Andrew R. Hsu

PET/MRI Dual-Modality Tumor Imaging Using Arginine-Glycine-Aspartic (RGD)–Conjugated Radiolabeled Iron Oxide Nanoparticles

The purpose of this study was to develop a bifunctional iron oxide (IO) nanoparticle probe for PET and MRI scans of tumor integrin αvβ3 expression. Methods: Polyaspartic acid (PASP)–coated IO (PASP-IO) nanoparticles were synthesized using a coprecipitation method, and particle size and magnetic properties were measured. A phantom study was used to assess the efficacy of PASP-IO as a T2-weighted MRI contrast agent. PASP-IO nanoparticles with surface amino groups were coupled to cyclic arginine-glycine-aspartic (RGD) peptides for integrin αvβ3 targeting and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″,-tetraacetic acid (DOTA) chelators for PET after labeling with 64Cu. IO nanoparticle conjugates were further tested in vitro and in vivo to determine receptor targeting efficacy and feasibility for dual PET/MRI. Results: PASP-IO nanoparticles made by single-step reaction have a core size of 5 nm with a hydrodynamic diameter of 45 ± 10 nm. The saturation magnetization of PASP-IO nanoparticles is about 117 emu/g of iron, and the measured r2 and r2* are 105.5 and 165.5 (s·mM)−1, respectively. A displacement competitive binding assay indicates that DOTA-IO-RGD conjugates bound specifically to integrin αvβ3 in vitro. Both small-animal PET and T2-weighted MRI show integrin-specific delivery of conjugated RGD-PASP-IO nanoparticles and prominent reticuloendothelial system uptake. Conclusion: We have successfully developed an IO-based nanoprobe for simultaneous dual PET and MRI of tumor integrin expression. The success of this bifunctional imaging approach may allow for earlier tumor detection with a high degree of accuracy and provide further insight into the molecular mechanisms of cancer.

Ultrasmall c(RGDyK)-Coated Fe3O4 Nanoparticles and Their Specific Targeting to Integrin αvβ3-Rich Tumor Cells

We report a direct synthesis of ultrasmall c(RGDyK) peptide-coated Fe3O4 NPs (<10 nm in hydrodynamic diameter) and demonstrate their in vivo tumor-specific targeting capability. The Fe3O4 NPs are synthesized by thermal decomposition of iron pentacarbonyl in the presence of 4-methylcatechol (4-MC), and the peptide is coupled to the nanoparticles through 4-MC via Mannich reaction. The c(RGDyK)-MC-Fe3O4 NPs have an overall diameter of approximately 8.4 nm and are stable in physiological conditions. When administrated intravenously, these c(RGDyK)-MC-Fe3O4 NPs accumulate preferentially in the integrin alphavbeta3-rich tumor area, which are readily tracked by MRI.

Biceps tenotomy versus tenodesis: a review of clinical outcomes and biomechanical results

HYPOTHESIS There are significant differences in incidence of cosmetic deformity and load to tendon failure between biceps tenotomy versus tenodesis for the treatment of long head of the biceps brachii (LHB) tendon lesions which are supported by the evidence-based strengths and weaknesses of each procedure in the literature. MATERIALS AND METHODS PubMed, Embase, and Cochrane databases were searched for eligible clinical and biomechanical articles relating to biceps tenotomy or tenodesis from 1966 to 2010. Keywords were biceps tenotomy, biceps tenodesis, long head of the biceps brachii, and Popeye sign. All relevant studies were included based on study objectives, and excluded studies consisted of abstracts, case reports, letters to the editor, and articles without outcome measures. RESULTS All articles reviewed were of level IV evidence. Combined results from reviewed papers on the differences between LHB tenotomy vs tenodesis demonstrated a higher incidence of cosmetic deformity in patients treated with biceps tenotomy. Complications were similar for each treatment, with a higher likelihood of bicipital pain associated with tenodesis. Lack of high levels of evidence from prospective randomized trials limits our ability to recommend one technique over another. DISCUSSION This review demonstrated a higher incidence of cosmetic deformity in patients treated with biceps tenotomy compared with tenodesis, with an associated lower load to tendon failure. However, there was no consensus in the literature regarding the use of tenotomy vs. tenodesis for LHB tendon lesions due to variable results and methodology of published studies. Individual patient factors and needs should guide surgeons on whether to use tenotomy or tenodesis. CONCLUSIONS There is a great need for future studies with high levels of evidence, control, randomization, and power, with well-defined study variables, to compare biceps tenotomy and tenodesis for the treatment of LHB tendon lesions.

Are quantum dots ready for in vivo imaging in human subjects

Nanotechnology has the potential to profoundly transform the nature of cancer diagnosis and cancer patient management in the future. Over the past decade, quantum dots (QDs) have become one of the fastest growing areas of research in nanotechnology. QDs are fluorescent semiconductor nanoparticles suitable for multiplexed in vitro and in vivo imaging. Numerous studies on QDs have resulted in major advancements in QD surface modification, coating, biocompatibility, sensitivity, multiplexing, targeting specificity, as well as important findings regarding toxicity and applicability. For in vitro applications, QDs can be used in place of traditional organic fluorescent dyes in virtually any system, outperforming organic dyes in the majority of cases. In vivo targeted tumor imaging with biocompatible QDs has recently become possible in mouse models. With new advances in QD technology such as bioluminescence resonance energy transfer, synthesis of smaller size non-Cd based QDs, improved surface coating and conjugation, and multifunctional probes for multimodality imaging, it is likely that human applications of QDs will soon be possible in a clinical setting.

Effects of oligofructose-enriched inulin on intestinal absorption of calcium and magnesium and bone turnover markers in postmenopausal women

Deficiency of oestrogen at menopause decreases intestinal Ca absorption, contributing to a negative Ca balance and bone loss. Mg deficiency has also been associated with bone loss. The purpose of the present investigation was to test the hypothesis that treatment with a spray-dried mixture of chicory oligofructose and long-chain inulin (Synergy1; SYN1) would increase the absorption of both Ca and Mg and alter markers of bone turnover. Fifteen postmenopausal women (72.2 (SD 6.4) years) were treated with SYN1 or placebo for 6 weeks using a double-blind, placebo-controlled, cross-over design. Fractional Ca and Mg absorption were measured using dual-tracer stable isotopes before and after treatment. Bone turnover markers were measured at baseline, 3 and 6 weeks. Fractional absorption of Ca and Mg increased following SYN1 compared with placebo (P < 0.05). Bone resorption (by urinary deoxypyridinoline cross-links) was greater than baseline at 6 weeks of active treatment (P < 0.05). Bone formation (by serum osteocalcin) showed an upward trend at 3 weeks and an increase following 6 weeks of SYN1 (P < 0.05). Closer examination revealed a variation in response, with two-thirds of the subjects showing increased absorption with SYN1. Post hoc analyses demonstrated that positive responders had significantly lower lumbar spine bone mineral density than non-responders (dual X-ray absorptiometry 0.887 +/- 0.102 v. 1.104 +/- 0.121 g/cm2; P < 0.01), and changes in bone turnover markers occurred only in responders. These results suggest that 6 weeks of SYN1 can improve mineral absorption and impact markers of bone turnover in postmenopausal women. Further research is needed to determine why a greater response was found in women with lower initial spine bone mineral density.

The outcomes and surgical techniques of the latarjet procedure.

PURPOSE To determine the optimal position and orientation of the coracoid bone graft for the Latarjet procedure for recurrent instability in patients with recurrent anterior instability and high degrees of glenoid bone loss. METHODS A systematic review of the literature including the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (1980-2012), and Medline (1980-2012) was conducted. The following search teams were used: glenoid bone graft, coracoid transfer, glenoid rim fracture, osseous glenoid defect, and Latarjet. Studies deemed appropriate for inclusion were then analyzed. Study data collected included level of evidence, patient demographic characteristics, preoperative variables, intraoperative findings, technique details, and postoperative recovery and complications where available. RESULTS The original search provided a total of 344 studies. A total of 334 studies were subsequently excluded because they were on an irrelevant topic, used an arthroscopic technique, or were not published in English or because they were review articles, leaving 10 studies eligible for inclusion. Given the different methods used in each of the studies included in the review, descriptive analysis was performed. The duration of follow-up ranged from 6 months to 14.3 years postoperatively. With the exception of 2 studies, all authors reported on recurrent shoulder instability after Latarjet reconstruction; the rate of recurrent anterior shoulder instability ranged from 0% to 8%. Overall patient satisfaction was listed in 4 studies, each of which reported good to excellent satisfaction rates of more than 90% at final follow-up. CONCLUSIONS As noted in this review, the current literature on Latarjet outcomes consists mostly of retrospective Level IV case series. Although promising outcomes with regard to a low rate of recurrent instability have been seen with these reports, it should be noted that subtle variations in surgical technique, among other factors, may drastically impact the likelihood of glenohumeral degenerative changes arising in these patients. LEVEL OF EVIDENCE Level IV, systematic review of Level IV studies.

Integrin αvβ3-Targeted Radioimmunotherapy of Glioblastoma Multiforme

Purpose: Abegrin is a monoclonal antibody to human integrin αVβ3, a cell adhesion molecule highly expressed on actively angiogenic endothelium and glioblastoma multiforme tumor cells. The purpose of this study was to evaluate the efficacy of a novel 90Y-Abegrin radioimmunotherapeutic agent in murine xenograft glioblastoma models with noninvasive in vivo molecular imaging modalities. Experimental Design: A s.c. U87MG human glioblastoma xenograft model was used to determine maximum tolerated dose (MTD), biodistribution, dose response, and efficacy of 90Y-Abegrin. Antitumor efficacy was also characterized in an orthotopic U87MG and in a HT-29 colorectal cancer model, a low integrin-expressing carcinoma. Small-animal positron emission tomography imaging was used to correlate histologic findings of treatment efficacy. Results: MTD and dose response analysis revealed 200 μCi per mouse as appropriate treatment dose with hepatic clearance and no organ toxicity. 90Y-Abegrin–treated U87MG tumor mice showed partial regression of tumor volume, with increased tumor volumes in 90Y-IgG, Abegrin, and saline groups. 18F-FDG imaging revealed a reduction of cell proliferation and metabolic activity whereas 18F-FLT reflected decreased DNA synthesis in the 90Y-Abegrin group. Ki67 analysis showed reduced proliferative index and quantitative terminal deoxynucleotidyl transferase dUTP nick-end labeling–positive analysis revealed increased DNA fragmentation and apoptosis in 90Y-Abegrin animals. CD31 and 4′,6-diamidino-2-phenylindole staining showed increased vascular fragmentation and dysmorphic vessel structure in 90Y-Abegrin animals only. Orthotopic U87MG tumors treated with 90Y-Abegrin displayed reduced tumor volume. HT-29 tumors showed no significant difference among the various groups. Conclusion: Radioimmunotherapy with 90Y-labeled Abegrin may prove promising in the treatment of highly vascular, invasive, and heterogeneous malignant brain tumors.

Ten-year outcome of serum metal ion levels after primary total hip arthroplasty: a concise follow-up of a previous report*.

We previously reported on the metal ion concentrations of cobalt, chromium, and titanium that were found in the serum of patients three years after they had undergone primary total hip arthroplasty as compared with the concentrations found in the serum of control patients who did not have an implant. This study is a concise update on the serum metal levels found in a cohort of these patients ten years after the time of hip implantation. Of the original seventy-five subjects, metal ion levels were available for forty patients (53%). Ten patients (hybrid group) had received a hybrid total hip replacement that consisted of a modular cobalt-alloy femoral stem with a cobalt-alloy femoral head that had been inserted with cement and a titanium acetabular socket that had been inserted without cement. Nine patients (cobalt-chromium [CoCr] group) had received an implant with an extensively porous-coated modular cobalt-alloy femoral stem and femoral head along with a titanium acetabular socket; the femoral and acetabular components had each been inserted without cement. Eight patients (titanium group) had undergone insertion of a proximally porous-coated modular titanium-alloy femoral stem with a cobalt-alloy femoral head and a titanium acetabular socket; the femoral and acetabular components had each been inserted without cement. Thirteen patients (control group) from the original control group of patients who had not received an implant served as control subjects. Serum metal levels were measured with use of high-resolution sector field inductively coupled plasma mass spectrometry. The hybrid total hip arthroplasty group had mean cobalt levels that were 3.2 times higher at 120 months than they were at baseline, and the cobalt levels in that group were significantly higher than those in the titanium total hip arthroplasty group at thirty-six, sixty, eighty-four, ninety-six, and 120 months (p < 0.01). The hybrid group had mean chromium levels that were 3.9 times higher at 120 months than they were at baseline, and the CoCr total hip arthroplasty group had chromium levels that were 3.6 times higher at 120 months than they were at baseline. The serum titanium levels were higher in the titanium group at all follow-up time intervals as compared with the levels in all other groups, and the level in the titanium group at 120 months was eighteen times higher than it was at baseline (p < 0.01). Patients with well-functioning primary metal-on-polyethylene total hip replacements had elevated serum metal levels for as many as ten years postoperatively. Furthermore, metal release at the modular femoral head-neck junctions, rather than passive dissolution from porous ingrowth surfaces, was likely the dominant source of serum cobalt and chromium.

Vascular endothelial growth factor and vascular endothelial growth factor receptor inhibitors as anti-angiogenic agents in cancer therapy.

New blood vessel formation (angiogenesis) is fundamental to the process of tumor growth, invasion, and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of ligands and receptors are well established as key regulators of these processes. VEGF is a glycoprotein with mitogenic activity on vascular endothelial cells. Specifically, VEGF-receptor pathway activation results in signaling cascades that promote endothelial cell growth, migration, differentiation, and survival from pre-existing vasculature. Thus, the role of VEGF has been extensively studied in the pathogenesis and angiogenesis of human cancers. Recent identification of seven VEGF ligand variants (VEGF [A-F], PIGF) and three VEGF tyrosine kinase receptors (VEGFR- [1-3]) has led to the development of several novel inhibitory compounds. Clinical trials have shown inhibitors to this pathway (anti-VEGF therapies) are effective in reducing tumor size, metastasis and blood vessel formation. Clinically, this may result in increased progression free survival, overall patient survival rate and will expand the potential for combinatorial therapies. Having been first described in the 1980s, VEGF patenting activity since then has focused on anti-cancer therapeutics designed to inhibit tumoral vascular formation. This review will focus on patents which target VEGF-[A-F] and/or VEGFR-[1-3] for use in anti-cancer treatment.

Positron Emission Tomography Imaging of Poststroke Angiogenesis

Background and Purpose— Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis. Methods— Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were subjected to weekly MRI, 18F-FDG PET, and 64Cu-DOTA-VEGF121 PET scans. Several control experiments were performed to confirm the VEGFR specificity of 64Cu-DOTA-VEGF121 uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and 125I-VEGF165 autoradiography on stroke brain tissue slices were performed to validate the in vivo findings. Results— T2-weighed MRI correlated with the “cold spot” on 18F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The 64Cu-DOTA-VEGF121 uptake in the stroke border zone peaked at ≈10 days after surgery, indicating neovascularization as confirmed by histology (VEGFR-2, BrdU, and lectin staining). VEGFR specificity of 64Cu-DOTA-VEGF121 uptake was confirmed by significantly lower uptake of 64Cu-DOTA-VEGFmutant in vivo and intense 125I-VEGF165 uptake ex vivo in the stroke border zone. No appreciable uptake of 64Cu-DOTA-VEGF121 was observed in the brain of sham-operated rats. Conclusions— For the first time to our knowledge, we successfully evaluated the VEGFR expression kinetics noninvasively in a rat stroke model. In vivo imaging of VEGFR expression could become a significant clinical tool to plan and monitor therapies aimed at improving poststroke angiogenesis.