Interstitial ultrasound ablation of vertebral and paraspinal tumours: Parametric and patient-specific simulations

Purpose: Theoretical parametric and patient-specific models are applied to assess the feasibility of interstitial ultrasound ablation of tumours in and near the spine and to identify potential treatment delivery strategies.

Methods: 3D patient-specific finite element models (n?=?11) of interstitial ultrasound ablation of tumours associated with the spine were generated. Gaseous nerve insulation and various applicator configurations, frequencies (3 and 7?MHz), placement trajectories, and tumour locations were simulated. Parametric studies with multilayered models investigated the impacts of tumour attenuation, tumour dimension, and the thickness of bone insulating critical structures. Temperature and thermal dose were calculated to define ablation (>240 equivalent minutes at 43?°C (EM43?°C)) and safety margins (<45?°C and <6 EM43?°C), and to determine performance and required delivery parameters.

Results: Osteolytic tumours (≤44?mm) encapsulated by bone could be successfully ablated with 7?MHz interstitial ultrasound (8.1–16.6?W/cm², 120–5900?J, 0.4–15?min). Ablation of tumours (94.6–100% volumetric) 0–14.5?mm from the spinal canal was achieved within 3–15?min without damaging critical nerves. 3 MHz devices provided faster ablation (390 versus 930?s) of an 18?mm diameter osteoblastic (high bone content) volume than 7?MHz devices. Critical anatomy in proximity to the tumour could be protected by selection of appropriate applicator configurations, active sectors, and applied power schemas, and through gaseous insulation. Preferential ultrasound absorption at bone surfaces facilitated faster, more effective ablations in osteolytic tumours and provided isolation of ablative energies and temperatures.

Conclusions: Parametric and patient-specific studies demonstrated the feasibility and potential advantages of interstitial ultrasound ablation treatment of paraspinal and osteolytic vertebral tumours.     

Intra-operative 3D guidance and edema detection in prostate brachytherapy using a non-isocentric C-arm

PurposeBrachytherapy (radioactive seed insertion) has emerged as one of the most effective treatment options for patients with prostate cancer, with the added benefit of a convenient outpatient procedure. The main limitation in contemporary brachytherapy is faulty seed placement, predominantly due to the presence of intra-operative edema (tissue expansion). Though currently not available, the capability to intra-operatively monitor the seed distribution, can make a significant improvement in cancer control. We present such a system here.MethodsIntra-operative measurement of edema in prostate brachytherapy requires localization of inserted radioactive seeds relative to the prostate. Seeds were reconstructed using a typical non-isocentric C-arm, and exported to a commercial brachytherapy treatment planning system. Technical obstacles for 3D reconstruction on a non-isocentric C-arm include pose-dependent C-arm calibration; distortion correction; pose estimation of C-arm images; seed reconstruction; and C-arm to TRUS registration.ResultsIn precision-machined hard phantoms with 40–100 seeds and soft tissue phantoms with 45–87 seeds, we correctly reconstructed the seed implant shape with an average 3D precision of 0.35 mm and 0.24 mm, respectively. In a DoD Phase-1 clinical trial on six patients with 48–82 planned seeds, we achieved intra-operative monitoring of seed distribution and dosimetry, correcting for dose inhomogeneities by inserting an average of over four additional seeds in the six enrolled patients (minimum 1; maximum 9). Additionally, in each patient, the system automatically detected intra-operative seed migration induced due to edema (mean 3.84 mm, STD 2.13 mm, Max 16.19 mm).ConclusionsThe proposed system is the first of a kind that makes intra-operative detection of edema (and subsequent re-optimization) possible on any typical non-isocentric C-arm, at negligible additional cost to the existing clinical installation. It achieves a significantly more homogeneous seed distribution, and has the potential to affect a paradigm shift in clinical practice. Large scale studies and commercialization are currently underway.     

Migraine associated cerebral hyperperfusion with arterial spin-labeled MR imaging

We present a case series demonstrating abnormal regional cerebral hyperperfusion associated with migraine headache using arterial spin-labeling (ASL). In 3 of 11 patients, regional cortical hyperperfusion was demonstrated during a headache episode that corresponded to previous aura symptoms.     

Clinical implementation of spin-tag perfusion magnetic resonance imaging

Arterial spin-labeled magnetic resonance imaging is a powerful method for generating quantitative cerebral perfusion data. Clinical adoption of this technique is hampered by the lack of availability of the final postprocessed images. This is predominantly due to the need for research personnel to handle image transfer, postprocessing, and image display/review. Here, we describe a fully automated pipeline for clinical implementation of a magnetic resonance spin-tag perfusion sequence that can be extended to any studies requiring off-line processing.     

PF-03475952: a potent and neutralizing fully human anti-CD44 antibody for therapeutic applications in inflammatory diseases

Introduction

CD44 is a cell adhesion molecule believed to play a critical role in T cell and monocyte infiltration in the inflammatory process. The reduction of CD44 expression or its ability to properly interact with its key ligand, hyaluronic acid (HA), inhibits migration and subsequent activation of cells within sites of inflammation. CD44-deficient mice exhibit decreased disease in a mouse arthritis model.

Methods

Accordingly, we developed PF-03475952, a fully human IgG2 anti-CD44 monoclonal antibody (mAb).

Results

Binding of PF-03475952 to CD44 inhibits binding of HA and induces loss of CD44 from the cell surface. PF-03475952 also passed a series of safety pharmacology assays designed to assess the risk of the mAb to bind Fc gamma receptors, stimulate cytokine release from human whole blood, and stimulate cytokine release from peripheral blood mononuclear cells (PBMC) using plate-bound antibodies. The latter assay was designed specifically to evaluate the risk of cytokine storm that had been observed with TGN1412 (immunostimulatory CD28 superagonist mAb). PF-003475952 exhibits high-affinity binding to both human and cynomolgus monkey CD44, but does not cross-react with rodent CD44. Thus, a rat anti-mouse CD44 mAb was used to demonstrate a dose-dependent decrease of disease in mouse collagen-induced arthritis. Importantly, efficacy was correlated with >50% loss of cell surface CD44 on circulating cells. Loss of CD44 expression on CD3{su+} lymphocytes was monitored following a single dose of PF-03475952 in cynomolgus monkeys as a pharmacodynamic marker. The recovery of CD44 expression was found to be dose-dependent. PF-03475952 doses of 1, 10, and 100 mg/kg reduced CD44 expression below 50% for 218, 373, and >504 hours, respectively.

Conclusion

Targeting of CD44 is a unique mechanism of action in the treatment of inflammatory diseases and is expected to reduce joint damage induced by inflammatory mediators, resulting in disease modification in inflammatory diseases such as rheumatoid arthritis.     

Hyperhomocysteinemia and transplant coronary artery disease in cardiac transplant recipients

BACKGROUND: In cardiac transplant recipients, long-term survival may be limited by transplant coronary artery disease (TxCAD). Hyperhomocysteinemia (Hhcy) has been associated with vascular disease and is common in transplant recipients. The objective of this study was to determine the relationship between fasting homocysteine (Hcy) concentrations and TxCAD in a cohort of cardiac transplant recipients. METHODS: Forty-eight patients more than 5 yr after transplant were recruited from a cohort of 72 consecutive patients with in-depth analysis of homocysteine levels from the Cardiac Transplant Clinic. Early morning fasting blood was obtained, and the plasma separated and frozen within 30 min. Hcy concentrations were determined by high-performance liquid chromatography (HPLC) with pulsed integrated amperometry. Coronary angiograms were reviewed in a blinded fashion. TxCAD was diagnosed, using the most recent angiogram, when a >25% lesion was present anywhere in the coronary tree. RESULTS: Forty-eight patients transplanted between 1985 and 1994 were studied. The mean Hcy concentration for the cohort was 23.5+/-5.0 micromol/L, all patients had homocysteine levels above the upper range of normal (5-15 micromol/L). Hcy concentrations were significantly higher in patients with angiographic evidence of TxCAD: 25.0+/-5.9 vs. 21.9+/-3.4 micromol/L, p=0.03. This effect persisted when covariates were taken into account using logistic regression analysis. CONCLUSIONS: Hhcy is associated with TxCAD. Prospective studies are required to confirm this association and to assess the efficacy of Hcy-lowering therapy in this patient population.     

Platelet-agglutinating protein P37 from a thrombotic thrombocytopenic purpura plasma forms a complex with human immunoglobulin G

We have previously reported the purification of a 37-kd platelet- agglutinating protein (PAP p37) from the plasma of a patient with thrombotic thrombocytopenic purpura (TTP) that was shown to be present in a subset of TTP patients. The platelet agglutination induced by PAP p37 has been shown to be inhibited by IgG from normal human adults and the same TTP patient after recovery. To elucidate the mechanism of inhibition of IgG, the interaction between PAP p37 and IgG was studied. The complex formation was demonstrated by the binding of fluid-phase IgG from normal adults and the same TTP patient after recovery to adsorbed PAP by using an enzyme-linked immunosorbent assay. The binding was specific, concentration dependent, and saturable. IgG purified from a 5-month-old baby and the same TTP patient during active disease did not form complex with PAP p37. The IgG covalently cross-linked to Sepharose 4B bound 125I-PAP p37 but not 125I-fibrinogen. Sucrose density gradient ultracentrifugation of a mixture of 125I-PAP p37 and IgG also revealed the fluid-phase complex formation with a sedimentation value of 19S. Complexes of molecular weight ranging from 180,000 to over 350,000 daltons were also detected by molecular sieve chromatography. The IgG that was bound to PAP p37 conjugated to Sepharose 4B inhibited the agglutination of washed platelets induced by TTP plasma containing PAP p37, whereas the IgG that was not bound to PAP p37 did not have a significant inhibitory effect. The complex formation between PAP p37 and specific IgG is likely to account for the in vitro inhibition of TTP plasma-induced agglutination and, at least partly, the in vivo successful treatment with specific IgG-containing normal plasma.