Heating induced near deep brain stimulation lead electrodes during magnetic resonance imaging with a 3 T transceive volume head coil.

Heating induced near deep brain stimulation (DBS) lead electrodes during magnetic resonance imaging with a 3 T transceive head coil was measured, modeled, and imaged in three cadaveric porcine heads (mean body weight = 85.47 ± 3.19 kg, mean head weight = 5.78 ± 0.32 kg). The effect of the placement of the extra-cranial portion of the DBS lead on the heating was investigated by looping the extra-cranial lead on the top, side, and back of the head, and placing it parallel to the coil's longitudinal axial direction. The heating was induced using a 641 s long turbo spin echo sequence with the mean whole head average specific absorption rate of 3.16 W kg(-1). Temperatures were measured using fluoroptic probes at the scalp, first and second electrodes from the distal lead tip, and 6 mm distal from electrode 1 (T(6 mm)). The heating was modeled using the maximum T(6 mm) and imaged using a proton resonance frequency shift-based MR thermometry method. Results showed that the heating was significantly reduced when the extra-cranial lead was placed in the longitudinal direction compared to the other placements (peak temperature change = 1.5-3.2 °C versus 5.1-24.7 °C). Thermal modeling and MR thermometry may be used together to determine the heating and improve patient safety online.

Biodistribution of TNF-alpha-coated gold nanoparticles in an in vivo model system.

AIM: In this study, we describe the biodistribution of CYT-6091, a colloidal gold (Au)-based nanomedicine that targets the delivery of TNF-alpha to solid tumors. MATERIALS & METHODS: A single intravenous injection of CYT-6091 coated with 5 microg TNF-alpha was given to human prostate tumor-bearing or naive (without tumor) nude mice. Tissues were harvested and analyzed at specific time points for Au nanoparticles by atomic emission spectroscopy and TNF-alpha by ELISA. RESULTS: The two constituents of CYT-6091, TNF-alpha and Au, exhibited different behavior in blood, with TNF-alpha showing a faster decay than the Au nanoparticles. Between 0 and 4 h after injection, TNF-alpha showed a preferential accumulation in the tumor. Au was observed to accumulate preferentially in the liver between 4 and 12 h, and showed some clearance over time (4 months). CONCLUSION: These data suggest that CYT-6091 delivers TNF-alpha preferentially to the tumor and that upon TNF-alpha degradation, the liver takes up Au, which is cleared slowly over time.

Tumor necrosis factor-alpha-induced accentuation in cryoinjury: mechanisms in vitro and in vivo.

Cryosurgical treatment of solid cancer can be greatly assisted by further translation of our finding that a cytokine adjuvant tumor necrosis factor-alpha (TNF-alpha) can achieve complete cancer destruction out to the intraoperatively imaged iceball edge (-0.5 degrees C) over the current clinical recommendation of reaching temperatures lower than -40 degrees C. The present study investigates the cellular and tissue level dose dependency and molecular mechanisms of TNF-alpha-induced enhancement in cryosurgical cancer destruction. Microvascular endothelial MVEC and human prostate cancer LNCaP Pro 5 (LNCaP) cells were frozen as monolayers in the presence of TNF-alpha. Normal skin and LNCaP tumor grown in a nude mouse model were also frozen at different TNF-alpha doses. Molecular mechanisms were investigated by using specific inhibitors to block nuclear factor-kappaB-mediated inflammatory or caspase-mediated apoptosis pathways. The amount of cryoinjury increased in a dose-dependent manner with TNF-alpha both in vitro and in vivo. MVEC were found to be more cryosensitive than LNCaP cells in both the presence and the absence of TNF-alpha. The augmentation in vivo was significantly greater than that in vitro, with complete cell death up to the iceball edge in tumor tissue at local TNF-alpha doses greater than 200 ng. The inhibition assays showed contrasting results with caspase-mediated apoptosis as the dominant mechanism in MVEC in vitro and nuclear factor-kappaB-mediated inflammatory mechanisms within the microvasculatures the dominant mechanism in vivo. These results suggest the involvement of endothelial-mediated injury and inflammation as the critical mechanisms in cryoinjury and the use of vascular-targeting molecules such as TNF-alpha to enhance tumor killing and achieve the clinical goal of complete cell death within an iceball.

Nanotherapeutics for enhancing thermal therapy of cancer.

PURPOSE: The current work describes the synergistic enhancement of hyperthermic cancer therapy by selective thermal sensitization and induction of vascular injury at the tumor site. The specificity of this response was mediated by CYT-6091: a pegylated colloidal gold-based nanotherapeutic designed to selectively deliver an inflammatory cytokine, tumor necrosis factor alpha (TNF), to solid tumors. MATERIALS AND METHODS: FSaII murine fibrosarcoma-bearing C3H mice received an intravenous injection of either soluble TNF or CYT-6091 (50-250 microg/kg TNF). Four hours later the tumors were exposed to localized heating (42.5 or 43.5 degrees C, 60 min). Tumor responses were assessed by growth delay and/or perfusion. RESULTS: Both soluble TNF and CYT-6091 reduced tumor perfusion by 80% of control (no treatment), 4 hours post administration. However, soluble TNF was toxic to the tumor burdened mice and resulted in 40% mortality alone and 100% mortality when combined with hyperthermia. Conversely, no toxicities were noted with CYT-6091 alone or when combined with hyperthermia. Additionally, CYT-6091 combined with heat yielded significant tumor regression in vivo as compared to heat or CYT-6091 alone as demonstrated by tumor growth delay. Pretreatment with soluble TNF or CYT-6091 followed by heating reduced in vitro tumor and endothelial cell survival by 40-50% (TNF) and 70-75% (CYT-6091) of the control cell (i.e. tumor and endothelial) values, respectively. CONCLUSIONS: CYT-6091, by selectively delivering TNF to solid tumors, improves the safety of TNF treatment. In addition, the targeted delivery of TNF augments cancer thermal therapy efficacy possibly by inducing a tumor-localized inflammatory response.

Model-based detection of endobronchial intubation.

To detect endobronchial intubation (EBI) noninvasively in real time, we developed a novel, automated, lumped model-based approach. The model uses routinely monitored airway pressure and flow as inputs. The specificity of the method in detecting EBI was determined by testing events of stiff chest wall (SCW) in the absence of EBI. EBI was induced in 10 anesthetized, paralyzed, and mechanically ventilated mongrel dogs (19-45 kg) by advancing the endotracheal tube into the right mainstem bronchus. The event of SCW was created by wrapping a pressure cuff around the chest. Airway pressure and flow were continuously recorded at the mouth, and respiratory impedance was estimated from these signals. Model parameters were iteratively identified until the root mean square error between the respiratory and model-predicted impedance was minimum. The change in model parameters during EBI from baseline was analyzed. In nine of 10 cases, it was determined that during EBI, the model's compliance element (C1) decreased > or =50% and model's resistance element (R2) changed < or =10-fold from baseline. Testing this rule on 40 cases of SCW, four false positives were obtained. During SCW, R1 and R2 increased, whereas C2 decreased significantly from baseline. This preliminary study is a promising step toward noninvasive, real-time detection of EBI to aid clinicians in decision making.

Enhancement of tumor thermal therapy using gold nanoparticle-assisted tumor necrosis factor-alpha delivery.

Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine with anticancer efficacy that can significantly enhance hyperthermic injury. However, TNF-alpha is systemically toxic, thereby creating a need for its selective tumor delivery. We used a newly developed nanoparticle delivery system consisting of 33-nm polyethylene glycol-coated colloidal gold nanoparticles (PT-cAu-TNF-alpha) with incorporated TNF-alpha payload (several hundred TNF-alpha molecules per nanoparticle) to maximize tumor damage and minimize systemic exposure to TNF-alpha. SCK mammary carcinomas grown in A/J mice were treated with 125 or 250 microg/kg PT-cAu-TNF-alpha alone or followed by local heating at 42.5 degrees C using a water bath for 60 minutes, 4 hours after nanoparticle injection. Increases in tumor growth delay were observed for both PT-cAu-TNF-alpha alone and heat alone, although the most dramatic effect was found in the combination treatment. Tumor blood flow was significantly suppressed 4 hours after an i.v. injection of free TNF-alpha or PT-cAu-TNF-alpha. Tumor perfusion, imaged by contrast enhanced ultrasonography, on days 1 and 5 after treatment revealed perfusion defects after the injection of PT-cAu-TNF-alpha alone and, in many regions, complete flow inhibition in tumors treated with combination treatment. The combination treatment of SCK tumors in vivo reduced the in vivo/in vitro tumor cell survival to 0.05% immediately following heating and to 0.005% at 18 hours after heating, suggesting vascular damage-mediated tumor cell killing. Thermally induced tumor growth delay was enhanced by pretreatment with TNF-alpha-coated gold nanoparticles when given i.v. at the proper dosage and timing.

Model-based detection of partially obstructed endotracheal tube.

OBJECTIVES: A five-element lumped pulmonary model was developed to estimate respiratory mechanics automatically and noninvasively. The model was applied to diagnose obstructed endotracheal tube. Events like bronchospasm and stiff chest wall were also tested to determine the specificity of the diagnosis. Cases with positive end-expiratory pressure were also included in the analysis to see the effects of positive end-expiratory pressure on the model. DESIGN: Randomized controlled animal study. SETTING: University department of anesthesiology. SUBJECTS: Ten anesthetized, paralyzed, and mechanically ventilated mongrel dogs (19-45 kg) of either gender. INTERVENTIONS: Two levels of upper airway obstruction were induced in ten dogs by partially constricting the endotracheal tube. Acute bronchial constriction was produced in five dogs by injecting methacholine through a central venous catheter. In the same five dogs, the chest wall was stiffened by wrapping a pressure cuff around the chest. Positive end-expiratory pressure was also applied as a separate event in these five animals. MEASUREMENTS AND MAIN RESULTS: Airway pressure and flow were continuously recorded at the mouth. Model parameters were iteratively identified until the root mean square error between respiratory impedance (obtained from airway pressure and flow) and model-predicted impedance (calculated using Ohm's law) was minimum. The peak inspiratory pressure increased and the peak expiratory flow rate decreased with increasing levels of partial obstruction. The value of the model parameters R(1) and C(2) increased and C(1) decreased with partial obstructed endotracheal tube, whereas R(1) increased and L and C(2) decreased with bronchospasm. With stiff chest wall, R(2) increased and C(2) decreased. With positive end-expiratory pressure, the L parameter decreased and no significant change in other model parameters was observed. Obstructed endotracheal tube is indicated if R(1) increased > or =30%, C(1) decreased > or =10%, and C(2) increased > or =10% from baseline. The test results using 45 events, including control, three complications, and positive end-expiratory pressure, show that when the model is used to diagnose obstructed endotracheal tube, the method has a sensitivity of 90% and specificity of 97%. CONCLUSIONS: During an obstructed endotracheal tube, model parameters change such that the event can be diagnosed noninvasively, automatically, and accurately. The model differentiates between upper airway obstruction and complications like bronchospasm and stiff chest wall.