic intervention during follow-up; 30 (12%) patients required an early intervention, and 67 (26%) were treated during late follow-up (100% for aneurysmal degeneration). Predictors of late aortic intervention included entry tear >10 mm (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.5-3.8; P = .03), total aortic diameter >40 mm at time of presentation (OR, 2.2; 95% CI, 1.8-4.3; P = .02), false lumen diameter >20 mm (OR, 1.8; 95% CI, 1.3-4.7; P = .03), and increase in total aortic diameter >5 mm between serial imaging studies (OR, 2.3; 95% CI, 1.3-3.5; P = .02). Complete thrombosis of the false lumen was protective against late operative intervention (OR, 0.22; 95% CI, 0.11-0.48; P < .01). ConclusionsNearly 40% of patients who present with an uncomplicated TBAD will ultimately require an aortic intervention. All of the late interventions were performed for aneurysmal degeneration. A variety of readily available anatomic features can predict the need for eventual operative intervention in TBAD; accordingly, these parameters can guide the desirability of early TEVAR.

18-month outcomes of heterologous bilateral hand transplantation in a child: a case report

Although heterologous vascular composite allotransplantation has become a burgeoning treatment option for adult amputees, there have been no successful cases previously reported in children. Here, we describe the surgical, immunological, and neurorehabilitation details with functional outcomes 18 months after heterologous bilateral hand and forearm transplantation in an 8-year-old child with quadrimembral amputations and a previous kidney transplant. 2 years of extensive preparation by medical and surgical teams preceded the hand-forearm transplantation of this child. The initial immunosuppressive protocol included thymoglobulin, tacrolimus, prednisone, and mycophenolate mofetil. In July, 2015, our vascularised composite allotransplantation team did the first bilateral hand and forearm transplantation in a child, an 8-year-old boy with previous living-related kidney transplantation. The surgery included four teams working simultaneously on the donor and recipient limbs, aided by customised cutting guides that aimed to reduce ischaemia time. Following an extended length of time in hospital, skin biopsies and close monitoring of renal function and drug concentrations occurred weekly for the first 3 months and were slowly tapered to monthly, and then quarterly. Skin biopsies were also done when tissue rejection was suspected. Paediatric-specific rehabilitation techniques were applied to promote patient engagement during rehabilitation. Progress was assessed by monthly sensory and motor function tests during routine clinic visits and with serial functional brain imaging studies, including structural brain MRI, magnetoencephalography and transcranial magnetic stimulation. The surgery lasted 10 h and 40 min. Vascular revision of the ulnar artery was required a few hours postoperatively. There were no further immediate postsurgical complications. Rejection episodes occurred throughout the first year but were reversed. An increase in serum creatinine led to the addition of sirolimus at 3 months after transplantation with concomitant reduction in tacrolimus targets. Sensibility to light touch was present by 6 months after transplantation. Intrinsic hand muscle innervation was present by 7-10 months after transplantation. At 18 months, the child had exceeded his previous adapted abilities. As of 18 months after transplantation surgery he is able to write and feed, toilet, and dress himself more independently and efficiently than he could do before transplantation. He remains on four immunosuppressive medications and functional neuroimaging studies have shown motor and somatosensory cortical reorganisation. Hand transplantation in a child can be surgically, medically, and functionally successful under carefully considered circumstances. Long-term data on the functional trajectory, neurological recovery, psychological sequelae, and the potential late effect of immunosuppression are still needed to support broader implementation of paediatric vascular composite allotransplantation. The Children's Hospital of Philadelphia.

Two-kidney one-clip is a pertinent approach to integrate arterial hypertension in animal models of stroke: Serial magnetic resonance imaging studies of brain lesions before and during cerebral ischemia

Although chronic arterial hypertension (CAH) represents the major comorbid factor in stroke, it is rarely integrated in preclinical studies of stroke. The majority of those investigations employ spontaneously hypertensive rats (SHR) which display a susceptibility to ischemic damage independent of hypertension. Here, we used a renovascular model of hypertension (RH) to examine, with magnetic resonance imaging (MRI), brain alterations during the development of hypertension and after brain ischemia. We also examined whether MRI-derived parameters predict the extent of ischemia-induced brain damage. RH was induced according to the two-kidney one-clip model and multiparametric MRI was performed at 3, 6, 9, and 12 weeks after hypertension and also at 10, 50, and 60 min following stroke. Blood pressure values increased progressively and reached a plateau at 6 weeks after RH induction. At 12 weeks, all hypertensive animals displayed spontaneous brain lesions (hemorrhages, deep and cortical lesions, ventricular dilatation), increased apparent diffusion coefficient (ADC) values in the corpus callosum and higher fractional anisotropy in the cortex. Following ischemia, these animals showed larger brain lesions (406 ± 82 vs. 179 ± 36 mm3, p < 0.002) which correlated with ADC values at chronic stage of hypertension. This model of hypertension displays many characteristics of the neuropathology of human CAH. The use of this model in stroke studies is relevant and desirable.

Inflammatory myofibroblastic tumor of the right frontal lobe

BackgroundWe aim to present an unique case of inflammatory myofibroblastic tumor (IMT) of the brain parenchyma and study the clinical presentation, imagine characteristic, intraoperative findings, and histopathology features of IMT in the brain parenchyma.Case PresentationA 36-year-old female with IMT come to see doctor presented with a 3-month history of progressively worsening weakness in the left upper limb along with alalia. Serial magnetic resonance imaging studies revealed a lesion within the right frontal lobe. The lesions were locally clear boundary with peripheral tissues. A right frontotemporal craniotomy was performed and the specimens were detected by immunohistochemical staining and light microscopy. Through the microscope, the tumor was composed of large number of chronic inflammatory cells and spindle cells. From immunohistochemical stains, it demonstrated CD34 (+), SMA (+), Vimentin (+), and actin (+) were positive meanwhile S-100(-) was negative.ConclusionIMT of the right frontal lobe is a rare lesions. Surgical resection is the best and the most effective treatment.

Upright, prone, and supine spinal morphology and alignment in adolescent idiopathic scoliosis

BackgroundPatients with adolescent idiopathic scoliosis (AIS) are usually investigated by serial imaging studies during the course of treatment, some imaging involves ionizing radiation, and the radiation doses are cumulative. Few studies have addressed the correlation of spinal deformity captured by these different imaging modalities, for which patient positioning are different. To the best of our knowledge, this is the first study to compare the coronal, axial, and sagittal morphology of the scoliotic spine in three different body positions (upright, prone, and supine) and between three different imaging modalities (X-ray, CT, and MRI).MethodsSixty-two AIS patients scheduled for scoliosis surgery, and having undergone standard pre-operative work-up, were included. This work-up included upright full-spine radiographs, supine bending radiographs, supine MRI, and prone CT as is the routine in one of our institutions. In all three positions, Cobb angles, thoracic kyphosis (TK), lumbar lordosis (LL), and vertebral rotation were determined. The relationship among three positions (upright X-ray, prone CT, and supine MRI) was investigated according to the Bland-Altman test, whereas the correlation was described by the intraclass correlation coefficient (ICC).ResultsThoracic and lumbar Cobb angles correlated significantly between conventional radiographs (68° ± 15° and 44° ± 17°), prone CT (54° ± 15° and 33° ± 15°), and supine MRI (57° ± 14° and 35° ± 16°; ICC ≥0.96; P < 0.001). The thoracic and lumbar apical vertebral rotation showed a good correlation among three positions (upright, 22° ± 12° and 11° ± 13°; prone, 20° ± 9° and 8° ± 11°; supine, 16° ± 11° and 6° ± 14°; ICC ≥0.82; P < 0.001). The TK and LL correlated well among three different positions (TK 26° ± 11°, 22° ± 12°, and 17° ± 10°; P ≤ 0.004; LL 49° ± 12°, 45° ± 11°, and 44° ± 12°; P < 0.006; ICC 0.87 and 0.85).ConclusionsAlthough there is a generalized underestimation of morphological parameters of the scoliotic deformity in the supine and prone positions as compared to the upright position, a significant correlation of these parameters is still evident among different body positions by different imaging modalities. Findings of this study suggest that severity of scoliotic deformity in AIS patients can be largely represented by different imaging modalities despite the difference in body positioning.

Optimizing image registration and infarct definition in stroke research.

ObjectiveAccurate representation of final infarct volume is essential for assessing the efficacy of stroke interventions in imaging‐based studies. This study defines the impact of image registration methods used at different timepoints following stroke, and the implications for infarct definition in stroke research.MethodsPatients presenting with acute ischemic stroke were imaged serially using magnetic resonance imaging. Infarct volume was defined manually using four metrics: 24‐h b1000 imaging; 1‐week and 1‐month T2‐weighted FLAIR; and automatically using predefined thresholds of ADC at 24 h. Infarct overlap statistics and volumes were compared across timepoints following both rigid body and nonlinear image registration to the presenting MRI. The effect of nonlinear registration on a hypothetical trial sample size was calculated.ResultsThirty‐seven patients were included. Nonlinear registration improved infarct overlap statistics and consistency of total infarct volumes across timepoints, and reduced infarct volumes by 4.0 mL (13.1%) and 7.1 mL (18.2%) at 24 h and 1 week, respectively, compared to rigid body registration. Infarct volume at 24 h, defined using a predetermined ADC threshold, was less sensitive to infarction than b1000 imaging. 1‐week T2‐weighted FLAIR imaging was the most accurate representation of final infarct volume. Nonlinear registration reduced hypothetical trial sample size, independent of infarct volume, by an average of 13%.InterpretationNonlinear image registration may offer the opportunity of improving the accuracy of infarct definition in serial imaging studies compared to rigid body registration, helping to overcome the challenges of anatomical distortions at subacute timepoints, and reducing sample size for imaging‐based clinical trials.

Case Report of Neonatal Proteus mirabilis Meningitis and Brain Abscess with Negative Initial Image Finding: Consideration of Serial Imaging Studies

Case Report of Neonatal <i>Proteus mirabilis</i> Meningitis and Brain Abscess with Negative Initial Image Finding: Consideration of Serial Imaging Studies

Co-clinical quantitative tumor volume imaging in ALK-rearranged NSCLC treated with crizotinib

PurposeTo evaluate and compare the volumetric tumor burden changes during crizotinib therapy in mice and human cohorts with ALK-rearranged non-small-cell lung cancer (NSCLC). MethodsVolumetric tumor burden was quantified on serial imaging studies in 8 bitransgenic mice with ALK-rearranged adenocarcinoma treated with crizotinib, and in 33 human subjects with ALK-rearranged NSCLC treated with crizotinib. The volumetric tumor burden changes and the time to maximal response were compared between mice and humans. ResultsThe median tumor volume decrease (%) at the maximal response was −40.4% (range: −79.5%–+11.7%) in mice, and −72.9% (range: −100%–+72%) in humans (Wilcoxon p=0.03). The median time from the initiation of therapy to maximal response was 6 weeks in mice, and 15.7 weeks in humans. Overall volumetric response rate was 50% in mice and 97% in humans. Spider plots of tumor volume changes during therapy demonstrated durable responses in the human cohort, with a median time on therapy of 13.1 months. ConclusionThe present study described an initial attempt to evaluate quantitative tumor burden changes in co-clinical imaging studies of genomically-matched mice and human cohorts with ALK-rearranged NSCLC treated with crizotinib. Differences are noted in the degree of maximal volume response between the two cohorts in this well-established paradigm of targeted therapy, indicating a need for further studies to optimize co-clinical trial design and interpretation.

OP.4B.04] LONGITUDINAL CHANGES IN LEFT VENTRICULAR STRUCTURE AND DIASTOLIC FUNCTION IN RELATION TO ARTERIAL PROPERTIES IN A GENERAL POPULATION

Objective: Serial imaging studies are needed to clarify the relation of change in left ventricular (LV) structure and function with arterial stiffness. In this longitudinal population study, we assessed in continuous and categorical analyses to what extent arterial properties predict alterations in echocardiographic indexes reflecting LV structure and function. Design and method: In 607 participants (50.7% women; mean age, 50.7 years), using conventional echocardiography and tissue Doppler imaging, we measured LV dimensions, transmitral blood flow and mitral annular tissue Doppler velocities at baseline and after 4.7 years. Using applanation tonometry, we assessed augmentation pressure (AP), central pulse pressure (cPP) and carotid-femoral pulse wave velocity (PWV) at baseline. Standardized effect size was expressed as percent of changes in standard deviation (SD) of δ echocardiographic indexes associated with 1-SD increase in baseline arterial indexes. Results: The clinical correlates of δLV indexes included baseline LV index, age, sex, body mass index, mean blood pressure, pulse rate and changes over time in these co-variables. After full adjustment, longitudinal increase in LV septal (standardized effect size: +14.6%; P = 0.0017) and posterior wall (+13.3%; P = 0.0015) thickness was significantly associated with higher PWV at baseline, whereas LV internal diameter (−12.2%; P = 0.014) decreased with PWV. Consequently, a greater increase in relative wall thickness was associated with baseline PWV (+17.2%; P < 0.0001). We observed similar longitudinal increase in LV wall thickness in relation to higher baseline PWV in men and women. In adjusted logistic analysis, higher baseline PWV was associated with a 156% increase in the odds of developing LV concentric remodeling during follow-up as compared to participants who improved LV geometry (P = 0.0088). Furthermore, in women, a higher baseline cPP predicted a greater increase in LV mass (+18.1%, P = 0.018) and E/e’ ratio (+25.8%, P = 0.0064). Conclusions: The key finding of this study is that longitudinal increase in LV relative wall thickness was associated with higher baseline PWV, measure of arterial stiffness. Moreover, in women, a higher cPP predicted worsening of LV diastolic function. Our study demonstrated the importance of arterial properties as a mediator of LV concentric remodeling in men and women, and diastolic dysfunction in women.

In Vivo Dynamic Metabolic Changes After Transplantation of Induced Pluripotent Stem Cells for Ischemic Injury.

Serial 18F-FDG PET, echocardiographic, immunohistochemical, and immunofluorescence studies were performed after transplantation of iPSCs and iPSC-CMs and compared with embryonic stem cells (ESCs), ESC-CMs, and a phosphate-buffered saline control group of rats with myocardial infarction. Increased glucose metabolism in periinfarct areas and improved myocardial function were observed in the stem cell transplantation groups compared with the control group, and serial immunofluorescence and immunohistochemical results exhibited the survival and migration of stem cells during the study period. Serial 18F-FDG PET and echocardiographic imaging studies demonstrated the dynamic metabolic changes and recovery of myocardial function after stem cell transplantation. 18F-FDG PET could be a potential approach to evaluating spatiotemporal dynamic metabolic changes in vivo after transplantation of iPSCs or iPSC-CMs for ischemic injury.

Branch graft patency after open repair of thoracoabdominal aortic aneurysms

ObjectivesThe long-term function of branch grafts to the visceral and renal arteries during open thoracoabdominal aortic aneurysm repair is unknown. We assessed the patency of single and multiple branch grafts with postoperative imaging studies in patients followed for up to 13 years. MethodsA total of 99 of 130 patients undergoing open thoracoabdominal aortic aneurysm repair who received a total of 298 branch grafts to the celiac, superior mesenteric, and renal arteries were evaluated with serial imaging studies at 6- to 12-month intervals. The mean duration of angiographic follow-up was 40.4 months and extended to 159 months. Thirty-three patients receiving 74 grafts were followed for more than 5 years, and 7 patents receiving 22 grafts were followed for more than 10 years. Eighty-four grafts were grafted to the celiac artery, 73 grafts were grafted to the superior mesenteric artery, 71 grafts were grafted to the left renal artery, and 70 grafts were grafted to the right renal artery. ResultsNine graft occlusions occurred in 6 patients. One of these patients died of intestinal ischemia after occlusion of the celiac and superior mesenteric artery grafts, and 1 patient developed occlusion of both renal artery grafts and remains on dialysis. Five graft occlusions in the other 4 patients were asymptomatic, and no interventions were required. One additional patient developed significant stenosis of the celiac, superior mesenteric, and right renal arteries and underwent successful percutaneous angioplasty. No other patient required intervention. Freedom from occlusion of the 298 grafts at 1, 5, and 10 years is 98%, 97%, and 93%, respectively. ConclusionsThis represents the largest series of patients with branch grafts for open thoracoabdominal aortic aneurysm repair with extended angiographic follow-up. The favorable long-term graft patency rates represent a benchmark against which methods for establishing flow to the visceral and renal arteries using alternative techniques can be compared.

Effect of hydration status on atrial and ventricular volumes and function in healthy adult volunteers.

Assessment of cardiac chamber volumes is a fundamental part of cardiac magnetic resonance (CMR) imaging. While the effects of inter- and intraobserver variability have been studied and have a recognized effect on the comparability of serial cardiac MR imaging studies, the effect of differences in hydration status has not been evaluated. To evaluate the effects of volume administration on cardiac chamber volumes. Thirteen healthy adults underwent a baseline cardiac MR to evaluate cardiac chamber volumes after an overnight fast. They were then given two saline boluses of 10ml/kg of body weight and the cardiac MR was repeated immediately after each bolus. From the baseline scan to the final scan there was a significant increase in all four cardiac chamber end-diastolic volumes. Right atrial volumes increased 8.0%, from 61.1 to 66.0ml/m2 (P<0.001), and left atrial volumes increased 10.0%, from 50.0 to 55.0ml/m2 (P<0.001). Right ventricular volumes increased 6.0%, from 91.1 to 96.5ml/m2 (P<0.001), and left ventricular volumes increased 3.2%, from 87.0 to 89.8ml/m2 (P<0.001). Hydration status has a significant effect on the end-diastolic volumes of all cardiac chambers assessed by cardiac MR. Thus, hydration represents a "variable" that should be taken into account when assessing cardiac chamber volumes, especially when performing serial imaging studies in a patient.

Therapeutic modulation of the natural history of coronary atherosclerosis: lessons learned from serial imaging studies

Despite advances in risk prediction, preventive and therapeutic strategies, atherosclerotic cardiovascular disease remains a major public health challenge worldwide, carrying considerable morbidity, mortality and health economic burden. There continues to be a need to better understand the natural history of this disease to guide the development of more effective treatment, integral to which is the rapidly evolving field of coronary artery imaging. Various imaging modalities have been refined to enable detailed visualization of the pathological substrate of atherosclerosis, providing accurate and reproducible measures of coronary plaque burden and composition, including the presence of high-risk characteristics. The serial application of such techniques, including coronary computed tomography angiography (CTA), intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have uncovered important insights into the progression of coronary plaque over time in patients with stable and unstable coronary artery disease (CAD), and its responsiveness to therapeutic interventions. Here we review the use of different imaging modalities for the surveillance of coronary atherosclerosis and the lessons they have provided about the modulation of CAD by both traditional and experimental therapies.

Atrophy is a Real Phenomenon that Can Result in Changes in Deep Brain Stimulation Outcome.

To the Editor We read the case report by Choi et. al. with great interest and would like to add to their observations and to lend strong support to the notion that atrophy impacts DBS outcome. Our experience was previously published in PLOSONE in 2014 but not cited in their report, and we think important for the readership to be aware of this phenomenon.1 Choi reported a 57-year old man who underwent bilateral thalamic DBS surgery for refractory epilepsy and had worsening of seizures following 8 years of reasonable seizure control. This exacerbation of symptoms was attributed to a lead migration into the third ventricle caused by significant ventricular enlargement and atrophy. Re-implantation of a new DBS lead revealed a clinically significant improvement. We agree with the authors that brain atrophy as a potential cause of lead migration leading to a loss of benefit from DBS is possible and should be a worrisome issue. DBS-induced side effects can also result from this phenomenon. We previously reported two Parkinson’s disease and one Essential Tremor patient with an unexpected loss of benefit and/or appearance of new side effects from DBS following several years of clinical benefit.2 Our patients underwent a DBS troubleshooting protocol and careful examination of the implantable pulse generator as well as a careful examination of the electrical system integrity (e.g. impedance and current drain). There were further studies of the DBS system with plain x-rays and no relevant issues were uncovered. We reviewed serial brain imaging studies inclusive of lead locations. We observed a substantial increase in brain atrophy indices (3rd ventricular width, Evans index, ventricular index, and cella media index) and also observed a relative lateral migration of the leads when compared to previous imaging examinations. The likely cause was atrophy which changed the relationship of the DBS leads over time to the surrounding neuroanatomical structures (i.e. a lead may be closer to the internal capsule and may more easily evoke side effects). There is pathological and imaging evidence that the brain changes with age, and that the most prominent changes have been in the frontal cortex, the temporal cortex, the putamen, the thalamus, and the nucleus accumbens though other regions are also at risk.3 We have now encountered another interesting case of shifting DBS leads due to atrophy. This case included serial brain scans and a post-mortenm pathological analysis in a Huntington’s disease patient with bilateral globus pallidus internus DBS. In this case, a change in lead position was observed over time (case has been accepted for publication and publication is pending). Atrophy is a real phenomenon that DBS clinicians should pay attention to as it could affect the long-term DBS outcome.

Survivin-TGFB3-TIMP1 Gene Therapy Via Lentivirus Vector Slows the Course of Intervertebral Disc Degeneration in an In Vivo Rabbit Model.

The ability of lentivirus vector (LV) survivin-transforming growth factor beta 3 (TGFB3)-tissue inhibitor of metalloproteinases 1 (TIMP1) on slowing disc degeneration was evaluated by an animal experiment. The aim of the study was to investigate the effect of LV survivin-TGFB3-TIMP1 on slowing disc degeneration in an in vivo rabbit model. Cell apoptosis, increase of catabolic activity, and decrease of anabolic activity were the mechanisms of disc degeneration. Meanwhile, survivin, TGFB3, and TIMP1 can influence above process, respectively. However, there were no researches conducted to evaluate the effect of an LV containing all three proteins (referred to as LV-survivin-TGFB3-TIMP1) on slowing disc degeneration in vivo. Twenty skeletally mature female New Zealand White rabbits were randomly divided into four groups: nonpunctured sham surgical group (group A, n = 5), punctured blank control group (group B, n = 5), punctured empty vector control group (group C, n = 5), and the treatment group (group D, n = 5). Computed tomography-guided puncture was performed at the L3-L4 and L4-L5 discs, in accordance with a previously validated rabbit annulotomy model for intervertebral disc degeneration. After 3 weeks, LV-carrying survivin, TGFB3, and TIMP1 were injected into the nucleus pulposus. Serial magnetic resonance imaging studies at 0, 3, and 12 weeks were performed. The rabbits were sacrificed at 12 weeks, and the histology, immunofluorescence, quantitative real-time polymerase chain reaction, Western blot, and caspase-3 activity was used for evaluation. Magnetic resonance imaging, histology, gene expression, protein content, and apoptosis analyses of group A showed no disc degeneration. Groups B and C showed disc degeneration, which increased over time, and no significant difference was observed between the two groups (P > 0.05). In group D, there was less disc degeneration compared to the punctured control groups and the difference was statistically significant (P < 0.05). The injection of LV-carrying survivin-TGFB3-TIMP1 into punctured rabbit intervertebral discs helps delay degenerative disc changes. Although data from animal models should be extrapolated to the human condition with caution, this study shows promise for gene therapy to decelerate disc degeneration. N/A.

Cerebrospinal Biomarkers in Alzheimer Disease—Potential Roles as Markers of Prognosis and Neuroplasticity

Cerebrospinal Biomarkers in Alzheimer Disease—Potential Roles as Markers of Prognosis and Neuroplasticity

Preclinical evaluation of isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu for folate receptor-positive tumor targeting.

The purpose of the present study was to prepare isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu (folate-GGCE), and to evaluate the feasibility of their use for folate receptor (FR)-targeted molecular imaging and as theranostic agents in a mouse tumor model. Folate-GGCE was synthesized using solid-phase peptide synthesis and radiolabeled with Tc-99m or Re-188. Radiochemical characterization was performed by radio-high-performance liquid chromatography. The biodistribution of Tc-99m-folate-GGCE was studied, with or without co-injection of excess free folate, in mice bearing both FR-positive (KB cell) and FR-negative (HT1080 cell) tumors. Biodistribution of Re-188-folate-GGCE was studied in mice bearing KB tumors. Serial planar scintigraphy was performed in the dual tumor mouse model after intravenous injection of Tc-99m-folate-GGCE. Serial micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies were performed, with or without co-injection of excess free folate, in the mouse tumor model after injection of Tc-99m-folate-GGCE or Re-188-folate-GGCE. The radiolabeling efficiency and radiochemical stability of Tc-99m- and Re-188-folate-GGCE were more than 95% for up to 4h after radiolabeling. Uptake of Tc-99m-folate-GGCE at 1, 2, and 4h after injection in KB tumor was 16.4, 23.2, and 17.6% injected dose per gram (%ID/g), respectively. This uptake was suppressed by 97.4% when excess free folate was co-administered. Tumor:normal organ ratios at 4h for blood, liver, lung, muscle, and kidney were 54.3, 25.2, 38.3, 97.8, and 0.3, respectively. Tumor uptake of Re-188-folate-GGCE at 2, 4, 8, and 16h after injection was 17.4, 21.7, 24.1, and 15.6%ID/g, respectively. Tumor:normal organ ratios at 8h for blood, liver, lung, muscle, and kidney were 126.8, 21.9, 54.8, 80.3, and 0.4, respectively. KB tumors were clearly visualized at a high intensity using serial scintigraphy and micro-SPECT/CT in mice injected with Tc-99m- or Re-188-folate-GGCE. The tumor uptake of these molecules was completely suppressed when excess free folate was co-administered. Isostructural Tc-99m- and Re-188-folate-GGCE showed high and FR-specific uptake by tumors and generally favorable tumor:normal organ ratios. The tumor targeting capabilities of Tc-99m- and Re-188-folate-GGCE were clearly evident on serial imaging studies. This isostructural pair may have potential diagnostic and theranostic applications for FR-positive tumors.

Severe Progressive Brain Atrophy in Pediatric Multiple Sclerosis

Background Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. Progressive brain atrophy is a known marker of patient disability and cognitive impairment in MS patient, but limited information is available about the clinical and cognitive consequences in the pediatric population. Case Report We present a case of aggressive pediatric-onset MS with severe rapidly progressive brain atrophy, neurological disability, and cognitive deterioration. Serial brain magnetic resonance imaging studies demonstrate ongoing cerebral atrophy correlating with severe deficits on serial neuropsychological testing. Conclusion A subset of pediatric MS patient may be vulnerable to severe cognitive deterioration associated with marked brain atrophy.

Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV)

Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).