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BACKGROUNDDistinguishing adenocarcinoma and squamous cell carcinoma subtypes of non-small cell lung cancers is critical to patient care. Preoperative minimally-invasive biopsy techniques, such as fine needle aspiration (FNA), are increasingly used for lung cancer diagnosis and subtyping. Yet, histologic distinction of lung cancer subtypes in FNA material can be challenging. Here, we evaluated the usefulness of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to diagnose and differentiate lung cancer subtypes in tissues and FNA samples.METHODSDESI-MSI was used to analyze 22 normal, 26 adenocarcinoma, and 25 squamous cell carcinoma lung tissues. Mass spectra obtained from the tissue sections were used to generate and validate statistical classifiers for lung cancer diagnosis and subtyping. Classifiers were then tested on DESI-MSI data collected from 16 clinical FNA samples prospectively collected from 8 patients undergoing interventional radiology guided FNA.RESULTSVarious metabolites and lipid species were detected in the mass spectra obtained from lung tissues. The classifiers generated from tissue sections yielded 100% accuracy, 100% sensitivity, and 100% specificity for lung cancer diagnosis, and 73.5% accuracy for lung cancer subtyping for the training set of tissues, per-patient. On the validation set of tissues, 100% accuracy for lung cancer diagnosis and 94.1% accuracy for lung cancer subtyping were achieved. When tested on the FNA samples, 100% diagnostic accuracy and 87.5% accuracy on subtyping were achieved per-slide.ConclusionsDESI-MSI can be useful as an ancillary technique to conventional cytopathology for diagnosis and subtyping of non-small cell lung cancers.

PURPOSE. Apoptosis, in the context of cancer, is a form of programmed cell death induced by chemotherapy, radiotherapy, and immunotherapy. As this is a central pathway in treatment response, considerable effort has been expended on the development of molecular imaging agents to non-invasively measure tumor apoptosis prior to quantitative changes in tumor dimensions. Despite these efforts, clinical trials directed at imaging apoptosis by PET, SPECT, and MRI have failed to robustly predict response to treatment with high sensitivity and specificity. Although these shortcomings may be linked to probe design, we propose that the combination of variability in the timing of maximal in vivo tumor apoptosis and sub-optimal sampling times fundamentally limits the predictive power of PET/SPECT apoptosis imaging. PROCEDURES. Herein, we surveyed the literature describing the time-course of therapy-induced tumor apoptosis in vivo and used these data to construct a mathematical model describing the onset, duration, amplitude, and variability of the apoptotic response. Uncertainty in the underlying time of initiation of tumor apoptosis was simulated by Gaussian, uniform, and Landau distributions centered at the median time-to-maximum apoptotic rate derived from the literature. We then computationally sampled these models for various durations to simulate PET/SPECT imaging agents with variable effective half-lives. RESULTS. Models with a narrow Gaussian distribution of initiation times for tumor apoptosis predicted high contrast ratios and strong predictive values for all effective tracer half-lives. However, when uncertainty in apoptosis initiation times were simulated with uniform and Landau distributions, high contrast ratios and predictive values were only obtained with extremely long imaging windows (days). The imaging contrast ratios predicted in these models were consistent with those seen in pre-clinical apoptosis PET/SPECT imaging studies and suggest that uncertainty in the timing of tumor cell death plays a significant role in the maximal contrast obtainable. Moreover, when uncertainty in both apoptosis initiation and imaging start times were simulated, the predicted contrast ratios were dramatically reduced for all tracer half-lives. CONCLUSIONS. These studies illustrate the effect of uncertainty of apoptosis initiation on the predictive power of PET/SPECT apoptosis imaging agents and suggest that long integration times are required to surmount uncertainty in the time domain of this biological process.

The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39-45 degrees C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 degrees C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors.

Background: Thermoembolization presents a unique treatment alternative for patients diagnosed with hepatocellular carcinoma. The approach delivers a reagent that undergoes an exothermic chemical reaction and combines the benefits of embolic as well as thermal- and chemical-ablative therapy modalities. The target tissue and vascular bed are subjected to simultaneous hyperthermia, ischemia, and chemical denaturation in a single procedure. To guide optimal delivery, we developed a mathematical model for understanding the competing diffusive and convective effects observed in thermoembolization delivery protocols.Methods: A mixture theory formulation was used to mathematically model thermoembolization as chemically reacting transport of an electrophile, dichloroacetyl chloride (DCACl), within porous living tissue. Mass and energy transport of each relevant constituent are considered. Specifically, DCACl is injected into the vessels and exothermically reacts with water in the blood or tissue to form dichloroacetic acid and hydrochloric acid. Neutralization reactions are assumed instantaneous in this approach. We validated the mathematical model predictions of temperature using MR thermometry of the thermoembolization procedure performed in ex vivo kidney.Results: Mathematical modeling predictions of tissue death were highly dependent on the vascular geometry, injection pressure, and intrinsic amount of exothermic energy released from the chemical species, and were able to recapitulate the temperature distributions observed in MR thermometry.Conclusion: These efforts present a first step toward formalizing a mathematical model for thermoembolization and are promising for providing insight for delivery protocol optimization. While our approach captured the observed experimental temperature measurements, larger-scale experimental validation is needed to prioritize additional model complexity and fidelity.

Simple Summary Liver cancer is a growing problem around the world. Drugs for liver cancer have limited effect, there are not enough donors for liver transplants and many patients are not candidates for surgery to remove the tumor. In many of these cases, hyperthermia can destroy the tumor in situ with minimally invasive methods such as radiofrequency or microwave ablation. In this paper we review the literature evaluating success rates for complete ablation as judged by actual examination of treated tumors that were removed when patients received a liver transplant. While notable successes can be achieved with ablation, the published studies indicate both that complete treatment is not as common as thought and that imaging methods such as computed tomography and magnetic resonance scans do not completely identify residual cancer. There is therefore an important opportunity for improvement in the treatment of this disease. Abstract Radiofrequency ablation (RFA) and microwave ablation (MWA) are the most widely studied and applied ablation techniques for treating primary and secondary liver tumors. These techniques are considered curative for small hepatic tumors, with post-ablation outcomes most commonly assessed by an imaging follow up. However, there is increasing evidence of a discrepancy between radiological and pathological findings when ablated lesions are evaluated following liver resection or liver transplantation. A comprehensive review of the available literature reporting the complete pathological response (cPR) following RFA and MWA was performed to estimate the success rate and identify the factors associated with treatment failure. Following RFA, cPR is reported in 26–96% of tumors compared to 57–95% with MWA. Larger tumor size and vessels larger than 3 mm adjacent to the treated tumor are the most important factors identified by previous studies associated with viable residual tumors after RFA. Correlating post-ablation radiological studies with pathological findings shows that computed tomography (CT) and magnetic resonance imaging (MRI) have low sensitivity but high specificity for detecting residual viable or recurrent hepatocellular carcinoma (HCC) tumors. There are promising recent reports combining multiprobe ablation techniques with three-dimensional treatment planning software and stereotactic-aiming instrumentation to achieve more than 90% cPR in both small and large HCC tumors. In conclusion, the reported success for achieving cPR in HCC following RFA and MWA is highly variable in different studies and decreases with increasing lesion size and unfavorable tumor characteristics. Very few studies have reported a high rate of cPR. As these studies are single-center and retrospective, they need to be further validated and reproduced in other clinical settings.

Searching the literature is often overlooked and receives inadequate attention. In this article, we seek to address this issue by presenting several strategies. Here, five steps are outlined and discussed to facilitate effective literature searching.

Interventional radiology (IR) needs comprehensive structure. The reactive structure of the past is strategically unwise for long-term growth of IR.IR needs a structured approach to move forward most effectively. A preliminary taxonomic scaffold is put forth and critically analyzed to illustrate new areas of research for the field, to identify new opportunities for growth, and to serve as a starting point for future discussion.

Purpose: MR temperature imaging (MRTI) was employed for visualizing the spatiotemporal evolution of the exotherm of thermoembolization, an investigative transarterial treatment for solid tumors. Materials and methods: Five explanted kidneys were injected with thermoembolic solutions, and monitored by MRTI. In three nonselective experiments, 5 ml of 4 mol/l dichloroacetyl chloride (DCA-Cl) solution in a hydrocarbon vehicle was injected via the main renal artery. For two of these three, MRTI temperature data were compared to fiber optic thermal probes. Another two kidneys received selective injections, treating only portions of the kidneys with 1 ml of 2 mol/l DCA-Cl. MRTI data were acquired and compared to changes in pre- and post-injection CT. Specimens were bisected and photographed for gross pathology 24 h post-procedure. Results: MRTI temperature estimates were within ±1 °C of the probes. In experiments without probes, MRTI measured increases of 30 °C. Some regions had not reached peak temperature by the end of the >18 min acquisition. MRTI indicated the initial heating occurred in the renal cortex, gradually spreading more proximally toward the main renal artery. Gross pathology showed the nonselective injection denatured the entire kidney whereas in the selective injections, only the treated territory was coagulated. Conclusion: The spatiotemporal evolution of thermoembolization was visualized for the first time using noninvasive MRTI, providing unique insight into the thermodynamics of thermoembolization. Précis Thermoembolization is being investigated as a novel transarterial treatment. In order to begin to characterize delivery of this novel treatment modality and aid translation from the laboratory to patients, we employ MR temperature imaging to visualize the spatiotemporal distribution of temperature from thermoembolization in ex vivo tissue.

Convective transport is an important phenomenon for nanomedicine delivery. We present an imaging-based approach to recover tissue properties that are significant in the accumulation of nanoparticles delivered via systemic methods. The classical pharmacokinetic analysis develops governing equations for the particle transport from a first principle mass balance. Fundamentally, the governing equations for compartmental mass balance represent a spatially invariant mass transport between compartments and do not capture spatially variant convection phenomena. Further, the parameters recovered from this approach do not necessarily have direct meaning with respect to the governing equations for convective transport. In our approach, a framework is presented for directly measuring permeability in the sense of Darcy flow through porous tissue. Measurements from our approach are compared to an extended Tofts model as a control. We demonstrate that a pixel-wise iterative clustering algorithm may be applied to reduce the parameter space of the measurements. We show that measurements obtained from our approach are correlated with measurements obtained from the extended Tofts model control. These correlations demonstrate that the proposed approach contains similar information to an established compartmental model and may be useful in providing an alternative theoretical framework for parameterizing mathematical models for treatment planning and diagnostic studies involving nanomedicine where convection dominated effects are important.

Primary liver cancer, or hepatocellular carcinoma (HCC), is a major worldwide cause of death from carcinoma. Most patients are not candidates for surgery and medical therapies, including new immunotherapies, have not shown major improvements since the modest benefit seen with the introduction of sorafenib over a decade ago. Locoregional therapies for intermediate stage disease are not curative but provide some benefit. However, upon close scrutiny, there is still residual disease in most cases. We review the current status for treatment of intermediate stage disease, summarize the literature on correlative histopathology, and discuss emerging methods at micro-, nano-, and pico-scales to improve therapy. These include transarterial hyperthermia methods and thermoembolization, along with microfluidics model systems and new applications of mass spectrometry imaging for label-free analysis of pharmacokinetics and pharmacodynamics.

In chronic liver diseases and hepatocellular carcinoma, the cells and extracellular matrix of the liver undergo significant alteration in response to chronic injury. Recent literature has highlighted the critical, but less studied, role of the liver vasculature in the progression of chronic liver diseases. Recent advancements in liver-on-a-chip systems has allowed in depth investigation of the role that the hepatic vasculature plays both in response to, and progression of, chronic liver disease. In this review, we first introduce the structure, gradients, mechanical properties, and cellular composition of the liver and describe how these factors influence the vasculature. We summarize state-of-the-art vascularized liver-on-a-chip platforms for investigating biological models of chronic liver disease and their influence on the liver sinusoidal endothelial cells of the hepatic vasculature. We conclude with a discussion of how future developments in the field may affect the study of chronic liver diseases, and drug development and testing.

Hepatocellular carcinoma is a growing worldwide problem with a high mortality rate. This malignancy does not respond well to chemotherapy, and most patients present late in their disease at which time surgery is no longer an option. Over the past three decades, minimally invasive methods have evolved to treat unresectable disease and prolong survival. Intra-arterial embolization techniques are used for large or multiple tumors but have distressingly high levels of local recurrence and can be costly to implement. A new method called thermoembolization was recently reported, which destroys target tissue by combining reactive exothermic chemistry with an extreme local change in pH and ischemia. Described herein are experiments performed using this technique in vivo in a swine model. A microcatheter was advanced under fluoroscopic guidance into a branch of the hepatic artery to deliver a targeted dose of dichloroacetyl chloride dissolved in ethiodized oil into the liver. The following day, the animals were imaged by computed tomography and euthanized. Assessing the reaction product distribution and establishing a correlation with the effects are important for understanding the effects. This presented a significant challenge, however, as the reagent used does not contain a chromophore and is not otherwise readily detectable. Mass spectrometry imaging was employed to determine spatial distribution in treated samples. Additional insights on the biology were obtained by correlating the results with histology, immunohistochemistry, and immunofluorescence. The results are encouraging and may lead to a therapy with less local recurrence and improved overall survival for patients with this disease.

Embolotherapies are commonly used for management of primary liver cancer. Explant studies of treated livers, however, reveal an untreated tumor in a high fraction of cases. To improve on this, we propose a new concept referred to as thermoembolization. In this technique, the embolic material reacts in local tissues. Highly localized heat energy is released simultaneously with the generation of acid in the target vascular bed. Combined with ischemia, this should provide a multiplexed attack. We report herein our initial results testing the feasibility of this method in vivo. Institutional approval was obtained, and three outbred swine were treated in a segmental hepatic artery branch (right or left medial lobe) with thermoembolic material (100, 400, or 500 µL). Solutions (2 or 4 mol/L) of an acid chloride were made using ethiodized oil as the vehicle. Animals were housed overnight, scanned by CT, and euthanized. Necropsy samples of treated tissue were obtained for histologic analysis. All animals survived the procedure. Vascular stasis occurred rapidly in all cases despite the small volumes used. The lower concentration (2 mol/L) penetrated more distally than the 4 mol/L solution. At CT the following day, vascular casts of ethiodized oil were observed, indicating recanalization had not occurred. Histology specimens demonstrated coagulative necrosis centered on the vessel lumen extending for several hundred microns with a peripheral inflammatory infiltrate. Thermoembolization is a new technique for embolization with initial promise. However, results indicate much work must be done to optimize the technique.

Simple Summary Minimally invasive procedures that directly deliver heat into tumors are commonly used to treat a wide range of malignancies. In this review, we discuss the potential role that these procedures can play in not only destroying small tumors but also educating the immune system to recognize and attack tumors throughout the body. Abstract Thermal ablation is a cornerstone in the management of cancer patients. Typically, ablation procedures are performed for patients with a solitary or oligometastatic disease with the intention of eradicating all sites of the disease. Ablation has traditionally played a less prominent role for patients with a widely metastatic disease. For such patients, attempting to treat numerous sites of disease compounds potential risks without a clear clinical benefit and, as such, a compelling justification for performing an intervention that is unlikely to alter a patient’s clinical trajectory is uncommon. However, the discovery of immune checkpoints and the development of immune checkpoint inhibitors have brought a new perspective to the relevance of local cancer therapies such as ablation for patients with a metastatic disease. It is becoming increasingly apparent that local cancer therapies can have systemic immune effects. Thus, in the new perspective of cancer care centered upon immunologic principles, there is a strong interest in exploring the utility of ablation for patients with a metastatic disease for its immunologic implications. In this review, we summarize the unmet clinical need for adjuvant interventions such as ablation to broaden the impact of systemic immunotherapies. We additionally highlight the extant preclinical and clinical data for the immunogenicity of common thermal ablation modalities.

Background Assessments of the quantitative limitations among the six commercially available dual-energy (DE) CT acquisition schemes used by major CT manufacturers could aid researchers looking to use iodine quantification as an imaging biomarker. Purpose To determine the limits of detection and quantification of DE CT in phantoms by comparing rapid peak kilovoltage switching, dual-source, split-filter, and dual-layer detector systems in six different scanners. Materials and Methods Seven 50-mL iohexol solutions were used, with concentrations of 0.03-2.0 mg iodine per milliliter. The solutions and water sample were scanned five times each in two phantoms (small, 20-cm diameter; large, 30 × 40-cm diameter) with six DE CT systems and a total of 10 peak kilovoltage settings or combinations. Iodine maps were created, and the mean iodine signal in each sample was recorded. The limit of blank (LOB) was defined as the upper limit of the 95% confidence interval of the water sample. The limit of detection (LOD) was defined as the concentration with a 95% chance of having a signal above the LOB. The limit of quantification (LOQ) was defined as the lowest concentration where the coefficient of variation was less than 20%. Results The LOD range was 0.021-0.26 mg/mL in the small phantom and 0.026-0.55 mg/mL in the large phantom. The LOQ range was 0.07-0.50 mg/mL in the small phantom and 0.20-1.0 mg/mL in the large phantom. The dual-source and rapid peak kilovoltage switching systems had the lowest LODs, and the dual-layer detector systems had the highest LODs. Conclusion The iodine limit of detection using dual-energy CT systems varied with scanner and phantom size, but all systems depicted iodine in the small and large phantoms at or below 0.3 and 0.5 mg/mL, respectively, and enabled quantification at concentrations of 0.5 and 1.0 mg/mL, respectively. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Hindman in this issue.

Computed tomography (CT) technology has rapidly evolved since its introduction in the 1970s. It is a highly important diagnostic tool for clinicians as demonstrated by the significant increase in utilization over several decades. However, much of the effort to develop and advance CT applications has been focused on improving visual sensitivity and reducing radiation dose. In comparison to these areas, improvements in quantitative CT have lagged behind. While this could be a consequence of the technological limitations of conventional CT, advanced dual-energy CT (DECT) and photon-counting detector CT (PCD-CT) offer new opportunities for quantitation. Routine use of DECT is becoming more widely available and PCD-CT is rapidly developing. This review covers efforts to address an unmet need for improved quantitative imaging to better characterize disease, identify biomarkers, and evaluate therapeutic response, with an emphasis on multi-energy CT applications. The review will primarily discuss applications that have utilized quantitative metrics using both conventional and DECT, such as bone mineral density measurement, evaluation of renal lesions, and diagnosis of fatty liver disease. Other topics that will be discussed include efforts to improve quantitative CT volumetry and radiomics. Finally, we will address the use of quantitative CT to enhance image-guided techniques for surgery, radiotherapy and interventions and provide unique opportunities for development of new contrast agents.

Purpose To evaluate trifluoroacetic acid (TFA) as a theranostic chemical ablation agent and determine the efficacy of TFA for both noninvasive imaging and tissue destruction. Materials and Methods Fluorine-19 magnetic resonance imaging (19F-MRI) was optimized at 7 T using a custom-built volume coil. Fluorine images were acquired with both rapid acquisition with relaxation enhancement and balanced steady-state free precession (bSSFP) sequences with varying parameters to determine the optimal sequence for TFA. The theranostic efficacy of chemical ablation was examined by injecting TFA (100 μL; 0.25, 0.5, 1.0, and 2.0M) into ex vivo porcine liver. 19F and proton MRI were acquired and superimposed to visualize distribution of TFA in tissue and quantify sensitivity. Tissue damage was evaluated with gross examination, histology, and fluorescence microscopy. Results The optimal 19F-MRI sequence was found to be bSSFP with a repetition time of 2.5 ms and flip angle of 70°. The minimum imageable TFA concentration was determined to be 6.7 ± 0.5 mM per minute of scan time (0.63×0.63×5.00 mm voxel), and real-time imaging (temporal resolution of at least 1 s-1) was achieved with 2M TFA both in vitro and in ex vivo tissue. TFA successfully coagulated tissue, and damage was locally confined. In addition to hepatic cord disruption, cytoskeletal collapse and chromatin clumping were observed in severely damaged areas in tissues treated with 0.5M or higher TFA concentrations. Conclusions TFA was determined to be a theranostic agent for chemical ablation of solid tissue. Ablation was both efficacious and imageable in ex vivo healthy tissue, even at low concentrations or with high temporal resolution.

OBJECTIVES/GOALS: The purpose of this work is to investigate natural buffering capacity of liver tissue and tumors, to understand and exploit differences for therapy. Using this work, we will determine the concentrations of reagents (acids or bases) used in ablation treatment to optimize treatment by increasing tumor toxicity and minimizing healthy tissue toxicity. METHODS/STUDY POPULATION: For this preliminary study, two methods will be used: benchtop pH experiments ex vivo and non-invasive imaging using acidoCEST MRI in vivo. For ex vivo, two types of tissues will be tested: non-cancerous liver and tumor tissue from HepG2 inoculated mice (n = 10). After mice are euthanized, pH will be measured in tissue homogenates at baseline and then the homogenates will be placed in either acidic (acetic acid) or basic (sodium hydroxide) solutions with varied concentrations (0.5–10M) and time recorded until pH returns to baseline. For in vivo imaging, Mia PaCA-2 flank model mice (n = 10) will be imaged with acidoCEST MRI to quantify pH at baseline. Mice will then be injected intratumorally with (up to 100 μL of) acid or base at increasing concentrations and imaged to quantify pH changes in the tumor. RESULTS/ANTICIPATED RESULTS: For this study, buffering capacity is defined as the concentration threshold for which tissue can buffer pH back to within normal range. Non-cancerous tissue is likely to buffer a wider range of concentrations compared to tumor tissue. From the benchtop experiment, comparison of time-to-buffer will be made for each concentration of acid/base for the two tissue types. AcidoCEST MRI will provide in vivo buffering capacity and potentially demonstrate tumor heterogeneity of buffering capacity. For both experiments, a pH vs. concentration curve for the two tissue types will allow for comparison of ex vivo to in vivo experiments, which will differentiate contributions of local tissue buffering capacity from the full body’s natural bicarbonate buffer system that depends on respiration and blood flow. DISCUSSION/SIGNIFICANCE OF IMPACT: The pH of the body must be maintained within a narrow range. With cancer, impairment in regulation of tumor metabolism causes acidosis, lowering extracellular pH in tumors. It remains unclear if pH plays a role in local recurrence or tumor toxicity. This work will determine if acidoCEST MRI can measure deliberate alteration of pH and how this change affects biology.

A molecular dynamics approach to understanding fundamental mechanisms of combined thermal and osmotic stress induced by thermochemical ablation (TCA) is presented.Structural models of fibronectin and fibronectin bound to its integrin receptor provide idealized models for the effects of thermal and osmotic stress in the extracellular matrix. Fibronectin binding to integrin is known to facilitate cell survival. The extracellular environment produced by TCA at the lesion boundary was modelled at 37 °C and 43 °C with added sodium chloride (NaCl) concentrations (0, 40, 80, 160, and 320 mM). Atomistic simulations of solvated proteins were performed using the GROMOS96 force field and TIP3P water model. Computational results were compared with the results of viability studies of human hepatocellular carcinoma (HCC) cell lines HepG2 and Hep3B under matching thermal and osmotic experimental conditions.Cell viability was inversely correlated with hyperthermal and hyperosmotic stresses. Added NaCl concentrations were correlated with a root mean square fluctuation increase of the fibronectin arginylglycylaspartic acid (RGD) binding domain. Computed interaction coefficients demonstrate preferential hydration of the protein model and are correlated with salt-induced strengthening of hydrophobic interactions. Under the combined hyperthermal and hyperosmotic stress conditions (43 °C and 320 mM added NaCl), the free energy change required for fibronectin binding to integrin was less favorable than that for binding under control conditions (37 °C and 0 mM added NaCl).Results quantify multiple measures of structural changes as a function of temperature increase and addition of NaCl to the solution. Correlations between cell viability and stability measures suggest that protein aggregates, non-functional proteins, and less favorable cell attachment conditions have a role in TCA-induced cell stress.

Multiple studies in the literature have proposed diagnostic thresholds based on Multi-Energy Computed Tomography (MECT) iodine maps. However, it is critical to determine the minimum detectable iodine concentration for MECT systems to assure the clinical accuracy for various measured concentrations for these image types. In this study, seven serial dilutions of iohexol were made with concentrations from 0.03 to 2.0 mg Iodine/mL in 50 mL centrifuge tubes. The dilutions and one blank vial were scanned five times each in two scatter conditions: within a 20.0 cm diameter (Head) phantom, and a 30.0 cm x 40.0 cm elliptical (Body) phantom. This was repeated on a total of six scanners from three vendors: fast-kVp switching, dual-source dual-energy CT, dual-layer detector CT, and split-filter CT. Scan parameters and dose were matched as closely as possible across systems, and iodine maps were reconstructed. Regions-of-Interest (ROIs) were placed on 5 consecutive images within each vial, for a total of 25 measurements per sample. The mean and standard deviation were calculated for each sample. The Limit of Detection (LOD) was defined as the concentration that had a 95% chance of having a signal above the 95% confidence interval of the measured blank samples. The range of LODs was 0.021 – 0.484 mg I/mL in the head phantom and 0.125 – 0.547 mg I/mL in the body phantom. The LOD for iodinated contrast using MECT systems changed with scatter and attenuation conditions. The limit of detection for all conditions was under 0.5 mg Iodine/mL.

Ablation is a common procedure for treating patients with cancer, cardiac arrhythmia, and other conditions, yet it can cause collateral injury to the respiratory diaphragm. Collateral injury can alter the diaphragm’s properties and/or lead to respiratory dysfunction. Thus, it is important to understand the diaphragm’s physiologic and biomechanical properties in response to ablation therapies, in order to better understand ablative modalities, minimize complications, and maximize the safety and efficacy of ablative procedures. In this study, we analyzed physiologic and biomechanical properties of swine respiratory diaphragm muscle bundles when exposed to 5 ablative modalities. To assess physiologic properties, we performed in vitro tissue bath studies and measured changes in peak force and baseline force. To assess biomechanical properties, we performed uniaxial stress tests, measuring force–displacement responses, stress–strain characteristics, and avulsion forces. After treating the muscle bundles with all 5 ablative modalities, we observed dose-dependent sustained reductions in peak force and transient increases in baseline force—but no consistent dose-dependent biomechanical responses. These data provide novel insights into the effects of various ablative modalities on the respiratory diaphragm, insights that could enable improvements in ablative techniques and therapies.

Purpose To assess cost effectiveness of radioembolization versus conventional transarterial chemoembolization. Materials and Methods The cost of radioembolization versus conventional transarterial chemoembolization was determined based on Medicare reimbursements. Three patient subgroups were defined based on the Barcelona Clinic Liver Cancer (BCLC) classification system (A, B, or C). Efficacy and safety outcomes after each procedure were obtained from the literature. A Monte Carlo case-based simulation was designed for 60 months in 250 patients in each subgroup. Survival was calculated based on average survival from the literature and the Monte Carlo model. The primary outcome was the cost effectiveness of radioembolization over transarterial chemoembolization by considering calculated survival. Results The costs approached $17,000 for transarterial chemoembolization versus $31,000 or $48,000 for unilobar or bilobar radioembolization, respectively. Based on the simulation, median estimated survival was greater with transarterial chemoembolization than radioembolization in BCLC-A and BCLC-B subgroups (40 months vs 30 months and 23 months vs 16 months, respectively, P = .001). However, in the BCLC-C subgroup, survival was greater with radioembolization than transarterial chemoembolization (13 months vs 17 months, P = .001). The incremental cost-effectiveness ratio of radioembolization over transarterial chemoembolization in the BCLC-C subgroup was $360 per month. The results were dependent on bilobar versus unilobar radioembolization and the total number of radioembolization procedures. Conclusions The model suggests radioembolization costs may be justified for patients with BCLC-C disease, whereas radioembolization may not be cost effective in patients with BCLC-A disease; however, many patients with BCLC-C disease have extensive disease precluding locoregional therapies. Secondary considerations may determine treatment choice in more borderline patients (BCLC-B disease) because there is no persistent survival benefit with radioembolization.

Understanding basic science and technical aspects is essential for scientists and engineers to develop and enhance ablative modalities, and for clinicians to effectively apply therapeutic ablative techniques. An overview of ablative modalities, anatomical locations, and indications for which ablations are performed is presented. Specifically, basic concepts, parameter selection, and underlying biophysics of tissue injury of five currently used therapeutic ablative modalities are reviewed: radiofrequency ablation (RFA), cryoablation (CRA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), and chemical ablation (CHA) (ablative agents: acetic acid, ethanol, hypertonic sodium chloride, and urea). Each ablative modality could be refined for expanding applications, either independently or in combination, for future therapeutic use.

Solid tumors such as hepatocellular carcinoma are very often not amenable to chemotherapy and radiotherapy. Local ablation methods, including chemical ablation with absolute ethanol, are therefore an option for treatment but lack of information about the mechanism of devitalization leading to cell death is a hindrance to further adoption. Systemic toxicity also has limited the amount of ethanol that can be used in a single treatment session. Therefore we evaluated the mechanism of urea, a denaturant with little or no systemic toxicity, for potential use in chemical ablation. In this study we report on the use of three methods to analyze the effects in cell culture with a view towards eventual clinical application. Human hepatoma HuH-7 cells were analyzed at several time points after treatment using FTIR, DSC, and Raman microspectroscopy based on MTT and PI-exclusion viability assays. Time course fractional denaturation data plotted against viability show that a 50% viability drop occurs after only a 10–20% drop in overall protein denaturation. Other methods of cell death such as apoptosis may also be operative, but this result implies that protein denaturation is one of the major mechanisms of cell death. This is in line with what has been previously suggested for purely thermal methods, and opens the way to mechanism-based improvements in chemical ablation of solid tumors.

To investigate simultaneous and sequential injection thermochemical ablation in a porcine model, and compare them to sham and acid-only ablation.This IACUC-approved study involved 11 pigs in an acute setting. Ultrasound was used to guide placement of a thermocouple probe and coaxial device designed for thermochemical ablation. Solutions of 10 M acetic acid and NaOH were used in the study. Four injections per pig were performed in identical order at a total rate of 4 mL/min: saline sham, simultaneous, sequential, and acid only. Volume and sphericity of zones of coagulation were measured. Fixed specimens were examined by HE stain.Average coagulation volumes were 11.2 mL (simultaneous), 19.0 mL (sequential) and 4.4 mL (acid). The highest temperature, 81.3°C, was obtained with simultaneous injection. Average temperatures were 61.1°C (simultaneous), 47.7°C (sequential) and 39.5°C (acid only). Sphericity coefficients (0.83-0.89) had no statistically significant difference among conditions.Thermochemical ablation produced substantial volumes of coagulated tissues relative to the amounts of reagents injected, considerably greater than acid alone in either technique employed. The largest volumes were obtained with sequential injection, yet this came at a price in one case of cardiac arrest. Simultaneous injection yielded the highest recorded temperatures and may be tolerated as well as or better than acid injection alone. Although this pilot study did not show a clear advantage for either sequential or simultaneous methods, the results indicate that thermochemical ablation is attractive for further investigation with regard to both safety and efficacy.

To explore the effects of volume and concentration in thermochemical ablation using an in vivo porcine model.Twelve swine 60-75 kg were used in this institutionally approved study. A needle design prototype coaxial device for reagent injections and a thermocouple were inserted into surgically exposed liver. Simultaneously, an acid and base (acetic acid and NaOH) were injected at 4 mL/min based on a 3 × 3 matrix with concentration (5, 10, and 15 mol/L) and volume on the axes (total volumes of 1, 2, and 4 mL). Three animals (centre grid position) strengthened the statistical analysis. Each animal received four identical injections (total 48). Temperatures and heart rate were recorded. Livers were formalin-fixed after sacrifice. After sectioning, coagulation zones were analysed by two observers. Area and slice thickness were used to calculate the volume, surface area, and sphericity for each treatment.Coagulation volumes ranged from 2.95 ± 0.29 to 14.72 ± 1.42 mL with a maximum of 18.3 mL. Highest peak temperature was 105°C with temperatures ranging 43.5 ± 2.6°C to 91.0 ± 6.5°C. There was no association between conditions and sphericity or heart rate.The method can be used successfully to ablate tissue in vivo. By neutralising acid in situ and releasing heat and a salt, this technique improves considerably upon the use of acetic acid used alone. Peak temperatures exceeded accepted coagulation thresholds even if the only mechanism operating was hyperthermia. Reagent concentrations and volumes increased the amount of the coagulum but not in a linear fashion.

MicroRNAs are small (~22 nt), noncoding RNA molecules that have critical cellular functions in proliferation, differentiation, angiogenesis and apoptosis. miRNA expression profiling has been used to create signatures of solid tumors and, in many cases, it has been shown to correlate with the severity of the disease. The rabbit VX2 tumor model has been used widely to study a number of human cancers. Our objective in this study is to generate an miRNA signature of the VX2 tumor and to identify miRNAs that are highly expressed in this aggressive tumor. In this study, we performed miRNA profiling of the rabbit VX2 tumor using a microarray that has probes for 1292 unique miRNAs. Their expression in tumor samples was quantified and analyzed. We found that 35 miRNAs were significantly up-regulated in the VX2 tumor. Among these, 13 human miRNAs and eight members of the let-7 family were previously identified in cancers. In addition, we show that the expression of three miRNAs (miR-923, miR-1275, and miR-1308) is novel for the rabbit VX2 tumor, and their expression was not previously shown to be associated with any type of cancer. For the first time, we show the miRNA signature profile for a solid tumor in a rabbit model. miRNAs highly expressed in the VX2 tumor may serve as novel candidates for molecular biomarkers and as potential drug targets.

To establish proof of concept in tissue, using the exothermic neutralization reaction of acetic acid and sodium hydroxide in ex vivo porcine liver and to conduct an initial probe into the relationships of volume and concentration of reagents to temperatures and the areas affected.A total of 0.5 mL or 2 mL of either 5 mole/L or 10 mole/L acid and base solutions was injected simultaneously into the periphery of ex vivo porcine liver using a prototype injection device. Tissue temperature was recorded at the injection site for 5 minutes using a type T thermocouple temperature probe inserted parallel to and near the tip of the injection device. The injections were repeated for infrared thermography, and ablated tissues were sectioned quickly and imaged. A gross photograph was captured in each case to provide correlation.Maximum temperatures (17°C baseline) ranged from 42.1° ± α3.34°C to 61.7° ± α10°C (P.05) when injecting 0.5 mL of 5 mole/L reactants and 2 mL of 10 mole/L reactants, respectively. The maximum temperature measured by infrared imaging ranged from 31°-47°C. Using an infrared viewing scale from 19°-40°C, the cross-sectional area of tissue heating above baseline measured from 1.07 cm(2)± 0.45 to 4.95 cm(2)± 0.28 (P05).The reaction of acetic acid and sodium hydroxide releases significant heat energy at the site of injection, and histologic changes are consistent with coagulation necrosis. Increased reagent concentration and volume were associated with larger temperature changes and larger areas of hyperthermia at gross pathology and infrared imaging.

Rationale Advances in image-guided drug delivery for liver cancer have shown a significant survival benefit. However, incomplete treatment is common and residual disease is often found in explanted liver specimens. In addition, the need to treat a malignancy from multiple mechanisms at the same time for optimal outcomes is becoming more widely appreciated. To address this, we hypothesized that an exothermic chemical reaction could be performed in situ. Such a strategy could in principle combine several angles of attack, including ischemia, hyperthermia, acidic protein denaturation, and metabolic modulation of the local environment. Methods The University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee approved this study. Outbred swine (25–35 kg, 5 control and 5 experimental) were treated under general anesthesia. Embolization was performed with coaxial microcatheter technique in a segmental hepatic arterial branch using either ethiodized oil as control or with thermoembolic solutionBlood samples were obtained before, immediately after, and the day following the procedure just before CT scans and euthanasia. Livers were explanted and samples were obtained for histologic analysis. Results All animals survived the procedure and laboratory values of the control and experimental groups remained within normal limits. The control group had a diffuse or cloudy pattern of attenuation on follow-up CT scan the day after, consistent with gradual antegrade sinusoidal transit of the embolic material. The experimental group had clearly defined vascular casts with some degree of peripheral involvement. At histology, the control group samples had the appearance of normal liver, whereas the experimental group had coagulative necrosis in small pale, punctate areas extending several hundred microns away from the treated vessels and a brisk inflammatory response just outside the margins. Conclusion In situ chemistry via thermoembolization shows early promise as a fundamentally new tactic for image-guided therapy of solid tumors.

To evaluate exothermic permanganate redox chemistry for utility in tumour ablation.Sodium permanganate (1-3 mL, 1 or 2 M) and glycerol (1 mL, 1 M) were injected in triplicate into a beaker using three injection orders: (1) simultaneous, (2) glycerol injection then permanganate injection, (3) permanganate injection then glycerol injection. Selected experiments were repeated with glucose, sucrose, dextrin, maltodextrin, different polysaccharides, and polyvinyl alcohol as substrates. Simultaneous injections of permanganate (0.5 and 1 mL, 2 M) and glucose (1 mL, 1 M) into explanted porcine muscle were also performed. Temperatures were recorded with a thermocouple probe or an infrared camera.With optimal conditions of 2 M permanganate and 1 M glycerol at 1 mL each, an average maximum temperature of 97.4 degrees C was obtained for all three injection orders. When glucose and sucrose were used as the substrates, similar temperatures were achieved but at different rates. Dextrin and maltodextrin (180 g/L) led to maximum temperatures of 42.5 degrees and 51.1 degrees C respectively when simultaneously injected with permanganate (1 mL, 2 M). Polysaccharides and polyvinyl alcohols under the same conditions resulted in a minimal temperature increase. Intramuscular injections of glucose (0.5 mL, 1 M) and permanganate (0.5 mL, 2 M) reached an average temperature of 76.5 degrees C at the lesion site.The permanganate redox reaction is a powerful system with potential to reach tumouricidal temperatures. The reagent volumes, concentrations, injection order, and substrate choice allow a measure of control over the reaction.

Animal models will play an increasingly important role in oncology research, especially for solid tumours such as hepatocellular carcinoma that are resistant to chemotherapy. Many models have been used, but there is a need for increased awareness of the limitations of these models and also a need for guidance for future model development.

Visualizing the movement of angiocatheters during endovascular interventions is typically accomplished using x-ray fluoroscopy. There are many potential advantages to developing magnetic resonance imaging-based approaches that will allow three-dimensional imaging of the tissue/vasculature interface while monitoring other physiologically-relevant criteria, without exposing the patient or clinician team to ionizing radiation. Here we introduce a proof-of-concept development of a magnetic resonance imaging-guided catheter tracking method that utilizes hyperpolarized silicon particles. The increased signal of the silicon particles is generated via low-temperature, solid-state dynamic nuclear polarization and the particles retain their enhanced signal for ≥40 minutes—allowing imaging experiments over extended time durations. The particles are affixed to the tip of standard medical-grade catheters and are used to track passage under set distal and temporal points in phantoms and live mouse models. With continued development, this method has the potential to supplement x-ray fluoroscopy and other MRI-guided catheter tracking methods as a zero-background, positive contrast agent that does not require ionizing radiation.

because the image processor usually accommodates their presence. The operator briefly saw the marker wire at the start of the procedure and was able to avoid irradiating the marked area during the intervention by working at different gantry angles. Because no clinical image of the marker was saved, its appearance was recreated using the same fluoroscope and a 20-cm-thick plastic phantom; this was similar to the main section of the Nationwide Evaluation of X-ray Trends abdominal phantom (3). A sample of the solder marker wire, two sections of a 0.014-inch guide wire, and a stent were placed in the center of the phantom. The assembly was placed on the fluoroscopic table with the wires at isocenter. The phantom was imaged using the 20-cm field of view, 15 frames/s, and the system’s lowest fluoroscopic dose-rate setting. Images were retrospectively captured and transferred to a picture archiving and communication system (PACS). Figure 2 is a small portion of a single fluoroscopic frame stored in the

Thermochemical ablation is a recently developed minimally invasive method with potential for solid tumor treatment such as in liver cancer. A recently described prototype device, however, is too large for use in the more common rodent models of cancer. In this report we describe a simple, low-cost variant of the device that is easy to assemble, small enough to be readily applicable to small animal models, and then demonstrate its use in an ex vivo model for ablation. It should therefore enable study of the method without requiring specialized equipment or access to a machine shop for device manufacture.