An Initial Cost-Effectiveness Analysis of Magnetic Resonance-Guided Laser Interstitial Thermal Therapy in Pediatric Epilepsy Surgery.

INTRODUCTION: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a new technology that provides a clinically efficacious and minimally invasive alternative to conventional microsurgical resection. However, little data exist on how costs compare to traditional open surgery. The goal of this paper is to investigate the cost-effectiveness of MRgLITT in the treatment of pediatric epilepsy. METHODS: We retrospectively analyzed the medical records of pediatric patients who underwent MRgLITT via the Visualase® thermal therapy system (Medtronic, Inc., Minneapolis, MN, USA) between December 2013 and September 2017. Direct costs associated with preoperative, operative, and follow-up care were extracted. Benefit was calculated in quality-adjusted life years (QALYs), and the cost-effectiveness was derived from the discounted total direct costs over QALY. Sensitivity analysis on 4 variables was utilized to assess the validity of our results. RESULTS: Twelve consecutive pediatric patients with medically refractory epilepsy underwent MRgLITT procedures. At the last postoperative follow-up, 8 patients were seizure free (Engel I, 66.7%), 2 demonstrated significant improvement (Engel II, 16.7%), and 2 patients showed worthwhile improvement (Engel III, 16.7%). The average cumulative discounted QALY was 2.11 over the lifetime of a patient. Adjusting for inflation, MRgLITT procedures had a cost-effectiveness of USD 22,211 per QALY. Our sensitivity analysis of cost variables is robust and supports the procedure to be cost--effective. CONCLUSION: Our data suggests that MRgLITT may be a cost-effective alternative to traditional surgical resection in pediatric epilepsy surgery.

In vitro assessment of the differences in retinal ganglion cell responses to intra- and extracellular electrical stimulation.

OBJECTIVE: To compare responses of retinal ganglion cells (RGCs) to intracellular and extracellular electrical stimulation of varying frequency and amplitude. APPROACH: In vitro patch clamp was used to record the responses of RGCs to sinusoidal current stimulation of varying frequency and amplitude. The results were simulated using the Neuron software package. MAIN RESULTS: The stimulation frequency yielding the greatest response was higher for extracellular stimulation compared to intracellular stimulation in the same cells (256 Hz versus 64 Hz). In fact, at the high end of the frequency range, where extracellular stimulation was highly efficacious, no responses could be generated using intracellular stimulation. A region in the amplitude-frequency stimulation space was identified where OFF-RGCs could be preferentially stimulated over ON-RGCs. We found that the inability of RGCs to respond at high frequencies of intracellular stimulation is likely the result of the axon acting as a low pass filter. SIGNIFICANCE: There is no direct translation of the results obtained with intracellular stimulation to those that employ extracellular stimulation.

A Bioimpedance Analysis Platform for Amputee Residual Limb Assessment.

OBJECTIVE: The objective of this research was to develop a bioimpedance platform for monitoring fluid volume in residual limbs of people with trans-tibial limb loss using prostheses. METHODS: A customized multifrequency current stimulus profile was sent to thin flat electrodes positioned on the thigh and distal residual limb. The applied current signal and sensed voltage signals from four pairs of electrodes located on the anterior and posterior surfaces were demodulated into resistive and reactive components. An established electrical model (Cole) and segmental limb geometry model were used to convert results to extracellular and intracellular fluid volumes. Bench tests and testing on amputee participants were conducted to optimize the stimulus profile and electrode design and layout. RESULTS: The proximal current injection electrode needed to be at least 25 cm from the proximal voltage sensing electrode. A thin layer of hydrogel needed to be present during testing to ensure good electrical coupling. Using a burst duration of 2.0 ms, intermission interval of 100 µs, and sampling delay of 10 µs at each of 24 frequencies except 5 kHz, which required a 200-µs sampling delay, the system achieved a sampling rate of 19.7 Hz. CONCLUSION: The designed bioimpedance platform allowed system settings and electrode layouts and positions to be optimized for amputee limb fluid volume measurement. SIGNIFICANCE: The system will be useful toward identifying and ranking prosthetic design features and participant characteristics that impact residual limb fluid volume.

Ultrasound Strain Relaxation Time Ratio: A Quantitative Marker for the Assessment of Cortical Inflammation/Edema in Renal Allografts.

Purpose: To evaluate the ability of ultrasound strain relaxation time ratio to assess cortical inflammation/edema in renal allografts. Materials and Methods: We prospectively assessed renal allograft cortical inflammation/edema in 16 renal transplants using ultrasound elasticity imaging and correlated the findings with kidney biopsy. Strain relaxation times in the renal cortex and reference soft tissue were produced by free-hand compression with the ultrasound transducer and estimated with 2 D speckle tracking. Compression was performed in 3-second compression-relaxation cycles (push for 1 second, constant pressure for 1 second, and release for 1 second). We propose a strain relaxation time ratio (time of cortical strain to return to zero/time of the reference strain return to zero) to assess the relationship of compression-induced time-dependent strain relaxation in the cortex and reference tissue. 16 patients were divided into a group with ≤ 25 % (n = 8) and a group with > 26 % (n = 8) cortical inflammation/edema based on the Banff score. A t-test was used to examine the difference in the strain relaxation time ratio between the two groups. The diagnostic accuracy, inter-rater reliability, and reproducibility of this technique in discriminating between the groups were tested. Results: The strain relaxation time ratio of cortex/reference tissue was significantly higher in patients with > 26 % than in patients with ≤ 25 % cortical inflammation/edema (1.15 ±â€Š0.10 vs. 0.91 ±â€Š0.08, P = 0.0002). The strain relaxation time ratio has high reliability (Pearson correlation coefficient, R²â€Š= 0.93), reproducibility (intraclass correlation coefficient = 0.98, P = 0.000), and accuracy (area under curve = 1) in determining > 26 % renal cortical inflammation/edema. Conclusion: The strain relaxation time ratio of cortex/reference tissue can be used as a quantitative marker for the assessment of cortical inflammation/edema in renal allografts.

New insight into the contrast in diffusional kurtosis images: does it depend on magnetic susceptibility?

PURPOSE: In this MRI study, diffusional kurtosis imaging (DKI) and T2 * multiecho relaxometry were measured from the white matter (WM) of human brains and correlated with each other, with the aim of investigating the influence of magnetic-susceptibility (Δχ (H2O-TISSUE) ) on the contrast. METHODS: We focused our in vivo analysis on assessing the dependence of mean, axial, and radial kurtosis (MK, K‖ , K⊥ ), as well as DTI indices on Δχ (H2O-TISSUE) (quantified by T2 *) between extracellular water and WM tissue molecules. Moreover, Monte Carlo (MC) simulations were used to elucidate experimental data. RESULTS: A significant positive correlation was observed between K⊥ , MK and R2 * = 1/T2 *, suggesting that Δχ (H2O-TISSUE) could be a source of DKI contrast. In this view, K⊥ and MK-map contrasts in human WM would not just be due to different restricted diffusion processes of compartmentalized water but also to local Δχ (H2O-TISSUE) . However, MC simulations show a strong dependence on microstructure rearrangement and a feeble dependence on Δχ (H2O-TISSUE) of DKI signal. CONCLUSION: Our results suggests a concomitant and complementary existence of multi-compartmentalized diffusion process and Δχ (H2O-TISSUE) in DKI contrast that might explain why kurtosis contrast is more sensitive than DTI in discriminating between different tissues. However, more realistic numerical simulations are needed to confirm this statement.

Robustness study of the different immittance spectra and frequency ranges in bioimpedance spectroscopy analysis for assessment of total body composition.

The estimation of body fluids is a useful and common practice for assessment of disease status and therapy outcomes. Electrical bioimpedance spectroscopy (EBIS) methods are noninvasive, inexpensive and efficient alternatives for determination of body fluids. One of the main source of errors in EBIS measurements in the estimation of body fluids is capacitive coupling. In this paper an analysis of capacitive coupling in EBIS measurements was performed and the robustness of the different immittance spectra against it tested. On simulations the conductance (G) spectrum presented the smallest overall error, among all immittance spectra, in the estimation of the impedance parameters used to estimate body fluids. Afterwards the frequency range of 10-500 kHz showed to be the most robust band of the G spectrum. The accuracy of body fluid estimations from the resulting parameters that utilized G spectrum and parameters provided by the measuring device were tested on EBIS clinical measurements from growth hormone replacement therapy patients against estimations performed with dilution methods. Regarding extracellular fluid, the correlation between each EBIS method and dilution was 0.93 with limits of agreement of 1.06 ± 2.95 l for the device, 1.10 ± 2.94 l for G [10-500 kHz] and 1.04 ± 2.94 l for G [5-1000 kHz]. Regarding intracellular fluid, the correlation between dilution and the device was 0.91, same as for G [10-500 kHz] and 0.92 for G [5-1000 kHz]. Limits of agreement were 0.12 ± 4.46 l for the device, 0.09 ± 4.45 for G [10-500 kHz] and 0.04 ± 4.58 for G [5-1000 kHz]. Such close results between the EBIS methods validate the proposed approach of using G spectrum for initial Cole characterization and posterior clinical estimation of body fluids status.

Dehydration: physiology, assessment, and performance effects.

This article provides a comprehensive review of dehydration assessment and presents a unique evaluation of the dehydration and performance literature. The importance of osmolality and volume are emphasized when discussing the physiology, assessment, and performance effects of dehydration. The underappreciated physiologic distinction between a loss of hypo-osmotic body water (intracellular dehydration) and an iso-osmotic loss of body water (extracellular dehydration) is presented and argued as the single most essential aspect of dehydration assessment. The importance of diagnostic and biological variation analyses to dehydration assessment methods is reviewed and their use in gauging the true potential of any dehydration assessment method highlighted. The necessity for establishing proper baselines is discussed, as is the magnitude of dehydration required to elicit reliable and detectable osmotic or volume-mediated compensatory physiologic responses. The discussion of physiologic responses further helps inform and explain our analysis of the literature suggesting a ≥ 2% dehydration threshold for impaired endurance exercise performance mediated by volume loss. In contrast, no clear threshold or plausible mechanism(s) support the marginal, but potentially important, impairment in strength, and power observed with dehydration. Similarly, the potential for dehydration to impair cognition appears small and related primarily to distraction or discomfort. The impact of dehydration on any particular sport skill or task is therefore likely dependent upon the makeup of the task itself (e.g., endurance, strength, cognitive, and motor skill).

Connective tissue of cervical carcinoma xenografts: associations with tumor hypoxia and interstitial fluid pressure and its assessment by DCE-MRI and DW-MRI.

Abstract Background. A high fraction of stroma in malignant tissues is associated with tumor progression, metastasis, and poor prognosis. Possible correlations between the stromal and physiologic microenvironments of tumors and the potential of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in quantification of the stromal microenvironment were investigated in this study. Material and methods. CK-160 cervical carcinoma xenografts were used as preclinical tumor model. A total of 43 tumors were included in the study, and of these tumors, 17 were used to search for correlations between the stromal and physiologic microenvironments, 11 were subjected to DCE-MRI, and 15 were subjected to DW-MRI. DCE-MRI and DW-MRI were carried out at 1.5 T with a clinical MR scanner and a slotted tube resonator transceiver coil constructed for mice. Fraction of connective tissue (CTFCol) and fraction of hypoxic tissue (HFPim) were determined by immunohistochemistry. A Millar SPC 320 catheter was used to measure tumor interstitial fluid pressure (IFP). Results. CTFCol showed a positive correlation to IFP and an inverse correlation to HFPim. The apparent diffusion coefficient assessed by DW-MRI was inversely correlated to CTFCol, whereas no correlation was found between DCE-MRI-derived parameters and CTFCol. Conclusion. DW-MRI is a potentially useful method for characterizing the stromal microenvironment of tumors.

Assessment of extracellular fluid volume and fluid status in hemodialysis patients: current status and technical advances.

The assessment of extracellular fluid volume (ECV) and fluid status is both important and challenging in hemodialysis patients. Extracellular fluid is distributed in two major sub-compartments: interstitial fluid and plasma. A variety of methods are used to assess the ECV, with tracer dilution techniques considered gold standard. However, ECV defined as the distribution space of bromide, sodium, chloride, and ferrocyanide appears to be larger than the distribution volume of inulin and sucrose, suggesting a partial distribution into the intracellular volume. Relative blood volume monitoring, measurement of inferior vena cava diameter by ultrasound and biochemical markers are indirect methods, which do not reflect the ECV and fluid status accurately. Bioimpedance spectroscopy (BIS) techniques enable assessment of ECV and intracellular volume. Currently, BIS appears to be the most practical method for assessing ECV volume and fluid status in dialysis patients.

Calf bioimpedance ratio improves dry weight assessment and blood pressure control in hemodialysis patients.

BACKGROUND: Chronic fluid overload due to overestimation of dry weight (DW) is the major factor in the development of hypertension in hemodialysis (HD) patients. The present study was undertaken to investigate whether bioimpedance ratio in the calf (Calf-BR = impedance at 200 kHz/impedance at 5 kHz) could be a useful hydration marker for estimation of DW and facilitate better control of blood pressure (BP) in HD patients. METHODS: Target range of Calf-BR was derived from 157 healthy Chinese subjects. Post-dialysis Calf-BR was measured in 117 stable, non-edematous HD patients. Those with Calf-BR(s) above target level had their DW(s) gradually reduced under the guidance of Calf-BR. RESULTS: The Calf-BR was normally distributed and increased with age, but was independent of BMI and gender in both healthy subjects and dialysis patients. HD patients with Calf-BR above age-stratified target range had significantly higher home BP, in spite of more antihypertensive treatments (p = 0.058). The patients who reached the target range of Calf-BR by decreasing DW, had their home BP significantly decreased, along with reduction in antihypertensive medications (p = 0.012). CONCLUSION: Recognition and correction of chronic fluid overload based on age-stratified Calf-BR is helpful in hypertension control in Chinese HD patients.

D2-40 immunohistochemical assessment of lymphangiogenesis in normal and edematous sinus mucosa and nasal polyp.

OBJECTIVE: The lymphatic system plays an important role in the maintenance of tissue fluid homeostasis, which facilitates interstitial protein transport. Until recently, the lymphatic system of the sinonasal mucosa has been relatively poorly studied. The authors aimed to investigate the distributional and quantitative changes of the lymphatic vessels in inflammatory sinus mucosa and nasal polyps in comparison with healthy sinus mucosa using D2-40 antibody. METHODS: Immunohistochemistry and Western blotting with D2-40 antibody were applied to normal and edematous ethmoid sinus mucosa and nasal polyps. The number, size, and length densities of lymphatic vessels were evaluated using tissue sections and whole mount preparations. RESULTS: Most lymphatic vessels in normal and edematous ethmoid sinus mucosa were distributed in the subepithelial layer. Some of these vessels were dilated, whereas others were compressed and had a slit-like lumen. No D2-40 positive vessels were found in samples of nasal polyps. Lymphatic vessels showed no statistically significant difference in their number, size, or length density between normal and edematous ethmoid sinus mucosa. Western blot also showed no differences in their expression levels. CONCLUSION: These findings indicate that lymphangiogenesis does not occur in edematous ethmoid sinus mucosa, which may not reuptake interstitial fluid efficiently in inflammatory conditions, resulting in the formation of mucosal edema in chronic inflammation.

A prospective phase I-II trial of the cyclooxygenase-2 inhibitor celecoxib in patients with carcinoma of the cervix with biomarker assessment of the tumor microenvironment.

PURPOSE: To evaluate the toxicity and effectiveness of celecoxib in combination with definitive chemoradiotherapy (CRT) in women with locally advanced cervical cancer. METHODS AND MATERIALS: Thirty-one patients were accrued to a phase I-II trial of celecoxib 400 mg by mouth twice per day for 2 weeks before and during CRT. Tumor oxygenation (HP(5)) and interstitial fluid pressure (IFP) were measured before and 2 weeks after celecoxib administration alone. The median follow-up time was 2.7 years (range, 1.1-4.4 years). RESULTS: The most common acute G3/4 toxicities were hematologic (4/31, 12.9%) and gastrointestinal (5/31, 16.1%) largely attributed to chemotherapy. Late G3/4 toxicity was seen in 4 of 31 patients (13.7% actuarial risk at 2 yr), including fistulas in 3 patients (9.7%). Within the first year of follow-up, 25 of 31 patients (81%) achieved complete response (CR), of whom 20 remained in CR at last follow-up. After 2 weeks of celecoxib administration before CRT, the median IFP decreased slightly (median absolute, -4.6 mm Hg; p = 0.09; relative, -21%; p = 0.07), whereas HP(5) did not change significantly (absolute increase, 3.6%; p = 0.51; median relative increase, 11%; p = 0.27). No significant associations were seen between changes in HP(5) or IFP and response to treatment (p = 0.2, relative HP(5) change and p = 0.14, relative IFP change). CONCLUSIONS: Celecoxib in combination with definitive CRT is associated with acceptable acute toxicity, but higher than expected late complications. Celecoxib is associated with a modest reduction in the angiogenic biomarker IFP, but this does not correspond with tumor response.

Assessment of the tumor microenvironment in cervix cancer using dynamic contrast enhanced CT, interstitial fluid pressure and oxygen measurements.

PURPOSE: Interstitial fluid pressure (IFP) and oxygen (pO(2)) measurements are prognostic factors in cervical cancer. The purpose of this study was to determine the relationship between IFP and oxygenation and parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT). METHODS AND MATERIALS: Dynamic contrast-enhanced computed tomography was performed in 32 patients with cervical cancer before radiation therapy. Images were acquired during intravenous contrast injection at 1 per s for 120 s and 1 per 15 s for 60 s. DCE-CT was analyzed using CT Perfusion 3 software (GE Medical Systems) to derive tumor blood flow (BF), permeability surface area product, blood volume, and mean transit time. Further analysis was performed to obtain relative peak enhancement, residual enhancement at 3 min after contrast injection (RE), time to peak and initial slope. Nodal status and tumor size were assessed with MRI. From in vivo IFP (n = 31) and pO(2) (n = 31) tumor measurements median pO(2) (mO(2)), percentage measurements less than 5 mm Hg (HP5) and mean IFP values were calculated. RESULTS: There was a positive correlation between BF and mO(2) (r = 0.47, p = 0.007) and between RE and HP5 (r = 0.39, p = 0.03). There was no correlation between IFP and DCE-CT parameters. CONCLUSION: There is a moderately positive, correlation between tumor oxygenation and BF as well as RE and HP5. Further study is required to determine if DCE-CT parameters are useful predictors of tumor behavior in cervical cancer.

Interstitial fluid analysis for assessment of organ function.

Evaluation methods are required for non-heart-beating donor (NHBD) kidneys to ensure the success of transplantation. In this study, the microdialysis technique was employed for the ex-vivo assessment of hypothermically preserved NHBD kidney function. Microdialysis probes were placed in the renal cortex of 2 h warm ischaemic porcine kidneys to monitor interstitial pyruvate dynamics during hypothermic machine perfusion with perfusate containing 29.4 mM fructose-1,6-diphosphate (FDP). The presence of exogenous FDP in the perfusate induced no changes in the renal flow rate and vascular resistance, renal artery effluent biochemistry, or pyruvate concentration relative to untreated control kidneys. Significant increases in pyruvate production (P < 0.05), however, were observed after 12 h of perfusion in the interstitial fluid of FDP-treated kidneys relative to control kidneys. After 24 h of perfusion, interstitial fluid concentrations of pyruvate were 149.1 +/- 58.4 vs. 55.6 +/- 17.9 micro M (P < 0.05) in the FDP and control group, respectively. The microdialysis probe collected the interstitial fluid directly from the cellular sites of metabolic and synthetic activity, where perfusate dilution was minimal. Consequently, the biochemical changes induced by the organ metabolic activity were detected only at the interstitial level, in the microdialysates. Interstitial fluid pyruvate may be a good indicator of kidney function. The addition of FDP to the perfusion solution during ischaemic kidney preservation resulted in enhanced pyruvate production in the extracellular space, indirectly reflecting an increase in anaerobic ATP production. The pyruvate will be transformed during organ reperfusion into acetyl Co-A enzyme allowing an immediate start of aerobic metabolism. This in turn can increase the amount of ATP available to the cells and may help prevent reperfusion injury upon transplantation.