Dual-Channel Stretchable, Self-Tuning, Liquid Metal Coils and Their Fabrication Techniques.

Flexible and stretchable radiofrequency coils for magnetic resonance imaging represent an emerging and rapidly growing field. The main advantage of such coil designs is their conformal nature, enabling a closer anatomical fit, patient comfort, and freedom of movement. Previously, we demonstrated a proof-of-concept single element stretchable coil design with a self-tuning smart geometry. In this work, we evaluate the feasibility of scaling this coil concept to a multi-element coil array and the associated engineering and manufacturing challenges. To this goal, we study a dual-channel coil array using full-wave simulations, bench testing, in vitro, and in vivo imaging in a 3 T scanner. We use three fabrication techniques to manufacture dual-channel receive coil arrays: (1) single-layer casting, (2) double-layer casting, and (3) direct-ink-writing. All fabricated arrays perform equally well on the bench and produce similar sensitivity maps. The direct-ink-writing method is found to be the most advantageous fabrication technique for fabrication speed, accuracy, repeatability, and total coil array thickness (0.6 mm). Bench tests show excellent frequency stability of 128 ± 0.6 MHz (0% to 30% stretch). Compared to a commercial knee coil array, the stretchable coil array is more conformal to anatomy and provides 50% improved signal-to-noise ratio in the region of interest.

Overview of Interventional Pulmonology for Radiologists.

Interventional pulmonology is a growing field specializing in minimally invasive procedures of the mediastinum, lungs, airways, and pleura. These procedures have both diagnostic and therapeutic indications and are performed for benign and malignant diseases. Endobronchial US has been combined with transbronchial needle aspiration to extend tissue sampling beyond the airways and into the lungs and mediastinum. Recent innovations extending the peripheral access of bronchoscopy include electromagnetic navigational bronchoscopy and thinner bronchoscopes. An important indication for therapeutic bronchoscopy is the relief of central airway obstruction, which may be severe and life threatening. Techniques for restoring patency of the central airways include mechanical debulking and multiple modalities for ablation, stent placement, and balloon bronchoplasty. Bronchoscopic lung volume reduction improves quality of life in certain patients with severe emphysema and is an important less invasive alternative to lung volume reduction surgery. Bronchial thermoplasty is likewise a nonpharmacologic treatment in patients with severe uncontrolled asthma. Many of these procedures have unique selection criteria that require precise evaluations at preprocedure imaging. Postprocedure imaging is also essential in determining outcome success and the presence of complications. Radiologists should be familiar with these procedures as well as the relevant imaging features in both planning and later surveillance. Evolving techniques that may become more widely available in the near future include robotic-assisted bronchoscopy, bronchoscopic transparenchymal nodule access, transbronchial cryobiopsy, ablation of early-stage cancers, and endobronchial intratumoral chemotherapy. An invited commentary by Wayne et al is available online. ©RSNA, 2021.

Shear Wave Elastography to Assess False Vocal Folds in Healthy Adults: A Feasibility Study.

OBJECTIVES: The aim of the study was to investigate the feasibility of using ultrasound shear wave elastography to quantify mechanical properties and movement symmetry of false vocal folds positioned in adduction and abduction. METHODS: We prospectively measured the shear wave velocity (SWV) within the bilateral false vocal folds in 10 healthy adults using acoustic radiation force impulse imaging. From a transcutaneous approach at the level of thyroid cartilage, 5 SWV measurements were obtained within each side of the false vocal folds twice in adduction and again in abduction for each participant. Configuration-related differences in the SWV within false vocal folds were compared between adduction and abduction, in addition to differences between the right and left false vocal folds and between men and women, by a paired t test. We developed an SWV index [(SWVgreater - SWVlesser )/SWVgreater ] to assess movement symmetry between the right and left false vocal folds. Intraobserver agreement on repeated measures was examined by the intraclass correlation coefficient. RESULTS: The 10 participants included 5 men and 5 women. We observed that the SWV within false vocal folds was significantly higher in adduction than in abduction (P < .001). The SWV within false vocal folds in adduction was also significantly higher in women compared to men (P < .001). There was no significant difference in the SWV between the right and left false vocal folds in adduction or in abduction or between men and women in abduction (P > .05). The mean SWV index was 0.05 (range, 0.03-0.07). The intraclass correlation coefficient for intraobserver agreement was 0.89 (P < .001). CONCLUSIONS: Shear wave elastography seems to be feasible to quantify mechanical properties and evaluate the symmetry of false vocal folds in healthy adults.

Single-Center Experience Implementing the LOINC-RSNA Radiology Playbook for Adult Abdomen/Pelvis CT and MR Procedures Using a Semi-Automated Method.

The LOINC-RSNA Radiology Playbook represents the future direction of standardization for radiology procedure names. We developed a software solution ("RadMatch") utilizing Python 2.7 and FuzzyWuzzy, an open-source fuzzy string matching algorithm created by SeatGeek, to implement the LOINC-RSNA Radiology Playbook for adult abdomen and pelvis CT and MR procedures performed at our institution. Execution of this semi-automated method resulted in the assignment of appropriate LOINC numbers to 86% of local CT procedures. For local MR procedures, appropriate LOINC numbers were assigned to 75% of these procedures whereas 12.5% of local MR procedures could only be partially mapped. For the standardized local procedures, only 63% of CT and 71% of MR procedures had corresponding RadLex Playbook identifier (RPID) codes in the LOINC-RSNA Radiology Playbook, which limited the utility of RPID codes. RadMatch is a semi-automated open-source software tool that can assist radiology departments seeking to standardize their radiology procedures via implementation of the LOINC-RSNA Radiology Playbook.

Establishing Normal Values for Shear-Wave Elastography of the Renal Cortex in Healthy Adults.

BACKGROUND: Shear-wave elastography of the kidney has emerged as a potential clinical application of this novel imaging tool. However, normal velocity values for shear-wave elastography involving the cortex of healthy kidneys have not been definitively established, and both inter- and intraobserver reliability has yet to be comprehensively evaluated. METHODS: This prospective study involved ultrasound examination of 11 healthy adults. Shear-wave velocity values were obtained at the renal cortex in the longitudinal and transverse planes by both junior (fellow) and senior (attending) radiologists. RESULTS: The mean shear-wave velocity values ranged between 2.82 and 2.9 m/s, which did not vary significantly between observers (junior vs. senior) or method of measurement (longitudinal vs. transverse planes), P = 0.533. However, there was a wide variation for these measurements (0.51-4.99 m/s). Separate analysis of the measurement depth demonstrated no statistically significant association with the shear-wave velocity values, P = 0.477. CONCLUSION: Our results agree with previous publications and help establish normal shear-wave velocity values and their range for the renal cortex in adults.

Imaging Properties of 3D Printed Materials: Multi-Energy CT of Filament Polymers.

Clinical applications of 3D printing are increasingly commonplace, likewise the frequency of inclusion of 3D printed objects on imaging studies. Although there is a general familiarity with the imaging appearance of traditional materials comprising common surgical hardware and medical devices, comparatively less is known regarding the appearance of available 3D printing materials in the consumer market. This work detailing the CT appearance of a selected number of common filament polymer classes is an initial effort to catalog these data, to provide for accurate interpretation of imaging studies incidentally or intentionally including fabricated objects. Furthermore, this information can inform the design of image-realistic tissue-mimicking phantoms for a variety of applications, with clear candidate material analogs for bone, soft tissue, water, and fat attenuation.

Computed Tomography Assessment of Ablation Zone Enhancement in Patients With Early-Stage Lung Cancer After Stereotactic Ablative Radiotherapy.

INTRODUCTION: Stereotactic ablative radiotherapy (SABR) offers a curative treatment for lung cancer in patients who are marginal surgical candidates. However, unlike traditional surgery the lung cancer remains in place after treatment. Thus, imaging follow-up for evaluation of recurrence is of paramount importance. MATERIALS AND METHODS: In this retrospective designed Institutional Review Board-approved study, follow-up contrast-enhanced computed tomography (CT) exams were performed on sixty one patients to evaluate enhancement pattern in the ablation zone at 1, 3, 6, and 12 months after SABR. RESULTS: Eleven patients had recurrence within the ablation zone after SABR. The postcontrast enhancement in the recurrence group showed a washin and washout phenomenon, whereas the radiation-induced lung injury group showed continuous enhancement suggesting an inflammatory process. CONCLUSIONS: The textural feature of the ablation zone of enhancement and perfusion as demonstrated in computed tomography nodule enhancement may allow early differentiation of recurrence from radiation-induced lung injury in patients' status after SABR or primary lung cancer.

Bioengineering Full-scale auricles using 3D-printed external scaffolds and decellularized cartilage xenograft.

Reconstruction of the human auricle remains a formidable challenge for plastic surgeons. Autologous costal cartilage grafts and alloplastic implants are technically challenging, and aesthetic and/or tactile outcomes are frequently suboptimal. Using a small animal "bioreactor", we have bioengineered full-scale ears utilizing decellularized cartilage xenograft placed within a 3D-printed external auricular scaffold that mimics the size, shape, and biomechanical properties of the native human auricle. The full-scale polylactic acid ear scaffolds were 3D-printed based upon data acquired from 3D photogrammetry of an adult ear. Ovine costal cartilage was processed either through mincing (1 mm3) or zesting (< 0.5 mm3), and then fully decellularized and sterilized. At explantation, both the minced and zested neoears maintained the size and contour complexities of the scaffold topography with steady tissue ingrowth through 6 months in vivo. A mild inflammatory infiltrate at 3 months was replaced by homogenous fibrovascular tissue ingrowth enveloping individual cartilage pieces at 6 months. All ear constructs were pliable, and the elasticity was confirmed by biomechanical analysis. Longer-term studies of the neoears with faster degrading biomaterials will be warranted for future clinical application. STATEMENT OF SIGNIFICANCE: Accurate reconstruction of the human auricle has always been a formidable challenge to plastic surgeons. In this article, we have bioengineered full-scale ears utilizing decellularized cartilage xenograft placed within a 3D-printed external auricular scaffold that mimic the size, shape, and biomechanical properties of the native human auricle. Longer-term studies of the neoears with faster degrading biomaterials will be warranted for future clinical application.

Customizable, biocompatible implants for dorsal nasal augmentation: An in vivo pilot study of eight polylactic acid scaffold designs.

Augmentation of the nasal dorsum often requires implantation of structural material. Existing methods include autologous, cadaveric or alloplastic materials and injectable hydrogels. Each of these options is associated with considerable limitations. There is an ongoing need for precise and versatile implants that produce long-lasting craniofacial augmentation. Four separate polylactic acid (PLA) dorsal nasal implant designs were 3D-printed. Two implants had internal PLA rebar of differing porosities and two were designed as "shells" of differing porosities. Shell designs were implanted without infill or with either minced or zested processed decellularized ovine cartilage infill to serve as a "biologic rebar", yielding eight total treatment groups. Scaffolds were implanted heterotopically on rat dorsa (N = 4 implants per rat) for explant after 3, 6, and 12 months followed by volumetric, histopathologic, and biomechanical analysis. Low porosity implants with either minced cartilage or PLA rebar infill had superior volume retention across all timepoints. Overall, histopathologic and immunohistochemical analysis showed a resolving inflammatory response with an M1/M2 ratio consistently favoring tissue regeneration over the study course. However, xenograft cartilage showed areas of degradation and pro-inflammatory infiltrate contributing to volume and contour loss over time. Biomechanical analysis revealed all constructs had equilibrium and instantaneous moduli higher than human septal cartilage controls. Biocompatible, degradable polymer implants can induce healthy neotissue ingrowth resulting in guided soft tissue augmentation and offer a simple, customizable and clinically-translatable alternative to existing craniofacial soft tissue augmentation materials. PLA-only implants may be superior to combination PLA and xenograft implants due to contour irregularities associated with cartilage degradation.

Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells.

BACKGROUND: Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure. RESULTS: We show that both non-tumorigenic (MCF 10A, MCF-12A) and tumorigenic (MCF7) breast epithelial cells exposed to cigarette smoke acquire mesenchymal properties such as fibroblastoid morphology, increased anchorage-independent growth, and increased motility and invasiveness. Moreover, transplantation experiments in mice demonstrate that treatment with cigarette smoke extract renders MCF 10A cells more capable to survive and colonize the mammary ducts and MCF7 cells more prone to metastasize from a subcutaneous injection site, independent of cigarette smoke effects on the host and stromal environment. The extent of transformation and the resulting phenotype thus appear to be associated with the differentiation state of the cells at the time of exposure. Analysis by flow cytometry showed that treatment with CSE leads to the emergence of a CD44(hi)/CD24(low) population in MCF 10A cells and of CD44+ and CD49f + MCF7 cells, indicating that cigarette smoke causes the emergence of cell populations bearing markers of self-renewing stem-like cells. The phenotypical alterations induced by cigarette smoke are accompanied by numerous changes in gene expression that are associated with epithelial to mesenchymal transition and tumorigenesis. CONCLUSIONS: Our results indicate that exposure to cigarette smoke leads to a more aggressive and transformed phenotype in human mammary epithelial cells and that the differentiation state of the cell at the time of exposure may be an important determinant in the phenotype of the final transformed state.

Knockdown of HMGA1 inhibits human breast cancer cell growth and metastasis in immunodeficient mice.

The high mobility group A1 gene (HMGA1) has been previously implicated in breast carcinogenesis, and is considered an attractive target for therapeutic intervention because its expression is virtually absent in normal adult tissue. Other studies have shown that knockdown of HMGA1 reduces the tumorigenic potential of breast cancer cells in vitro. Therefore, we sought to determine if silencing HMGA1 can affect breast cancer development and metastatic progression in vivo. We silenced HMGA1 expression in the human breast cancer cell line MDA-MB-231 using an RNA interference vector, and observed a significant reduction in anchorage-independent growth and tumorsphere formation, which respectively indicate loss of tumorigenesis and self-renewal ability. Moreover, silencing HMGA1 significantly impaired xenograft growth in immunodeficient mice, and while control cells metastasized extensively to the lungs and lymph nodes, HMGA1-silenced cells generated only a few small metastases. Thus, our results show that interfering with HMGA1 expression reduces the tumorigenic and metastatic potential of breast cancer cells in vivo, and lend further support to investigations into targeting HMGA1 as a potential treatment for breast cancer.

Association between left atrial volume index and infarct volume in patients with ischemic stroke.

Background: Left atrial volume index (LAVI) is one marker of atrial myopathy, which is increasingly being recognized as a cause of cardioembolic stroke even in the absence of atrial fibrillation. Cardiac embolism is associated with larger strokes than other stroke mechanisms. The purpose of this study was to examine the association between LAVI and total brain infarct volume in patients with ischemic stroke. Methods: This was a retrospective study of 545 patients prospectively enrolled in the Cornell ActuE Stroke Academic Registry (CAESAR), which includes all acute ischemic stroke patients admitted to our hospital since 2011. LAVI measurements were obtained from our echocardiography image store system (Xclera, Philips Healthcare). Brain infarcts on diffusion-weighted images (DWI) were manually segmented and infarct volume was obtained on 3D Slicer. We used multiple linear regression models adjusted for age, sex, race, and vascular comorbidities including atrial fibrillation. Results: Among 2,945 CAESAR patients, 545 patients had both total infarct volume and LAVI measured. We found an association between LAVI and log-transformed total brain infarct volume in both unadjusted (ß = 0.018; p = 0.002) and adjusted (ß = 0.024; p = 0.001) models. Conclusion: We found that larger left atrial volume was associated with larger brain infarcts. This association was independent of known cardioembolic risk factors such as atrial fibrillation and heart failure. These findings support the concept that atrial myopathy may be a source of cardiac embolism even in the absence of traditionally recognized mechanisms such as atrial fibrillation.

Percutaneous closure of giant aneurysmal coronary artery-to-coronary sinus fistulae with guidance from three-dimensional printed models: a case series.

Background: Coronary artery fistulae are abnormal communications of coronary arteries with systemic vasculature, pulmonary vasculature, or cardiac chambers. Use of multimodality imaging can be paramount to understanding anatomical and functional features of these complex vascular lesions, therefore optimizing success of potential curative interventions. Case summary: We present two patients with incidentally discovered giant aneurysmal coronary arteries with distal fistulous connections to the coronary sinus, which were successfully closed percutaneously with Amplatzer Septal Occluders using the assistance of three-dimensional (3D) printed heart models. Conclusion: Computed tomography-guided reconstruction with 3D multiplanar, multicolour printed models can help augment visuospatial understanding of the size, origin, course, and drainage of giant aneurysmal coronary artery-to-coronary sinus fistulae, and with manual bench testing can assist with choosing accurately sized and shaped devices for closure.

Silicone-based materials with tailored MR relaxation characteristics for use in reduced coil visibility and in tissue-mimicking phantom design.

BACKGROUND: The development of materials with tailored signal intensity in MR imaging is critically important both for the reduction of signal from non-tissue hardware, as well as for the construction of tissue-mimicking phantoms. Silicone-based phantoms are becoming more popular due to their structural stability, stretchability, longer shelf life, and ease of handling, as well as for their application in dynamic imaging of physiology in motion. Moreover, silicone can be also used for the design of stretchable receive radio-frequency (RF) coils. PURPOSE: Fabrication of materials with tailored signal intensity for MRI requires knowledge of precise T1 and T2 relaxation times of the materials used. In order to increase the range of possible relaxation times, silicone materials can be doped with gadolinium (Gd). In this work, we aim to systematically evaluate relaxation properties of Gd-doped silicone material at a broad range of Gd concentrations and at three clinically relevant magnetic field strengths (1.5 T, 3 T, and 7 T). We apply the findings for rendering silicone substrates of stretchable receive RF coils less visible in MRI. Moreover, we demonstrate early stage proof-of-concept applicability in tissue-mimicking phantom development. MATERIALS AND METHODS: Ten samples of pure and Gd-doped Ecoflex silicone polymer samples were prepared with various Gd volume ratios ranging from 1:5000 to 1:10, and studied using 1.5 T and 3 T clinical and 7 T preclinical scanners. T1 and T2 relaxation times of each sample were derived by fitting the data to Bloch signal intensity equations. A receive coil made from Gd-doped Ecoflex silicone polymer was fabricated and evaluated in vitro at 3 T. RESULTS: With the addition of a Gd-based contrast agent, it is possible to significantly change T2 relaxation times of Ecoflex silicone polymer (from 213 ms to 20 ms at 1.5 T; from 135 ms to 17 ms at 3 T; and from 111.4 ms to 17.2 ms at 7 T). T1 relaxation time is less affected by the introduction of the contrast agent (changes from 608 ms to 579 ms; from 802.5 ms to 713 ms at 3 T; from 1276 ms to 979 ms at 7 T). First results also indicate that liver, pancreas, and white matter tissues can potentially be closely mimicked using this phantom preparation technique. Gd-doping reduces the appearance of the silicone-based coil substrate during the MR scan by up to 81%. CONCLUSIONS: Gd-based contrast agents can be effectively used to create Ecoflex silicone polymer-based phantoms with tailored T2 relaxation properties. The relative low cost, ease of preparation, stretchability, mechanical stability, and long shelf life of Ecoflex silicone polymer all make it a good candidate for "MR invisible" coil development and bears promise for tissue-mimicking phantom development applicability.

Segmentation of Vestibular Schwannomas on Postoperative Gadolinium-Enhanced T1-Weighted and Noncontrast T2-Weighted Magnetic Resonance Imaging Using Deep Learning.

OBJECTIVE: Surveillance of postoperative vestibular schwannomas currently relies on manual segmentation and measurement of the tumor by content experts, which is both labor intensive and time consuming. We aimed to develop and validate deep learning models for automatic segmentation of postoperative vestibular schwannomas on gadolinium-enhanced T1-weighted magnetic resonance imaging (GdT1WI) and noncontrast high-resolution T2-weighted magnetic resonance imaging (HRT2WI). STUDY DESIGN: A supervised machine learning approach using a U-Net model was applied to segment magnetic resonance imaging images into pixels representing vestibular schwannoma and background pixels. SETTING: Tertiary care hospital. PATIENTS: Our retrospective data set consisted of 122 GdT1WI and 122 HRT2WI studies in 82 postoperative adult patients with a vestibular schwannoma treated with subtotal surgical resection between September 1, 2007, and April 17, 2018. Forty-nine percent of our cohort was female, the mean age at the time of surgery was 49.8 years, and the median time from surgery to follow-up scan was 2.26 years. INTERVENTIONS: N/A. MAIN OUTCOME MEASURES: Tumor areas were manually segmented in axial images and used as ground truth for training and evaluation of the model. We measured the Dice score of the predicted segmentation results in comparison to manual segmentations from experts to assess the model's accuracy. RESULTS: The GdT1WI model achieved a Dice score of 0.89, and the HRT2WI model achieved a Dice score of 0.85. CONCLUSION: We demonstrated that postoperative vestibular schwannomas can be accurately segmented on GdT1WI and HRT2WI without human intervention using deep learning. This artificial intelligence technology has the potential to improve the postoperative surveillance and management of patients with vestibular schwannomas.

Binding of low molecular weight inhibitors promotes large conformational changes in the dengue virus NS2B-NS3 protease: fold analysis by pseudocontact shifts.

The two-component dengue virus NS2B-NS3 protease (DEN NS2B-NS3pro) is an established drug target, but inhibitor design is hampered by the lack of a crystal structure of the protease in its fully active form. In solution and without inhibitors, the functionally important C-terminal segment of the NS2B cofactor is dissociated from DEN NS3pro ("open state"), necessitating a large structural change to produce the "closed state" thought to underpin activity. We analyzed the fold of DEN NS2B-NS3pro in solution with and without bound inhibitor by nuclear magnetic resonance (NMR) spectroscopy. Multiple paramagnetic lanthanide tags were attached to different sites to generate pseudocontact shifts (PCS). In the face of severe spectral overlap and broadening of many signals by conformational exchange, methods for assignment of (15)N-HSQC cross-peaks included selective mutation, combinatorial isotope labeling, and comparison of experimental PCSs and PCSs back-calculated for a structural model of the closed conformation built by using the structure of the related West Nile virus (WNV) protease as a template. The PCSs show that, in the presence of a positively charged low-molecular weight inhibitor, the enzyme assumes a closed state that is very similar to the closed state previously observed for the WNV protease. Therefore, a model of the protease built on the closed conformation of the WNV protease is a better template for rational drug design than available crystal structures, at least for positively charged inhibitors. To assess the open state, we created a binding site for a Gd(3+) complex and measured paramagnetic relaxation enhancements. The results show that the specific open conformation displayed in the crystal of DEN NS2B-NS3pro is barely populated in solution. The techniques used open an avenue to the fold analysis of proteins that yield poor NMR spectra, as PCSs from multiple sites in combination with model building generate powerful information even from incompletely assigned (15)N-HSQC spectra.

DOTA-amide lanthanide tag for reliable generation of pseudocontact shifts in protein NMR spectra.

Structural studies of proteins and protein-ligand complexes by nuclear magnetic resonance (NMR) spectroscopy can be greatly enhanced by site-specific attachment of lanthanide ions to create paramagnetic centers. In particular, pseudocontact shifts (PCS) generated by paramagnetic lanthanides contain important and unique long-range structure information. Here, we present a high-affinity lanthanide binding tag that can be attached to single cysteine residues of proteins. The new tag has many advantageous features that are not available in this combination from previously published tags: (i) it binds lanthanide ions very tightly, minimizing the generation of nonspecific effects, (ii) it produces PCSs with high reliability as its bulkiness prevents complete motional averaging of PCSs, (iii) it can be attached to single cysteine residues, alleviating the need of detailed prior knowledge of the 3D structure of the target protein, and (iv) it does not display conformational exchange phenomena that would increase the number of signals in the NMR spectrum. The performance of the tag is demonstrated with the N-terminal domain of the E. coli arginine repressor and the A28C mutant of human ubiquitin.

A murine xenograft model of spontaneous metastases of human lung adenocarcinoma.

BACKGROUND: The flank is commonly used for primary xenografts in mice, but it is rare for these tumors to metastasize. Tail vein injection creates a pattern of metastases, but is artificial. We hypothesized that the liver is a convenient alternative xenograft site and that metastases would gradually proceed spontaneously. MATERIALS AND METHODS: Using 15 NOD.CB17-Prkdc(scid)/NcrCrl (NOD/SCID) mice, 10,000 A549 cells were xenografted into the liver while a second group of five mice were xenografted in the flank with 100,000 A549 cells as a control. Mice were euthanized and grossly dissected at 7 wk. A third group of seven mice received liver xenografts with A549 and a mouse each week was euthanized for 7 wk and evaluated. The liver, lung, and spleen were examined histologically. RESULTS: At 7 wk, 15/15 liver xenografted mice had gross primary tumor in the liver. Histologic review confirmed multiple microscopic foci of metastatic disease in all mice (15/15) throughout the lungs, mediastinal nodes, and spleen. The control group had primary tumor in the flank (4/5), but none had histologic evidence of metastases. Serially euthanized liver xenografted mice revealed evidence of a gradual spontaneous metastatic model system with the first histologic findings of micrometastases appearing in the lungs by wk 5, which became wide spread by wk 7. Splenic and mediastinal lymph node metastases developed in wk 6 and 7. CONCLUSIONS: Liver xenografting of A549 cells into NOD/SCID mice is a reliable way of developing widespread micrometastases. This model allows the study of a gradually developing solid tumor with subsequent metastatic spread.