Hypoxia-Targeting Fluorescent Nanobodies for Optical Molecular Imaging of Pre-Invasive Breast Cancer

Purpose

The aim of this work was to develop a CAIX-specific nanobody conjugated to IRDye800CW for molecular imaging of pre-invasive breast cancer.

Procedures

CAIX-specific nanobodies were selected using a modified phage display technology, conjugated site-specifically to IRDye800CW and evaluated in a xenograft breast cancer mouse model using ductal carcinoma in situ cells (DCIS).

Results

Specific anti-CAIX nanobodies were obtained. Administration of a CAIX-specific nanobody into mice with DCIS xenografts overexpressing CAIX showed after 2 h a mean tumor-to-normal tissue ratio (TNR) of 4.3?±?0.6, compared to a TNR of 1.4?±?0.2 in mice injected with the negative control nanobody R2-IR. In DCIS mice, a TNR of 1.8?±?0.1 was obtained. Biodistribution studies demonstrated an uptake of 14.0?±?1.1 %I.D./g in DCIS?+?CAIX tumors, 4.6?±?0.8 %I.D./g in DCIS tumors, while 2.0?±?0.2 %I.D./g was obtained with R2-IR.

Conclusions

These results demonstrate the successful generation of a CAIX-specific nanobody-IRDye800CW conjugate that can be used for rapid imaging of (pre-)invasive breast cancer.

     

High Vascular Delivery of EGF, but Low Receptor Binding Rate Is Observed in AsPC-1 Tumors as Compared to Normal Pancreas

Purpose

Cellular receptor targeted imaging agents present the potential to target extracellular molecular expression in cancerous lesions; however, the image contrast in vivo does not reflect the magnitude of overexpression expected from in vitro data. Here, the in vivo delivery and binding kinetics of epidermal growth factor receptor (EGFR) was determined for normal pancreas and AsPC-1 orthotopic pancreatic tumors known to overexpress EGFR.

Procedures

EGFR in orthotopic xenograft AsPC-1 tumors was targeted with epidermal growth factor (EGF) conjugated with IRDye800CW. The transfer rate constants (k _e, K ₁₂, k ₂₁, k ₂₃, and k ₃₂) associated with a three-compartment model describing the vascular delivery, leakage rate and binding of targeted agents were determined experimentally. The plasma excretion rate, k _e, was determined from extracted blood plasma samples. K ₁₂, k ₂₁, and k ₃₂ were determined from ex vivo tissue washing studies at time points ??24?h. The measured in vivo uptake of IRDye800CW-EGF and a non-targeted tracer dye, IRDye700DX-carboxylate, injected simultaneously was used to determined k ₂₃.

Results

The vascular exchange of IRDye800CW-EGF in the orthotopic tumor (K ₁₂ and k ₂₁) was higher than in the AsPC-1 tumor as compared to normal pancreas, suggesting that more targeted agent can be taken up in tumor tissue. However, the cellular associated (binding) rate constant (k ₂₃) was slightly lower for AsPC-1 pancreatic tumor (4.1?×?10^?4?s^?1) than the normal pancreas (5.5?×?10^?4?s^?1), implying that less binding is occurring.

Conclusions

Higher vascular delivery but low cellular association in the AsPC-1 tumor compared to the normal pancreas may be indicative of low receptor density due to low cellular content. This attribute of the AsPC-1 tumor may indicate one contributing cause of the difficulty in treating pancreatic tumors with cellular targeted agents.     

Near-Infrared Fluorescence Molecular Imaging of Ductal Carcinoma In Situ with CD44v6-Specific Antibodies in Mice: A Preclinical Study

Purpose

The purpose of this study was to develop a molecular imaging technique using tracers specific for ductal carcinoma in situ (DCIS) to improve visualization and localization of DCIS during surgery. As CD44v6 is frequently expressed in DCIS, we used near-infrared fluorescently labeled CD44v6-targeting antibodies for detection of DCIS.

Procedure

Mice bearing orthotopically transplanted CD44v6-positive MCF10DCIS DCIS-like tumors and CD44v6-negative MDA-MB-231 control tumors were intravenously injected with IRDye800CW conjugated to CD44v6-specific antibodies or control IgGs. Noninvasive imaging was performed for 8 days postinjection, followed by intraoperative imaging. Antibody accumulation and intratumor distribution were examined.

Results

Maximum accumulation of CD44v6-specific antibodies was obtained 24 h postinjection. Maximum tumor-to-background ratio for MCF10DCIS tumors was 4.5?±?0.2, compared to 1.4?±?0.1 (control tumors, p?=?0.006), and 1.7?±?0.1 (control IgG, p?=?0.014), for 8 days postinjection. Ex vivo, tumor-to-background ratios were comparable to those obtained by intraoperative imaging.

Conclusions

We show the applicability of noninvasive and intraoperative optical imaging of DCIS-like lesions in vivo using CD44v6-specific antibodies.     

[68Ga]-Albumin-PET in the Monitoring of Left Ventricular Function in Murine Models of Ischemic and Dilated Cardiomyopathy: Comparison with Cardiac MRI

Purpose

The purpose of this study is to evaluate left ventricular functional parameters in healthy mice and in different murine models of cardiomyopathy with the novel blood pool (BP) positron emission tomography (PET) tracer [⁶⁸Ga]-albumin.

Procedures

ECG-gated microPET examinations were obtained in healthy mice, and mice with dilative (DCM) and ischemic cardiomyopathy (ICM) using the novel BP tracer [⁶⁸Ga]-albumin (Alb_BP), as well as [¹⁸F]-FDG microPET. Cine-magnetic resonance imaging (MRI) examination performed on a clinical 1.5-T MRI provided the reference standard measurements.

Results

When considering the combined group of healthy controls, DCM and ICM Alb_BP-PET significantly overestimated the magnitudes of EDV (Alb_BP, 181?±?86 μl; cine-MRI, 125?±?80 μl; P?<?0.001) and ESV (Alb_BP, 136?±?92 μl; cine-MRI, 96?±?77 μl; P?<?0.001), whereas the EF (Alb_BP, 31?±?16 %; cine-MRI, 33?±?21 %; P?=?0.910) matched closely to cine-MRI results, as did findings with [¹⁸F]-FDG. High correlations were found between the measured cardiac parameters (EDV: R?=?0.978, ESV: R?=?0.989, and LVEF: R?=?0.992).

Conclusions

Measuring left ventricular function in mice with [⁶⁸Ga]-albumin BP PET is feasible and showed a high correlation compared to cine-MRI, which was used as a reference standard.     

Pilot Study of a Novel 18F-labeled FSHR Probe for Tumor Imaging

Purpose

Follicle-stimulating hormone receptor (FSHR) is overexpressed in primary and metastatic tumor. Molecular imaging of FSHR is beneficial for prognosis and therapy of cancer. FSHβ(33–53) (YTRDLVYKDPARPKIQKTCTF), denoted as FSH1, is a FSHR antagonist. In the present study, maleimide-NOTA conjugate of FSH1 (NOTA-MAL-FSH1) was designed and labeled with [¹⁸F] aluminum fluoride. The resulting tracer, ¹⁸F-Al-NOTA-MAL-FSH1, was preliminarily evaluated in PET imaging of FSHR-positive tumor.

Procedures

NOTA-MAL-FSH1 was synthesized and radiolabeled with Al¹⁸F complex. The tumor-targeting potential and pharmacokinetic profile of the ¹⁸F-labeled compound were evaluated in vitro and in vivo using a PC3 human prostate tumor model.

Results

¹⁸F-Al-NOTA-MAL-FSH1 can be efficiently produced within 30 min with a non-decay-corrected yield of 48.6?±?2.1 % and a radiochemical purity of more than 95 %. The specific activity was at least 30 GBq/μmol. The radiotracer was stable in phosphate-buffered saline and human serum for at least 2 h. The IC₅₀ values of displacement ¹⁸F-Al-NOTA-MAL-FSH1 with FSH1 were 252?±?1.12 nM. The PC3 human prostate tumor xenografts were clearly visible with high contrast after injection of ¹⁸F-Al-NOTA-MAL-FSH1 via microPET. At 30, 60 and 120 min postinjection, the tumor uptakes were 2.98?±?0.29 % injected dose (ID)/g, 2.53?±?0.20 %ID/g and 1.36?±?0.12 %ID/g, respectively. Dynamic PET scanning showed that tumor uptake reached a plateau by about 6 min. Heart peaked earlier and then cleared quickly. Biodistribution studies confirmed that the normal organs except kidney uptakes were all below 1 %ID/g at 1 h p.i. The tumor-to-blood and tumor-to-muscle ratio at 10 min, 0.5, 1, and 2 h after injection were 1.64?±?0.36, 2.97?±?0.40, 9.31?±?1.06, and 13.59?±?2.33 and 7.05?±?1.10, 10.10?±?1.48, 16.17?±?3.29, and 30.88?±?4.67, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. FSHR-binding specificity was also demonstrated by reduced tumor uptake of ¹⁸F-Al-NOTA-MAL-FSH1 after coinjection with an excess of unlabeled FSH1 peptide.

Conclusion

NOTA-MAL-FSH1 could be labeled rapidly and efficiently with ¹⁸F using one step method. Favorable preclinical data suggest that ¹⁸F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo.     

In Vivo Imaging of Sentinel Nodes Using Fluorescent Silica Nanoparticles in Living Mice

Purpose

We examine the feasibility of fluorescent imaging system for sentinel lymph node detection by using functionalized silica nanoparticles.

Materials and Methods

We developed a functionalized RITC-SiO₂ nanoparticles containing fluorescent dye, C₂₈H₃₁N₂O₃Cl (rhodamine B isothiocyanate) inside, and subsequently synthesized ⁶⁸Ga-NOTA-RITC-SiO₂ nanoparticles.

Results

At 5 min after RITC-doped silica nanoparticles injection, fluorescent signals were shown in both right axillary lymph node (ALN) and injection site of living mice. Fluorescent signals were also observed at these locations in a biodistribution study. In addition, fluorescence was detected in frozen ALN sections microscopically. The percentages of doses injected per gram of tissue of axillary and brachial lymph nodes near footpad treated with ⁶⁸Ga-NOTA-RITC-SiO₂ nanoparticles were 308.3?±?3.4 and 41.5?±?6.1, respectively. Little ⁶⁸Ga radioactivity was found in other organs.

Conclusion

Our data provide strong evidence that functionalized silica nanoparticles has a promising potential as organic lymphatic tracer in biomedical imaging such as pre- and intraoperative surgical guidance.     

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.     

Cardiovascular magnetic resonance in pregnancy: Insights from the cardiac hemodynamic imaging and remodeling in pregnancy (CHIRP) study

Background

Cardiovascular disease in pregnancy is the leading cause of maternal mortality in North America. Although transthoracic echocardiography (TTE) is the most widely used imaging modality for the assessment of cardiovascular function during pregnancy, little is known on the role of cardiovascular magnetic resonance (CMR). The objective of the Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) study was to compare TTE and CMR in the non-invasive assessment of maternal cardiac remodeling during the peripartum period.

Methods

Between 2010–2012, healthy pregnant women aged 18 to 35 years were prospectively enrolled. All women underwent TTE and CMR during the third trimester and at least 3 months postpartum (surrogate for non-pregnant state).

Results

The study population included a total of 34 women (mean age 29?±?3 years). During the third trimester, TTE and CMR demonstrated an increase in left ventricular end-diastolic volume from 95?±?11 mL to 115?±?14 mL and 98?±?6 mL to 125?±?5 mL, respectively (p?<?0.05). By TTE and CMR, there was also an increase in left ventricular (LV) mass during pregnancy from 111?±?10 g to 163?±?11 g and 121?±?5 g to 179?±?5 g, respectively (p?<?0.05). Although there was good correlation between both imaging modalities for LV mass, stroke volume, and cardiac output, the values were consistently underestimated by TTE.

Conclusion

This CMR study provides reference values for cardiac indices during normal pregnancy and the postpartum state.     

Radiosynthesis of [124I]Iodometomidate and Biological Evaluation Using Small-Animal PET

Purpose

The application of radiolabelled inhibitors of cytochrome P450 enzymes is a novel approach for molecular imaging of adrenocortical masses to detect adrenal tumours. One potential tracer is radiolabelled iodometomidate (IMTO) with a common option for scintigraphic diagnosis and therapeutic applications. The aim of this study was to radiolabel iodometomidate with the positron-emitting radionuclide iodine-124 (¹²⁴I) for the investigation of the biological behaviour and pharmacokinetics with positron emission tomography (PET).

Procedures

[¹²⁴I]IMTO has been synthesized by oxidative radioiodo-destannylation, purified via semi-preparative HPLC and formulated in acetate-buffered saline, which contained ascorbic acid and ethanol to avoid radiolytic decomposition. Biological evaluation was performed in rats which received 5.5?±?0.7 MBq [¹²⁴I]IMTO in vivo. The radioactivity distribution (n?=?3) has been dynamically imaged from 0–120 min after intravenous (i.v.) injection by small-animal PET. Regions of interest have been defined manually in the reconstructed PET images, and the activity concentration was expressed as percent injected dose per gram tissue (%ID/g).

Results

[¹²⁴I]IMTO was prepared with a radiochemical yield of 83?±?5 % (n?=?3) and a radiochemical purity of >97 %. The final formulation of [¹²⁴I]IMTO was stable for up to 48 h at room temperature. Two hours after i.v. administration in rats, radioactivity concentration in the adrenal glands were 2.1?±?0.3 %ID/g, which was sufficient to achieve highest-contrast adrenal PET images.

Conclusions

In the present study, the biological characteristics of radioiodinated metomidate were evaluated. [¹²⁴I]IMTO appears as an attractive PET tracer for imaging of adrenals.     

Dimeric [68Ga]DOTA-RGD Peptide Targeting αvβ3 Integrin Reveals Extracellular Matrix Alterations after Myocardial Infarction

Purpose

We evaluated a dimeric RGD-peptide, [⁶⁸Ga]DOTA-E-[c(RGDfK)]₂, for positron emission tomography (PET) imaging of myocardial integrin expression associated with extracellular matrix remodeling after myocardial infarction (MI) in rat.

Procedures

Male Sprague-Dawley rats were studied at 7 days and 4 weeks after MI induced by permanent ligation of the left coronary artery and compared with sham-operated controls.

Results

In vivo imaging revealed higher tracer uptake in the infarcted area than in the remote non-infarcted myocardium of the same rats both at 7 days (MI/remote ratio, 2.25?±?0.24) and 4 weeks (MI/remote ratio, 2.13?±?0.37) post-MI. Compared with sham-operated rats, tracer uptake was higher also in the remote, non-infarcted myocardium of MI rats both at 7 days and 4 weeks where it coincided with an increased interstitial fibrosis. Standardized uptake values correlated well with the results of tracer kinetic modeling. Autoradiography confirmed the imaging results showing 5.1 times higher tracer uptake in the infarcted than remote area. Tracer uptake correlated with the amount of β₃ integrin subunits in the infarcted area.

Conclusions

Our results show that integrin-targeting [⁶⁸Ga]DOTA-E-[c(RGDfK)]₂ is a potential tracer for monitoring of myocardial extracellular matrix remodeling after MI using PET.     

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.     

Direct, Quantitative, and Noninvasive Imaging of the Transport of Active Agents Through Intact Brain with Positron Emission Tomography

Purpose

Our goal was to use positron emission tomography (PET) to analyze the movement of radiolabeled agents in tissue to enable direct measurement of drug delivery to the brain.

Procedures

Various ¹¹C- and ¹⁸?F-labeled compounds were delivered directly to an agarose phantom or rat striatum. Concentration profiles were extracted for analysis and fitted to diffusion models.

Results

Diffusion coefficients ranged from 0.075?±?0.0026 mm²/min ([¹⁸?F]fluoride ion, 18 Da) to 0.0016?±?0.0018 mm²/min ([¹⁸?F]NPB4-avidin, 68 kDa) and matched well with predictions based on molecular weight (R ²?=?0.965). The tortuosity of the brain extracellular space was estimated to be 1.56, with the tissue clearance halftime of each tracer in the brain varying from 19 to 41 min.

Conclusions

PET is an effective modality to directly quantify the movement of locally delivered drugs or drug carriers. This continuous, noninvasive assessment of delivery will aid the design of better drug delivery methods.     

Dose-Dependent Uptake of 3′-deoxy-3′-[18 F]Fluorothymidine by the Bowel after Total-Body Irradiation

Purpose

The aim of this study is to non-invasively assess early, irradiation-induced normal tissue alterations via metabolic imaging with 3′-deoxy-3′-[¹⁸?F]fluorothymidine ([¹⁸?F]FLT).

Procedures

Twenty-nine male C57BL/6 mice were investigated by [¹⁸?F]FLT positron emission tomography for 7 days after total body irradiation (1, 4, and 8 Gy) versus ‘sham’ irradiation (0 Gy). Target/background ratios were determined. The imaging results were validated by histology and immunohistochemistry (Thymidine kinase 1, Ki-67).

Results

[¹⁸?F]FLT demonstrated a dose-dependent intestinal accumulation post irradiation. Mean target/background ratio (±standard error) 0 Gy: 1.4 (0.2), 1 Gy: 1.7 (0.1), 4 Gy: 3.1 (0.3), 8 Gy: 4.2 (0.6). Receiver operating characteristic analysis (area under the curve, p value): 0 vs. 1 Gy: 0.81, 0.049; 0 vs. 4 Gy: 1.0, 0.0016; and 0 vs. 8 Gy: 1.0, 0.0020. Immunohistochemistry confirmed the results.

Conclusions

[¹⁸?F]FLT seems to provide dose-dependent information on radiation-induced proliferation in the bowel. This opens the perspective for monitoring therapy-related side-effects as well as assessing, e.g., radiation accident victims.     

Anorexia nervosa: Essstörung mit Folgen

Introduction

Anorexia nervosa (AN) is a psychiatric disorder and often associated with osteopenia or osteoporosis. The reason for bone loss in AN is still unknown but a multifactorial genesis is suspected. The purpose of this study was to understand the mechanisms involved in bone loss in AN.

Methods

We prospectively measured bone mineral density by dual x-ray absorptiometry in 20 women with AN (mean? age ±? SD, 22.9?±?4.3 years) and 20 healthy age-matched controls.

Results

Bone mineral density was significantly reduced in the spine (AN, 0.99?±?0.14 g/cm² vs. controls, 1.20?±?0.12 g/cm², p?<?0.0001) and hips (AN, 0.86?±?0.13 g/cm² vs. controls, 1.06?±?0.11 g/cm²; p?<?0.0001) in all patients with AN compared with controls.

Conclusions

Bone mineral density is significantly reduced in patients with AN. Long-term influences on bone mineral density as well as on peak bone mass are expected in these patients.     

Syntheses and Radiosyntheses of Two Carbon-11 Labeled Potent and Selective Radioligands for Imaging Vesicular Acetylcholine Transporter

Purpose

The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. The syntheses and C-11 labeling of two potent enantiopure VAChT inhibitors are reported here.

Procedures

Two VAChT inhibitors, (±)-2 and (±)-6, were successfully synthesized. A chiral HPLC column was used to resolve the enantiomers from each corresponding racemic mixture for in vitro characterization. The radiosyntheses of (?)-[¹¹C]2 and (?)-[¹¹C]6 from the corresponding desmethyl phenol precursor was accomplished using [¹¹C]methyl iodide or [¹¹C]methyl triflate, respectively.

Results

The synthesis of (?)-[¹¹C]2 was accomplished with 40–50 % radiochemical yield (decay-corrected), SA?>?480 GBq/μmol (EOB), and radiochemical purity >99 %. Synthesis of (?)-[¹¹C]6 was accomplished with 5–10 % yield, SA?>?140 GBq/μmol (EOB), and radiochemical purity >97 %. The radiosynthesis and dose formulation of each tracer was completed in 55–60 min.

Conclusions

Two potent enantiopure VAChT ligands were synthesized and ¹¹C-labeled with good radiochemical yield and specific activity.     

A High-Affinity Near-Infrared Fluorescent Probe to Target Bombesin Receptors

Purpose

This study aimed to create new optical surgical navigation NIRF probes for prostate and breast cancers.

Procedures

IR800-linker-QWAVGHLM-NH₂ with linker = GSG, GGG, and G-Abz4 were synthesized and characterized. IC₅₀ for bombesin receptors (BBN-R) in PC-3 prostate and T47D breast cancer cells, fluorescence microscopy in PC-3 cells, and NIRF imaging in mice PC-3 tumor xenografts were studied.

Results

GGG, GSG, and G-Abz4 derivatives had IC₅₀ (nM) for BBN-R+ PC-3 cells?=?187?±?31, 56?±?5, and 2.6?±?0.2 and T47D cells?=?383?±?1, 57.4?±?1.2, and 3.1?±?1.1, respectively. By microscopy the Abz4 derivative showed the highest uptake, was competed with by BBN, and had little to no binding to BBN-R? cells. In NIRF imaging the G-Abz4 probe was brighter than GGG probe in BBN-R+ tissues in vivo and tissues, tumors, and tumor slices ex vivo. Uptake could be partially blocked in BBN-R+ pancreas but not visibly in tumor.

Conclusions

Linker choice can dominate peptidic BBN-R binding. The G-Abz4 linker yields a higher affinity and specific BBN-R binder in this series of molecules.     

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.     

Assessment of Airway Distribution of Transnasal Solutions in Mice by PET/CT Imaging

Purpose

Transnasal administration is one of the most common routes for allergen challenge in mouse models of airway diseases. Although this technique is widely used, neither the amount of allergen that reaches the lung nor its airway distribution has been well established. We used positron emission tomography (PET) and computed tomography (CT) to examine the anatomical distribution of a solution containing a tracer immediately after transnasal delivery and to determine the possible influence of age and administered volume.

Procedures

Forty-six female BALB/c mice were divided into three groups according to instillation volume and age: (A) 15 μl, 8–10 weeks old (N?=?10), (B) 30 μl, 8–10 weeks old (N?=?20), and (C) 30 μl, 32 weeks old (N?=?16). Anesthetized animals underwent a dynamic scan in a dedicated small-animal PET scanner immediately after transnasal administration of a solution containing ¹⁸FDG. Regions of interest were used to obtain quantitative data. Animals were also imaged with a small-animal CT scanner to obtain complementary anatomical information.

Results

Mean?±?SD (5.69?±?4.51%) of the solution administered reached the lungs in group A, 41.84?±?8.03% in group B, and 36.65?±?16.15% in group C. A comparable percentage was delivered to the left and right lungs in all the groups. Analysis of variance revealed a significant difference between the groups in the proportion of the solution that reached the lungs depending on the injection volume (P?Conclusions In this first report on quantitative imaging by PET and CT in small animals, we confirmed the suitability of the transnasal route with an instilled volume of 30 μl delivering fluids into the lower airways, although only about 40% of the dose reaches the lungs.     

Apparent diffusion coefficient quantification as an early imaging biomarker of response and predictor of survival following yttrium-90 radioembolization for unresectable infiltrative hepatocellular carcinoma with portal vein thrombosis

Purpose

To investigate early diffusion-weighted imaging (DWI) at 30-days post-yttrium-90 (Y-90) radioembolization as a predictor of treatment response and survival in unresectable infiltrative hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT).

Materials and methods

In a prospective study, 18 consecutive patients with unresectable infiltrative HCC and PVT underwent Y-90 therapy. MR imaging was obtained pre Y-90, and at 1 and 3 months post-therapy with DWI fat-suppressed tri-directional diffusion gradient (b = 50, 400, 800 s/mm²). Response was evaluated using target mRECIST and EASL. Relative change in apparent diffusion coefficient (ADC) value of tumors was evaluated. Statistical analysis using receiver operator characteristic curves was performed. Paired t test and Pearson correlation coefficient (r) were used to assess intra- and inter-observer variability. Survival analysis was performed using Kaplan-Meier estimation and log-rank test.

Results

Mean ADC values of all HCC’s at baseline and at 30-days post-Y90 therapy was 0.86 × 10^?3 and 1.17×10^?3 mm²/s, respectively (p < 0.001). Tumors with objective response by mRECIST had significantly increased ADC value when compared to “non-responders” (1.27 vs. 1.05×10^?3 mm²/s, p = 0.002). A >30% increase in ADC value at 30-days was found to be at least 90% sensitive in predicting response at 90 days. A >30% increase in ADC value at 30-days predicted significantly prolonged survival.

Conclusion

A 30% increase in ADC value at 30-days measured post Y90 is a reproducible early imaging response biomarker predicting tumor response and prolonged survival following Y-90 therapy in infiltrative HCC with PVT.     

Patterns of physical activity participation across the cancer trajectory in colorectal cancer survivors

Purpose

The purpose of the present study was to explore the participation in physical activity (PA) by colorectal cancer survivors across cancer trajectories and based on selected demographic and medical variables.

Methods

A total of 431 participants were surveyed individually at the Shinchon Severance Hospital, Seoul, Korea, to determine their PA levels before diagnosis, during treatment and after completion of cancer treatment.

Results

Percentage of survivors meeting American College of Sports Medicine guideline significantly reduced from 27 % before diagnosis to 10 % during treatment due to reduced strenuous intensity PA (28.8?±?106.2 vs 11.8?±?95.9 min, p?=?0.042), while total PA and mild intensity PA did not change. Total (187.2?±?257.7 vs. 282.6?±?282.0 min, p?<?0.001) and mild (99.1?±?191.5 vs. 175.1?±?231.2 min, p?<?0.001) intensity PA significantly increased after the completion of treatments compared with their PA level before diagnosis. Further analyses showed that age (more vs. equal or less than 60 years) and chemotherapy (chemotherapy vs. no chemotherapy) significantly influenced the level of physical activity (p?=?0.004). Survivors who were older or received chemotherapy increased their total PA and mild intensity PA after the completion of treatment more than those who did not receive chemotherapy.

Conclusions

The level and the pattern of physical activity by colorectal cancer survivors differed across cancer trajectories, which were significantly influenced by age and adjuvant chemotherapy.