Single-Chain VEGF/Cy5.5 Targeting VEGF Receptors to Indicate Atherosclerotic Plaque Instability

Purpose

Unstable plaques may cause clinical events. Plaque destabilization results from the synergy between intraplaque angiogenesis and inflammation. Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) are considered to be involved in these processes. We investigated the efficacy of the anti-VEGFR mimic single-chain VEGF (scVEGF) to map intra-plaque VEGFR expression and atherosclerotic plaque instability using near-infrared fluorescence (NIRF).

Procedures

Human carotid plaques were retrieved from 15 symptomatic and five asymptomatic patients. NIRF plaque imaging was performed pre-/post-incubation with scVEGF/Cy5.5. Biopsies taken from regions with high (hot spot) and low (cold spot) NIRF signals were examined for VEGF-A, VEGFR-1 and VEGFR-2 mRNA expression levels using real-time RT-PCR analysis. Immunohistochemistry for CD31 (endothelium), CD68 (macrophages) and αSMA (smooth muscle cells) was performed to evaluate plaque composition.

Results

NIRF imaging of 20 plaques revealed a heterogeneous distribution of scVEGF/Cy5.5 binding. After incubation NIRF activity increased from 3.9×10^?5?±?5.2×10^?6 to 3.0×10^?4?±?2.2×10^?5 and 5.8×10^?5?±?1.9×10^?5 to 3.1×10^?4?±?1.9×10^?5 photons/s/cm²/sr/illumination intensity on the intraluminal and extraluminal side, respectively (both p?<?0.001). Real-time RT-PCR analysis showed a ~1.2- and ~16.4-fold increased mRNA expression of VEGFR-1 and VEGFR-2, respectively, in hot spots (vs. cold spots). Immunohistochemistry exhibited higher intraplaque capillary density in hot spots (vs. cold spots) (17.2?±?3.7 vs. 5.4?±?2.2 capillary/mm²; p?=?0.037). Hot spots contained significantly reduced numbers of α-SMA-positive cells (vs. cold spots) (2.2?±?0.7 % vs. 6.9?±?1.5 %; p?=?0.038). Finally, a ~2-fold increase of CD68⁺ infiltrating macrophages within hot spots (vs. cold spots) was observed (not significant, p?=?0.17). Significant higher capillary density in hot spots (vs. cold spots) was observed in plaques from symptomatic patients but not in plaques from asymptomatic patients.

Conclusion

Our data support that scVEGF/Cy5.5 is a suitable indicator for plaque instability and a promising diagnostic tool for risk assessment in cardiovascular diseases.     

Axl-Targeted Cancer Imaging with Humanized Antibody h173

Purpose

The tyrosine kinase receptor Axl is overexpressed in various types of cancer and correlated with cancer malignancy. Selective Axl blockade reduces tumor growth and metastasis. The purpose of this study was to examine whether the humanized anti-Axl antibody humanized 173 (h173) labeled with near-infrared fluorescence (NIRF) dye Cy5.5 could be applied as a molecular imaging probe for NIRF imaging of Axl expression in tumor models.

Procedures

NIRF dye Cy5.5 was conjugated to h173 or human normal immunoglobulin G (hIgG) control through amino groups. The resulting probes were evaluated in both A549 (Axl positive) and NCI-H249 (Axl negative) lung cancer xenografts through in vivo NIRF imaging. Ex vivo imaging and probe distribution assay were also carried out to confirm the in vivo imaging results.

Results

After conjugation, binding activity of h173-Cy5.5 was determined to be 97.75 %?±?2.09 % of the unmodified h173. In vitro fluorescence-activated cell sorting (FACS) and fluorescence microscopy analysis validated the specific binding of h173 toward Axl-positive A549 cells. h173-Cy5.5 was then applied to image Axl expression in vivo. In A549 (Axl positive) cancer xenografts, the tumor uptake of h173-Cy5.5 was significantly higher than that of the hIgG-Cy5.5 control (P?<?0.05) at late time points (1, 2, 3, 4, and 7 days). On the contrary, in NCI-H249 (Axl negative) cancer xenografts, the tumor uptake of both hIgG-Cy5.5 and h173-Cy5.5 was low and showed no significant difference (P?>?0.05) at all time points examined. Ex vivo imaging and immunofluorescence staining analysis further validated the in vivo imaging results.

Conclusions

Collectively, all in vitro, in vivo, and ex vivo data suggested that h173-Cy5.5 could serve as a valid probe for Axl-targeted cancer imaging, which could therefore aid in tumor diagnosis, prognosis, and treatment monitoring.     

TEG® and RapidTEG® are unreliable for detecting warfarin-coagulopathy: a prospective cohort study

Background

Thromboelastography^® (TEG) utilizes kaolin, an intrinsic pathway activator, to assess clotting function. Recent published studies suggest that TEG results are commonly normal in patients receiving warfarin, despite an increased International Normalized Ratio (INR). Because RapidTEG? includes tissue factor, an extrinsic pathway activator, as well as kaolin, we hypothesized that RapidTEG would be more sensitive in detecting a warfarin-effect.

Methods

Included in this prospective study were 22 consecutive patients undergoing elective cardioversion and receiving warfarin. Prior to cardioversion, blood was collected to assess INR, Prothrombin Time, TEG, and RapidTEG.

Results

INR Results: 2.8?±?0.5 (1.6 to 4.2). Prothrombin Time Results: 19.1?±?2.2 (13.9. to 24.3). TEG Results (Reference Range): R-Time: 8.3?±?2.7 (2–8); K-Time: 2.1?±?1.4 (1–3); Angle: 62.5?±?10.3 (55–78); MA: 63.2?±?10.3 (51–69); G: 9.4?±?3.5 (4.6-10.9); R-Time within normal range: 10 (45.5%) with INR 2.9?±?0.3; Correlation coefficients for INR and each of the 5 TEG variables were insignificant (P?>?0.05). RapidTEG Results (Reference Range): ACT: 132?±?58 (86–118); K-Time: 1.2?±?0.5 (1–2); Angle: 75.4?±?5.2 (64–80); MA: 63.4?±?5.1 (52–71); G: 8.9?±?2.0 (5.0-11.6); ACT within normal range: 9 (40.9%) with INR 2.7?±?0.5; Correlation coefficients for INR and each of the 5 RapidTEG variables were insignificant (P?>?0.05).

Conclusions

TEG, using kaolin activation, and RapidTEG, with kaolin and tissue factor activation, were normal in a substantial percent of warfarin patients, despite an increased INR. The false-negative rate for detecting warfarin coagulopathy with either test is unacceptable. The lack of correlation between INR and all TEG and RapidTEG components further indicates that these methodologies are insensitive to warfarin effects. Findings suggest that intrinsic pathway activation may mitigate detection of an extrinsic pathway coagulopathy.     

Tracheal suction by closed system without daily change versus open system

Background

Tracheal suctioning costs are higher with a closed tracheal suction system (CTSS) than with an open system (OTSS), due to the need for complete daily change as recommended by the manufacturer. However, is it necessary to change the closed system daily?

Objective

To evaluate the tracheal suctioning costs and incidence of ventilator-associated pneumonia (VAP) using closed system without daily change vs OTSS.

Design

Prospective and randomised study.

Setting

An Intensive Care Unit in a university hospital.

Patients

Patients requiring mechanical ventilation.

Interventions

Patients were randomly assigned to CTSS without daily change or OTSS. We used a CTSS that allowed partial or complete change.

Measurements and results

There were no significant differences between both groups of patients (236 with CTSS and 221 with OTSS) in gender, age, diagnosis, APACHE-II score, mortality, number of aspirations per day, percentage of patients who developed VAP (13.9 vs 14.1%) or the number of ventilator-associated pneumonia per 1000 days of mechanical ventilation (14.1 vs 14.6). There were not significant differences in tracheal suctioning costs per patient/day between CTSS vs OTSS (2.3?±?3.7 vs 2.4?±?0.5 Euros; p?=?0.96); however, when length of mechanical ventilation was lower than 4?days, the cost was higher with CTSS than with OTSS (7.2?±?4.7 vs 1.9?±?0.6?Euros; p?p?Conclusion CTSS without daily change is the optimal option for patients needing tracheal suction longer than 4?days.     

Transpulmonary thermodilution measurements are not affected by continuous veno-venous hemofiltration at high blood pump flow

Purpose

To assess whether continuous veno-venous hemofiltration (CVVH) with high blood pump flow alters the measurements of cardiac index (CI), global end-diastolic volume indexed (GEDVI), and extravascular lung water indexed (EVLWI) performed by transpulmonary thermodilution.

Methods

Sixty-nine patients were included if they were monitored by a PiCCO2 device and received CVVH through a femoral (n?=?62) or an internal jugular (n?=?7) dialysis catheter. The blood pump flow was set at 250?mL/min (n?=?31) or 350?mL/min (n?=?38) and the filtration flow at 6,000?mL/h. A first set of data was collected with a first transpulmonary thermodilution (TD_on). The blood pump was stopped and the continuous CI derived from pulse contour analysis was recorded (PC_off). A second data set (TD_off) was collected before and a last one (TD_on-last) after restarting the blood pump.

Results

$ {\text{CI}}_{{{\text{TD}}_{\text{on}} }} $ , $ {\text{CI}}_{{{\text{PC}}_{\text{off}} }} $ , $ {\text{CI}}_{{{\text{TD}}_{\text{off}} }} $ , and $ {\text{CI}}_{{{\text{TD}}_{{{\text{on}} - {\text{last}}}} }} $ were not significantly different in patients with a femoral dialysis catheter (3.49?±?0.96, 3.51?±?0.96, 3.51?±?0.99, and 3.44?±?1.00?L?min^?1?m^?2, respectively). This was observed with a blood pump flow at 350?mL/min and at 250?mL/min. In these patients with a femoral dialysis catheter, GEDVI did not significantly change when the blood pump was stopped. EVLWI significantly decreased when the blood pump was stopped but to a non-clinically relevant extent (?0.3?±?0.8?mL/kg). No significant changes in CI, GEDVI, and EVLWI were observed in patients with an internal jugular dialysis catheter over the study period.

Conclusions

CVVH with a high blood flow pump does not alter the transpulmonary thermodilution measurements of CI, GEDVI, and EVLWI.     

An optimized set-up for helmet noninvasive ventilation improves pressure support delivery and patient�Cventilator interaction

Objective

To test the effects on mechanical performance of helmet noninvasive ventilation (NIV) of an optimized set-up concerning the ventilator settings, the ventilator circuit and the helmet itself.

Subjects and methods

In a bench study, helmet NIV was applied to a physical model. Pressurization and depressurization rates and minute ventilation (MV) were measured under 24 conditions including pressure support of 10 or 20?cmH₂O, positive end expiratory pressure (PEEP) of 5 or 10?cmH₂O, ventilator circuit with ??high??, ??intermediate?? or ??low?? resistance, and cushion deflated or inflated. In a clinical study pressurization and depressurization rates, MV and patient?Cventilator interactions were compared in six patients with acute respiratory failure during conventional versus an ??optimized?? set-up (PEEP increased to 10?cmH₂O, low resistance circuit and cushion inflated).

Results

In the bench study, all adjustments simultaneously applied (increased PEEP, inflated cushion and low resistance circuit) increased pressurization rate (46.7?±?2.8 vs. 28.3?±?0.6?%, p?<?0.05), depressurization rate (82.9?±?1.9 vs. 59.8?±?1.1?%, p????0.05) and patient MV (8.5?±?3.2 vs. 7.4?±?2.8?l/min, p?<?0.05), and decreased leaks (17.4?±?6.0 vs. 33.6?±?6.0?%, p?<?0.05) compared to the basal set-up. In the clinical study, the optimized set-up increased pressurization rate (51.0?±?3.5 vs. 30.8?±?6.9?%, p?<?0.002), depressurization rate (48.2?±?3.3 vs. 34.2?±?4.6?%, p?<?0.0001) and total MV (27.7?±?7.0 vs. 24.6?±?6.9?l/min, p?<?0.02), and decreased ineffective efforts (3.5?±?5.4 vs. 20.3?±?12.4?%, p?<?0.0001) and inspiratory delay (243?±?109 vs. 461?±?181?ms, p?<?0.005).

Conclusions

An optimized set-up for helmet NIV that limits device compliance and ventilator circuit resistance as much as possible is highly effective in improving pressure support delivery and patient?Cventilator interaction.     

Transient decrease in PaCO2 and asymmetric chest wall dynamics in early progressing pneumothorax

Purpose

Diagnosis of pneumothorax (PTX) in newborn infants has been reported as late. To explore diagnostic indices for early detection of progressing PTX, and offer explanations for delayed diagnoses.

Methods

Progressing PTX was created in rabbits (2.3?±?0.5?kg, n?=?7) by injecting 1?ml/min of air into the pleural space. Hemodynamic parameters, tidal volume, EtCO₂, SpO₂, blood gas analyses and chest wall tidal displacements (TDi) on both sides of the chest were recorded.

Results

(Mean?±?SD): A decrease in SpO₂ below 90?% was detected only after 46.6?±?11.3?min in six experiments. In contrary to the expected gradual increase of CO₂, there was a prolonged transient decrease of 14.2?±?4.5?% in EtCO₂ (p?<?0.01), and a similar decrease in PaCO₂ (p?<?0.025). EtCO₂ returned back to baseline only after 55.2?±?24.7?min, and continued to rise thereafter. The decrease in CO₂ was a mirror image of the 14.6?±?5.3?% increase in tidal volume. The analysis of endotracheal flow and pressure dynamics revealed a paradoxical transient increase in the apparent compliance. Significant decrease in mean arterial blood pressure was observed after 46.2?±?40.1?min. TDi provided the most sensitive and earliest sign of PTX, decreasing on the PTX side after 16.1?±?7.2?min. The TDi progressively decreased faster and lower on the PTX side, thus enabling detection of asymmetric ventilation.

Conclusions

The counterintuitive transient prolonged decrease in CO₂ without changes in SpO₂ may explain the delay in diagnosis of PTX encountered in the clinical environment. An earlier indication of asymmetrically decreased ventilation on the affected side was achieved by monitoring the TDi.     

Positron Emission Tomography of 64Cu-DOTA-Rituximab in a Transgenic Mouse Model Expressing Human CD20 for Clinical Translation to Image NHL

Purpose

This study aims to evaluate ⁶⁴Cu-DOTA-rituximab (PETRIT) in a preclinical transgenic mouse model expressing human CD20 for potential clinical translation.

Procedures

⁶⁴Cu was chelated to DOTA-rituximab. Multiple radiolabeling, quality assurance, and imaging experiments were performed. The human CD20 antigen was expressed in B cells of transgenic mice (CD20TM). The mice groups studied were: (a) control (nude mice, n?=?3) that received 7.4?MBq/dose, (b) with pre-dose (CD20TM, n?=?6) received 2?mg/kg pre-dose of cold rituximab prior to PETRIT of 7.4?MBq/dose, and (c) without pre-dose (CD20TM, n?=?6) PETRIT alone received 7.4?MBq/dose. Small animal PET was used to image mice at various time points (0, 1, 2, 4, 24, 48, and 72?h). The OLINDA/EXM software was used to determine the human equivalent dose for individual organs.

Results

PETRIT was obtained with a specific activity of 545?±?38.91?MBq/nmole, radiochemical purity >95%, and immunoreactivity >75%. At 24?h, spleenic uptake of PETRIT%ID/g (mean?±?STD) with and without pre-dose was 1.76?±?0.43% and 16.5?±?0.45%, respectively (P value?=?0.01). Liver uptake with and without pre-dose was 0.41?±?0.51% and 0.52?±?0.17% (P value?=?0.86), respectively. The human equivalents of highest dose organs with and without pre-dose are osteogenic cells at 30.8?±?0.4???Sv/MBq and the spleen at 99?±?4???Sv/MBq, respectively.

Conclusions

PET imaging with PETRIT in huCD20 transgenic mice provided human dosimetry data for eventual applications in non-Hodgkins lymphoma patients.     

Septic cardiomyopathy: hemodynamic quantification, occurrence, and prognostic implications

Introduction

In sepsis, severe reduction of afterload may often mask cardiac impairment. By establishing the parameter ??afterload-related cardiac performance (ACP)?? we wanted to determine the extent, frequency, and prognostic relevance of septic cardiomyopathy.

Methods

Over a 12?months period, all patients of our medical intensive care ward were included into the study when they were classified as having ??septic MODS?? (sepsis score ??12 as long as APACHE II score was ??20). Hemodynamic assessments were performed using a pulmonary artery catheter.

Results

A total of 524 patients were screened, and from these 39 had septic MODS. In survivors, APACHE II score values declined from day 0 (day of diagnosis, 27.6?±?8.0) to day 4 (17.8?±?8.0), while in non-survivors, score values remained high (day 0: 31.8?±?5.7; day 4: 33.2?±?6.7; p?<?0.001). Hemodynamic measurements showed an inverse correlation of cardiac output (CO_measured) and SVR which can be described as CO?=??? ₀?×?SVR ^??1. The upper limit of 80% tolerance range of CO was defined as the ??normal?? CO values (CO_normal). The parameter ??afterload-related cardiac performance (ACP)?? was calculated as ACP (%)?=?CO_measured/CO_normal?×?100. It turned out that ACP shows a stronger correlation with APACHE II- and sepsis-score than CO, cardiac index (CI), cardiac power (CPO), or cardiac power index (CPI). Furthermore, ACP correlated with sepsis-induced myocardial damage as indicated by elevations of troponin I and significantly differed between surviving (86.9?±?1.6%) and non-surviving patients (69.2?±?1.4%; p?<?0.0001). While 75% of the surviving patients showed an ACP >60%, 38% of the non-survivors had a moderate (ACP 40?C60%) and 25% a severe impairment of cardiac function (ACP?<?40%).

Conclusion

By using the parameter ??afterload-related cardiac performance, ACP??, the impairment of cardiac function can be reliably quantified showing that septic cardiomyopathy occurs frequently and is of prognostic relevance in patients with septic MODS.     

Noninvasive Detection of Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Teratoma with an Integrin-Targeting Agent 99mTc-3PRGD2

Purpose

Since their discovery in 2006, induced pluripotent stem cells (iPSCs) have gained increasing interest for tissue regeneration and transplantation therapies. However, teratoma formation after iPSC transplantation is one of the most serious drawbacks that may limit their further clinical application. We investigated here whether human iPSC-derived teratomas could be detected by an integrin-targeting agent ^99mTc-PEG₄-E[PEG₄-c(RGDfK)]₂ (^99mTc-3PRGD2).

Methods

Human-induced pluripotent stem cells (hiPSCs) were generated and characterized. In vitro integrin α_vβ₃ expression levels of hiPSC- and hiPSC-derived teratoma cells were determined by flow cytometry. ^99mTc-3PRGD2 was prepared, and planar gamma imaging and biodistribution studies were carried out in teratoma-bearing severe combined immunodeficient (SCID) mice. Positron emission tomography (PET) imaging of teratomas with 2-deoxy-2-[¹⁸F]fluoro-d-glucose (¹⁸F-FDG) was also performed for comparison. Integrin α_vβ₃ expression in teratoma tissues was determined by immunofluorescence staining.

Results

^99mTc-3PRGD2 showed high (2.82?±?0.21 and 2.69?±?0.73%ID/g at 0.5 and 1 h pi, respectively) and specific (teratoma uptake decreased from 2.69?±?0.73 to 0.53?±?0.26%ID/g after blocking with cold 3PRGD2) uptake in teratoma tissues, and planar gamma imaging demonstrated the feasibility of noninvasively detecting the teratoma formation with ^99mTc-3PRGD2. ¹⁸F-FDG showed low teratoma uptake and thus failed to detect the teratomas. Ex vivo immunofluorescence staining validated the integrin α_vβ₃ expression in the vasculature during teratoma formation.

Conclusion

Gamma imaging with ^99mTc-3PRGD2 is a promising approach for the noninvasive monitoring of tumorigenicity after hiPSCs transplantation.     

Initial Experience with the Radiotracer Anti-1-amino-3-[18F]Fluorocyclobutane-1-Carboxylic Acid (Anti-[18F]FACBC) with PET in Renal Carcinoma

Purpose

Assessment of renal masses with conventional imaging may be challenging. Anti-1-amino-3-[¹⁸F]fluorocyclobutane-1-carboxylic acid (anti-[18F]FACBC) is a synthetic l-leucine analog with relatively little renal excretion. The present study examines anti-[¹⁸F]FACBC positron emission tomography uptake in patients with renal masses.

Procedures

Six patients with seven renal lesions were imaged dynamically for 2 h after injection of 10–10.9 mCi (370–403 MBq) anti-[¹⁸F]FACBC. Lesions were evaluated qualitatively and quantitatively and correlated with histology.

Results

Four clear cell and one Rosai–Dorfman lesion were hypo/isointense to normal cortex; two papillary lesions in the same patient were hyperintense. Mean SUV_max?±?SD at 30 min was 2.8?±?0.24 for clear cell carcinomas and 4.5?±?1.7 for papillary cell lesions. Mean SUV_max/SUV_mean ratios?±?SD of lesion to normal cortex at 30 min was 1.15?±?0.19 for the clear cell carcinomas and 2.3?±?0.84 for papillary cell.

Conclusions

In this small patient sample, relative amino acid transport compared with renal cortex is elevated in renal papillary cell carcinoma but not in clear cell carcinoma.     

Magnetomotive Optical Coherence Tomography for the Assessment of Atherosclerotic Lesions Using αvβ3 Integrin-Targeted Microspheres

Purpose

We investigated the early-stage fatty streaks/plaques detection using magnetomotive optical coherence tomography (MM-OCT) in conjunction with α_vβ₃ integrin-targeted magnetic microspheres (MSs). The targeting of functionalized MSs was investigated by perfusing ex vivo aortas from an atherosclerotic rabbit model in a custom-designed flow chamber at physiologically relevant pulsatile flow rates and pressures.

Procedures

Aortas were extracted and placed in a flow chamber. Magnetic MS contrast agents were perfused through the aortas and MM-OCT, fluorescence confocal, and bright field microscopy were performed on the ex vivo aorta specimens for localizing the MSs.

Results

The results showed a statistically significant and stronger MM-OCT signal (3.30?±?1.73 dB) from the aorta segment perfused with targeted MSs, compared with the nontargeted MSs (1.18?±?0.94 dB) and control (0.78?±?0.41 dB) aortas. In addition, there was a good co-registration of MM-OCT signals with confocal microscopy.

Conclusions

Early-stage fatty streaks/plaques have been successfully detected using MM-OCT in conjunction with α_vβ₃ integrin-targeted magnetic MSs.     

ECMO criteria for influenza A (H1N1)-associated ARDS: role of transpulmonary pressure

Purpose

To assess whether partitioning the elastance of the respiratory system (E _RS) between lung (E _L) and chest wall (E _CW) elastance in order to target values of end-inspiratory transpulmonary pressure (PPLAT_L) close to its upper physiological limit (25?cmH₂O) may optimize oxygenation allowing conventional treatment in patients with influenza A (H1N1)-associated ARDS referred for extracorporeal membrane oxygenation (ECMO).

Methods

Prospective data collection of patients with influenza A (H1N1)-associated ARDS referred for ECMO (October 2009?CJanuary 2010). Esophageal pressure was used to (a) partition respiratory mechanics between lung and chest wall, (b) titrate positive end-expiratory pressure (PEEP) to target the upper physiological limit of PPLAT_L (25?cmH₂O).

Results

Fourteen patients were referred for ECMO. In seven patients PPLAT_L was 27.2?±?1.2?cmH₂O; all these patients underwent ECMO. In the other seven patients, PPLAT_L was 16.6?±?2.9?cmH₂O. Raising PEEP (from 17.9?±?1.2 to 22.3?±?1.4?cmH₂O, P?=?0.0001) to approach the upper physiological limit of transpulmonary pressure (PPLAT_L?=?25.3?±?1.7?cm H₂O) improved oxygenation index (from 37.4?±?3.7 to 16.5?±?1.4, P?=?0.0001) allowing patients to be treated with conventional ventilation.

Conclusions

Abnormalities of chest wall mechanics may be present in some patients with influenza A (H1N1)-associated ARDS. These abnormalities may not be inferred from measurements of end-inspiratory plateau pressure of the respiratory system (PPLAT_RS). In these patients, titrating PEEP to PPLAT_RS may overestimate the incidence of hypoxemia refractory to conventional ventilation leading to inappropriate use of ECMO.     

Radiolabeled RGD Tracer Kinetics Annotates Differential αvβ3 Integrin Expression Linked to Cell Intrinsic and Vessel Expression

Purpose

The purpose of this paper is to study the association between RGD binding kinetics and α_vβ₃ integrin receptor density in the complex tumor milieu.

Procedures

We assessed α_vβ₃ in vitro and by ⁶⁸Ga-DOTA-[c(RGDfK)]₂ positron emission tomography (PET) in tumors with varying α_vβ₃.

Results

Intrinsic α_vβ₃ expression decreased in the order of M21?>>>?MDA-MB-231?>?M21L in cells. Tumor volume of distribution by PET, V _T, was significantly higher in M21 compared to isogenic M21L tumors (0.40?±?0.01 versus 0.25?±?0.02; p?<?0.01) despite similar microvessel density (MVD) likely due to higher α_vβ₃. V _T for MDA-MB-231 (0.40?±?0.04) was comparable to M21 despite lower α_vβ₃ but in keeping with the higher MVD, suggesting superior tracer distribution.

Conclusions

This study demonstrates that radioligand binding kinetics of PET data can be used to discriminate tumors with different α_vβ₃ integrin expression—a key component of the angiogenesis phenotype—in vivo.     

Feasibility and safety of transradial approach for catheter ablation of idiopathic left ventricular tachycardia

Background

The feasibility and safety of the transradial approach for catheter ablation of idiopathic left ventricular tachycardia (ILVT) have not been evaluated. The aim of this study was to investigate the feasibility and safety of transradial approach for catheter ablation in ILVT patients.

Methods

Thirty consecutive ILVT patients with negative Allen??s test undergoing catheter ablation via transradial approach were enrolled to compare the safety and efficacy with 30 other ILVT patients who previously underwent catheter ablation via transfemoral approach.

Results

Ablation was successfully performed in all patients. In the transradial group, the total procedural and the fluoroscopy time (42.8?±?6.9?min and 9.7?±?1.9?min, respectively) were significantly shorter when compared with transfemoral group (52.8?±?8.4?min and 11.5?±?2.1?min, respectively) (both P?<?0.05). The two groups were similar in the number of current applications (4.1?±?0.8 vs. 4.4?±?1.1, P?>?0.05), the power energy (47.3?±?7.3 vs. 49.7?±?6.9?W, P?>?0.05), and the total duration of current application (110.3?±?15.6 vs. 112.3?±?16.5?s, P?>?0.05), respectively. The duration of hospitalization in transradial group was shorter than that in transfemoral group (4.1?±?0.9 vs. 5.8?±?1.1?days, P?<?0.05). During follow-up, there was no recurrence of tachycardia in all patients. One patient in transfemoral group developed access site complications while none occurred in the transradial group.

Conclusions

The transradial approach is feasible and safe for catheter ablation of ILVT.     

Adverse effects of permanent atrial fibrillation on heart failure in patients with preserved left ventricular function and chronic right apical pacing for complete heart block

Background

The impact of atrial fibrillation (AF) on heart failure (HF) was evaluated in patients with preserved left ventricular (LV) function and long-term right ventricular (RV) pacing for complete heart block.

Methods

Clinical, echocardiographic, and laboratory parameters of HF were assessed in 35 patients with established AF who had undergone ablation of the atrioventricular node and pacemaker implantation (Group A) and 31 patients who received dual-chamber pacing for spontaneous complete heart block (Group B).

Results

During a follow-up period of 12.7?±?7.5?years, New York Heart Association (NYHA) functional class increased from 1.3?±?0.5 to 2.1?±?0.6 (p?p?p?p?=?0,21) in Group B. At the end of follow-up, markers of LV function were moderately depressed in Group A compared with those in Group B: NYHA class 2.1?±?0.6 versus 1.6?±?0.7, p?=?0.001; LVEF 53.0?±?8.2 versus 56.9?±?7.0?%, p?p?p?10?%, increasing NYHA class ≥1, and NT-proBNP levels >1,000?pg/ml.

Conclusions

Permanent AF was associated with adverse effects on LV function and symptoms of HF in patients with long-term RV pacing for complete heart block, and appears to play an important role in the development of HF in this specific patient cohort.     

Longitudinal heterogeneity of coronary artery distensibility in plaques related to acute coronary syndrome

Background

How coronary distensibility contributes to stable or unstable clinical manifestations remains obscure. We postulated that the heterogeneous plaque distensibility is associated with unstable clinical presentations in patients with acute coronary syndrome (ACS).

Methods and results

Seventeen and 19 ACS-related and -unrelated lesions, respectively, were visualized using intravascular ultrasound imaging with simultaneous intracoronary pressure recording. Systolic and diastolic lumen cross-sectional areas were measured at the lesion site and at five evenly spaced sites between the proximal and distal reference sites. The coronary distensibility index and stiffness index β were calculated for each site and averaged for each coronary segment. Maximal distensibility index, standard deviation and the difference between maximal and minimal distensibility indices within each segment were significantly higher in the ACS-related than -unrelated plaques (5.6?±?2.3 vs. 3.7?±?1.8, p?p?p?p?=?0.022) than that in ACS-unrelated plaques.

Conclusions

Coronary artery distensibility is longitudinally more heterogeneous in ACS-related than-unrelated plaques, especially between the lesion and the immediate proximal site.     

Effect of transcatheter aortic valve implantation on the ascending aorta’s elasticity

Background

The elastic properties of the ascending aorta were studied before and 1?week after transcatheter aortic valve implantation (TAVI). Previous studies have shown that the distensibility of the ascending aorta was decreased in the early post-operative period after aortic valve replacement. Aortic stiffness is a major moderator of arterio-ventricular coupling and an independent predictor of cardiovascular risk and mortality. We evaluated the effect of TAVI on the elastic properties of the ascending aorta in the early post-operative period.

Methods

Aortic distensibility (AD) and Aortic Stiffness Index (ASI) were evaluated using echocardiographic techniques and brachial artery pressure obtained by sphygmomanometry 2–3?days before and 7–8?days after TAVI.

Results

A total of 30 patients (14 males) were studied with a mean age of 79.9?±?4.7?years and aortic valve area before TAVI of 0.61?±?0.16?cm². Mean arterial pressure decreased significantly after TAVI (from 89.6?±?8.9?mmHg to 83.3?±?10.9?mmHg, p?=?0.004). AD did not change significantly after TAVI (pre: 1.89?±?1.11?cm²/(dynes?×?10⁶), post: 2.05?±?1.50?cm²/(dynes?×?10⁶); p?=?0.813). ASI also remained unchanged (pre: 11.4?±?6.5, post: 15.6?±?14.9; p?=?0.349).

Conclusions

The elastic properties of the ascending aorta did not change significantly in the early post-procedural period after TAVI. This may in part be attributable to the less invasive procedure (compared to aortic valve replacement) which has no effect on vasa vasorum flow.     

Fully Automated Radiosynthesis of 2-[18F]Fludarabine for PET Imaging of Low-Grade Lymphoma

Purpose

An efficient and fully automated radiosynthesis of 2-[¹⁸F]fluoro-9-β-d-arabinofuranosyl-adenine (2-[¹⁸F]fludarabine, [¹⁸F]-5) based on a GE TRACERlab? FX-FN module has been developed.

Procedures

A 2-nitro purine derivative 3 was developed as precursor for labeling with fluorine-18. The radiosynthesis of [¹⁸F]-5 was performed in two steps in a single reactor with an intermediary purification on Sep-Pak® silica which involved the addition of a three-way valve on the original module. After hydrolysis, [¹⁸F]-5 was purified by semi-preparative high-pressure liquid chromatography (HPLC) and a quality control was established.

Results

The labeling precursor 3 was obtained in 45 % overall yield. Nucleophilic substitution with K¹⁸F/K_2.2.2 afforded protected 2-[¹⁸F]fludarabine ([¹⁸F]-4) in 73?±?4 % , radiochemical yield (decay corrected to the end of bombardment (EOB)) and based on the initial [¹⁸F]F^? activity. An aqueous ammonia/methanol solution was used for the deprotection reaction and gave the desired [¹⁸F]-5 in 67?±?3 % yield after 20 min at 70 °C based on HPLC profile.

Conclusions

The process afforded pure 2-[¹⁸F]fludarabine in 48?±?3 % yield (decay corrected to the EOB) in 85 min, with a specific activity of 310?±?72 GBq/μmol at the end of synthesis (EOS) and a radiochemical purity up to 99 %.     

Does femoral venous pressure measurement correlate well with intrabladder pressure measurement? A multicenter observational trial

Purpose

To investigate if femoral venous pressure (FVP) measurement can be used as a surrogate measure for intra-abdominal pressure (IAP) via the bladder.

Methods

This was a prospective, multicenter observational study. IAP and FVP were simultaneously measured in 149 patients. The effect of BMI on IAP was investigated.

Results

The incidences of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) were 58 and 7% respectively. The mean APACHE II score was 22?±?10, SAPS 2 score 42?±?20, and SOFA score 9?±?4. The mean IAP was 11.2?±?4.5?mmHg versus 12.7?±?4.7?mmHg for FVP. The bias and precision for all measurements were ?1.5 and 3.6?mmHg respectively with the lower and upper limits of agreement being ?8.6 and 5.7. When IAP was above 20?mmHg, the bias between IAP and FVP was 0.7 with a precision of 2.0?mmHg (lower and upper limits of agreement ?3 and 4.6 respectively). Excluding those with ACS, according to the receiver operating curve analysis FVP?=?11.5?mmHg predicted IAH with a sensitivity and specificity of 84.8 and 67.0% (AUC of 0.83 (95% CI 0.81?C0.86) with P?P?2 was 10.6?±?4.0?mmHg versus 13.8?±?3.8?mmHg in patients with a BMI????30?kg/m² (P?Conclusions FVP cannot be used as a surrogate measure of IAP unless IAP is above 20?mmHg.