Maria Stanczak

Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue

Radiation therapy is frequently used in the treatment of malignancies, but tumors are often more resistant than the surrounding normal tissue to radiation effects, because the tumor microenvironment is hypoxic. This manuscript details the fabrication and characterization of an ultrasound-sensitive, injectable oxygen microbubble platform (SE61O2) for overcoming tumor hypoxia. SE61O2 was fabricated by first sonicating a mixture of Span 60 and water-soluble vitamin E purged with perfluorocarbon gas. SE61O2 microbubbles were separated from the foam by flotation, then freeze dried under vacuum to remove all perfluorocarbon, and reconstituted with oxygen. Visually, SE61O2 microbubbles were smooth, spherical, with an average diameter of 3.1 μm and were reconstituted to a concentration of 6.5 E7 microbubbles/ml. Oxygen-filled SE61O2 provides 16.9 ± 1.0 dB of enhancement at a dose of 880 μl/l (5.7 E7 microbubbles/l) with a half-life under insonation of approximately 15 min. In in vitro release experiments, 2 ml of SE61O2 (1.3 E8 microbubbles) triggered with ultrasound was found to elevate oxygen partial pressures of 100ml of degassed saline 13.8 mmHg more than untriggered bubbles and 20.6 mmHg more than ultrasound triggered nitrogen-filled bubbles. In preliminary in vivo delivery experiments, triggered SE61O2 resulted in a 30.4 mmHg and 27.4 mmHg increase in oxygen partial pressures in two breast tumor mouse xenografts.

How to perform Contrast-Enhanced Ultrasound (CEUS)

“How to perform contrast-enhanced ultrasound (CEUS)” provides general advice on the use of ultrasound contrast agents (UCAs) for clinical decision-making and reviews technical parameters for optimal CEUS performance. CEUS techniques vary between centers, therefore, experts from EFSUMB, WFUMB and from the CEUS LI-RADS working group created a discussion forum to standardize the CEUS examination technique according to published evidence and best personal experience. The goal is to standardise the use and administration of UCAs to facilitate correct diagnoses and ultimately to improve the management and outcomes of patients.

Exosomal αvβ6 integrin is required for monocyte M2 polarization in prostate cancer

Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel αvβ6-mediated signaling pathway that has profound effects on the microenvironment. We show that αvβ6 is transferred from cancer cells to monocytes, including β6-null monocytes, by exosomes and that monocytes from prostate cancer patients, but not from healthy volunteers, express αvβ6. Cancer cell exosomes, purified via density gradients, promote M2 polarization, whereas αvβ6 down-regulation in exosomes inhibits M2 polarization in recipient monocytes. Also, as evaluated by our proteomic analysis, αvβ6 down-regulation causes a significant increase in donor cancer cells, and their exosomes, of two molecules that have a tumor suppressive role, STAT1 and MX1/2. Finally, using the Ptenpc-/- prostate cancer mouse model, which carries a prostate epithelial-specific Pten deletion, we demonstrate that αvβ6 inhibition in vivo causes up-regulation of STAT1 in cancer cells. Our results provide evidence of a novel mechanism that regulates M2 polarization and prostate cancer progression through transfer of αvβ6 from cancer cells to monocytes through exosomes.

Effect of Pulse Shaping on Subharmonic Aided Pressure Estimation In Vitro and In Vivo.

Subharmonic imaging (SHI) is a technique that uses the nonlinear oscillations of microbubbles when exposed to ultrasound at high pressures transmitting at the fundamental frequency ie, fo and receiving at half the transmit frequency (ie, fo/2). Subharmonic aided pressure estimation (SHAPE) is based on the inverse relationship between the subharmonic amplitude of the microbubbles and the ambient pressure change.

Subharmonic and Endoscopic Contrast Imaging of Pancreatic Masses: A Pilot Study

To use subharmonic imaging (SHI) to depict the vascularity of pancreatic masses compared to contrast‐enhanced endoscopic ultrasound (EUS) and pathologic results.

Photoacoustic Oxygenation Quantification in Patients with Raynaud's: First-in-Human Results

The purpose of this study was to investigate the use of photoacoustic imaging for quantifying fingertip oxygenation as an approach to diagnosing and monitoring Raynauds phenomenon. After 30 min of acclimation to room temperature, 22 patients (7 patients with secondary Raynauds associated to Scleroderma and 15 healthy controls) provided informed consent to undergo fingertip Doppler imaging and high-frequency photoacoustic imaging before and 5, 15 and 30 min after cold stimulus (submerged hand in a 15 °C water bath for 1 min). High-frequency ultrasound and photoacoustic imaging was performed on the nail bed of each patients second through fifth finger on their dominant hand, using a Vevo 2100 LAZR system with an LZ-250 probe (Fujifilm VisualSonics, Toronto, ON, Canada) in oxy-hemoglobin quantification mode. During each exam, volumetric data across a 3-mm span of data was acquired to produce a volumetric image of percent oxygenation and hemoglobin concentration. Changes in fingertip oxygenation between Raynauds patients and healthy volunteers were compared, using receiver operator characteristic (ROC) analysis. Photoacoustic signal was detected in both the nail bed and nailfold in all study participants. Doppler ultrasound resulted in poor differentiation of Raynauds patients from healthy volunteers, with an area under the ROC curve (Az) of 0.51. Photoacoustic imaging demonstrated improved accuracy at baseline (Az = 0.72), which improved when quantifying normalized changes after cold stimulus (Az = 0.89 5-min post stimulus, Az = 0.91 15-min post stimulus, and Az = 0.85 after stimulus). Oxygenation levels derived using photoacoustic imaging are able to identify patients with Raynauds and safely evaluate their response to a cold stimulus over time.

Ultrasound Detection of Microcalcifications in Surgical Breast Specimens

The objective was to evaluate a commercial image processing technique (MicroPure, Canon Medical Systems, Tustin, CA, USA) for detection of microcalcifications in breast surgical specimens. Twenty women scheduled for surgical excision of an area with breast calcifications were enrolled, their surgical specimens underwent grayscale ultrasound (US) and MicroPure examination using an Aplio XG scanner (Canon). Four independent and blinded readers analyzed 54 US and 54 MicroPure digital clips to determine the number of calcifications and scored image quality and artifacts on a 10-point scale. All readers saw significantly more microcalcifications with MicroPure than with US, 14.0 ± 12.0 versus 3.0 ± 3.2 (p <0.0001). Three readers preferred MicroPure image quality over that of US (p <0.009) and vice versa for one reader (p = 0.003). Three readers saw fewer Coopers ligament artifacts with MicroPure than with US (p <0.0001); one reader saw no significance difference between them (p = 0.58). In conclusion MicroPure identified more breast microcalcifications than grayscale US in ex vivo surgical breast specimens.

Contrast-enhanced ultrasound identifies early extrahepatic collateral contributing to residual hepatocellular tumor viability after transarterial chemoembolization

The mainstay of treatment for unresectable hepatocellular carcinoma is locoregional therapy including percutaneous ablation and transarterial chemo- and radioembolization. While monitoring for tumor response after transarterial chemoembolization is crucial, current imaging strategies are suboptimal. The standard of care is contrast-enhanced magnetic resonance imaging or computed tomography imaging performed at least 4 to 6 weeks after therapy. We present a case in which contrast-enhanced ultrasound identified a specific extra-hepatic collateral from the gastroduodenal artery supplying residual viable tumor and assisting with directed transarterial management.

Subdermal Ultrasound Contrast Agent Injection for Sentinel Lymph Node Identification: An Analysis of Safety and Contrast Agent Dose in Healthy Volunteers: Subdermal Contrast Agent for Sentinel Lymph Node Identification

Mapping of the lymphatic chain for identification of the sentinel lymph node (SLN) is an important aspect of predicting outcomes for patients with breast cancer, and it is usually performed as an intraoperative procedure using blue dye and/or radiopharmaceutical agents. Recently, the use of contrast‐enhanced ultrasound (CEUS) has been proposed as an alternative imaging technique for this mapping. The objective of this study was to evaluate the use of subdermal administration of the ultrasound (US) contrast agent Sonazoid (GE Healthcare, Oslo, Norway) in terms of patient safety and to select the dose to be used for lymphatic applications in humans.

Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles

Tumor hypoxia has been shown to decrease the sensitivity of solid tumors to radiation. Systemic efforts to increase tumor oxygenation levels immediately prior to therapy, however, have largely proven unsuccessful. The objective of this work was to determine the utility of oxygen-filled, ultrasound sensitive microbubbles for locally delivering oxygen and sensitizing tissue to radiation in a breast cancer model.