Anne M. Kennedy

Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles

The paper reports the results of nanotherapy of ovarian, breast, and pancreatic cancerous tumors by paclitaxel-loaded nanoemulsions that convert into microbubbles locally in tumor tissue under the action of tumor-directed therapeutic ultrasound. Tumor accumulation of nanoemulsions was confirmed by ultrasound imaging. Dramatic regression of ovarian, breast, and orthotopic pancreatic tumors was observed in tumor therapy through systemic injections of drug-loaded nanoemulsions combined with therapeutic ultrasound, signifying efficient ultrasound-triggered drug release from tumor-accumulated nanodroplets. The mechanism of drug release in the process of droplet-to-bubble conversion is discussed. No therapeutic effect from the nanodroplet/ultrasound combination was observed without the drug, indicating that therapeutic effect was caused by the ultrasound-enhanced chemotherapeutic action of the tumor-targeted drug, rather than the mechanical or thermal action of ultrasound itself. Tumor recurrence was observed after the completion of the first treatment round; a second treatment round with the same regimen proved less effective, suggesting that drug-resistant cells were either developed or selected during the first treatment round.

Ultrasound-Mediated Tumor Imaging and Nanotherapy using Drug Loaded, Block Copolymer Stabilized Perfluorocarbon Nanoemulsions

Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or (19)F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent hard to control phenomenon of irreversible droplet-to-bubble transition upon injection. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. PFCE nanodroplets manifest both ultrasound and fluorine ((19)F) MR contrast properties, which allows using multimodal imaging and (19)F MR spectroscopy for monitoring nanodroplet pharmacokinetics and biodistribution. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. As manifested by the (19)F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation 2h after the systemic injection. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to-bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization of nanodroplets underwent stable cavitation. The nanodroplet size (200nm to 350nm depending on a type of the shell and conditions of emulsification) as well as long residence in circulation favored their passive accumulation in tumor tissue that was confirmed by ultrasonography. In the breast and pancreatic cancer animal models, ultrasound-mediated therapy with paclitaxel-loaded PFCE nanoemulsions showed excellent therapeutic properties characterized by tumor regression and suppression of metastasis. Anticipated mechanisms of the observed effects are discussed.

Ultrasonic Nanotherapy of Pancreatic Cancer: Lessons from Ultrasound Imaging

Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer death in the United States, with a median survival time of only 3-6 months for forty percent of patients. Current treatments are ineffective, and new PDA therapies are urgently needed. In this context, ultrasound-mediated chemotherapy by polymeric micelles and/or nanoemulsion/microbubble encapsulated drugs may offer an innovative approach to PDA treatment. PDA xenografts were orthotopically grown in the pancreas tails of nu/nu mice by surgical insertion of red fluorescence protein (RFP)-transfected MiaPaCa-2 cells. Tumor growth was controlled by fluorescence imaging. Occasional sonographic measurements correlated well with the formal tumor tracking by red fluorescence. Tumor accumulation of paclitaxel-loaded nanoemulsion droplets and droplet-to-bubble transition under therapeutic ultrasound was monitored by diagnostic ultrasound imaging. MiaPaCa-2 tumors manifested resistance to treatment by gemcitabine (GEM). This drug is the gold standard for PDA therapy. The GEM-resistant tumors proved sensitive to paclitaxel. Among six experimental groups studied, the strongest therapeutic effect was exerted by the following drug formulation: GEM + nanodroplet-encapsulated paclitaxel (nbGEN) combined with tumor-directed 1-MHz ultrasound that was applied for 30 s four to five hours after the systemic drug injection. Ultrasound-mediated PDA therapy by either micellar or nanoemulsion encapsulated paclitaxel resulted in substantial suppression of metastases and ascites, suggesting ultrasound-enhanced killing of invasive cancerous cells. However, tumors relapsed after the completion of therapy, indicating survival of some tumor cells. The recurrent tumors manifested development of paclitaxel resistance. Ultrasound imaging suggested nonuniform distribution of nanodroplets in the tumor volume due to irregular vascularization, which may result in the development of zones with subtherapeutic drug concentration. This is implicated as a possible cause of the resistance development, which may be pertinent to various modes of tumor nanotherapy.

Microbubble Generation in Phase-Shift Nanoemulsions used as Anticancer Drug Carriers.

The paper describes droplet-to-bubble transition in block copolymer stabilized perfluoropentane nanoemulsions. Three physical factors that trigger droplet-to-bubble transition in liquid emulsions and gels were evaluated, namely heat, ultrasound, and injections through fine-gauge needles. Among those listed, ultrasound irradiation was found the most efficient factor. Possible mechanisms of bubble generation and growth discussed in the paper include liquid-to-gas transition inside the individual bubble; bubble coalescence; and diffusion of dissolved air and/or perfluoropentane from small bubbles into larger bubbles (i.e., Oswald ripening). The last two factors result in irreversibility of the droplet-to-bubble transition. In gel matrices, ultrasound-induced droplet-to-bubble transition was substantially inhibited but was catalyzed by large (hundred micron) pre-existing bubbles irradiated by low frequency (hundred kilohertz) ultrasound. The dependence of the droplet-to-bubble transition on initial bubble size is theoretically treated and the role of increase of surface area in promoting bubble coalescence is discussed. Therapeutic implications of observed effects are discussed.

Cavitation Properties of Block Copolymer Stabilized Phase-Shift Nanoemulsions Used as Drug Carriers

Cavitation properties of block copolymer stabilized perfluoropentane nanoemulsions have been investigated. The nanoemulsions were stabilized by two biodegradable amphiphilic block copolymers differing in the structure of the hydrophobic block, poly(ethylene oxide)-co-poly(L-lactide) (PEG-PLLA) and poly(ethylene oxide)-co-polycaprolactone (PEG-PCL). Cavitation parameters were measured in liquid emulsions and gels as a function of ultrasound pressure for unfocused or focused 1-MHz ultrasound. Acoustic droplet vaporization preceded generation of acoustic cavitation in liquid matrices and gels. Both stable and inertial cavitation was observed for focused ultrasound while only stable cavitation was observed for unfocused ultrasound.

MRI of the female pelvis

MRI is a proven modality to evaluate the female pelvis. Excellent soft tissue contrast, sensitivity for the detection of fluid, and the multiplanar imaging capabilities of MR allow noninvasive demonstration of normal anatomy and pathological processes. Most female pelvic MRI studies are performed to answer specific questions and must, therefore, follow carefully developed protocols, which are discussed in this article. The principal MRI techniques and strategies outlined in this work include: (1) the evaluation of reproductive dysfunction, anatomic variants; (2) specific obstetrical applications; (3) oncologic evaluation and tumor staging; (4) problem solving (i.e., the characterization of abnormalities detected by ultrasound); and (5) the evaluation of urethral disease.

Accuracy of ultrasound for the prediction of placenta accreta

OBJECTIVE Ultrasound has been reported to be greater than 90% sensitive for the diagnosis of accreta. Prior studies may be subject to bias because of single expert observers, suspicion for accreta, and knowledge of risk factors. We aimed to assess the accuracy of ultrasound for the prediction of accreta. STUDY DESIGN Patients with accreta at a single academic center were matched to patients with placenta previa, but no accreta, by year of delivery. Ultrasound studies with views of the placenta were collected, deidentified, blinded to clinical history, and placed in random sequence. Six investigators prospectively interpreted each study for the presence of accreta and findings reported to be associated with its diagnosis. Sensitivity, specificity, positive predictive, negative predictive value, and accuracy were calculated. Characteristics of accurate findings were compared using univariate and multivariate analyses. RESULTS Six investigators examined 229 ultrasound studies from 55 patients with accreta and 56 controls for 1374 independent observations. 1205/1374 (87.7% overall, 90% controls, 84.9% cases) studies were given a diagnosis. There were 371 (27.0%) true positives; 81 (5.9%) false positives; 533 (38.8%) true negatives, 220 (16.0%) false negatives, and 169 (12.3%) with uncertain diagnosis. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 53.5%, 88.0%, 82.1%, 64.8%, and 64.8%, respectively. In multivariate analysis, true positives were more likely to have placental lacunae (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.4-1.6), loss of retroplacental clear space (OR, 2.4; 95% CI, 1.1-4.9), or abnormalities on color Doppler (OR, 2.1; 95% CI, 1.8-2.4). CONCLUSION Ultrasound for the prediction of placenta accreta may not be as sensitive as previously described.

Bisphenol A and phthalates and endometriosis: the Endometriosis: Natural History, Diagnosis and Outcomes Study

OBJECTIVE To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis. DESIGN Matched cohort design. SETTING Fourteen clinical centers. PATIENT(S) The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, whereas the population cohort comprised 131 women matched on age and residence. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Surgically visualized or pelvic magnetic resonance imaging diagnosed endometriosis in the two cohorts, respectively. RESULT(S) Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index, and creatinine. In the population cohort, six phthalate metabolites-mono-n-butyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate, mono (2-ethyl-5-carboxyphentyl) phthalate, mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-hydroxyhexyl) phthalate, and mono (2-ethyl-5-oxohexyl) phthalate-were significantly associated with an approximately twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (monooctyl phthalate; OR 1.38; 95% CI 1.10-1.72) or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis [mono (2-ethylhexyl) phthalate; OR 1.35; 95% CI 1.03-1.78]. CONCLUSION(S) Select phthalates were associated with higher odds of an endometriosis diagnosis for women with magnetic resonance imaging-diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings.

Assessment of acute abdominal pain in the pregnant patient

The request to image a pregnant patient with abdominal pain often leads to concern and frustration for the referring clinician as well as the radiologist. In this report we will review the basic principles of radiation safety when imaging the pregnant woman, consider the diagnostic possibilities for the causes of abdominopelvic pain, and discuss the available imaging modalities to provide a basis for tailoring an imaging plan to the individual patient.

The Cavum Septi Pellucidi Why Is It Important

Objective. The cavum septi pellucidi (CSP) is routinely imaged in the fetal brain during obstetric sonography; in fact, for well over a decade, assessment of the CSP has been considered part of the required elements of a standard examination of fetal morphology in guidelines developed by multiple specialty societies. Our objective is to present the 4 reasons why all practicing sonologists and sonographers should be familiar with this anatomic structure. Methods. Prenatal sonograms and magnetic resonance imaging examinations are used to review the following topics: terminology, embryology, and anatomy of the CSP; pitfalls in its identification; and a wide variety of abnormalities (predominantly relating to nonvisualization) associated with the CSP. Results. Embryologic development of the CSP is intimately associated with the corpus callosum (CC); thus, correct identification of the CSP essentially excludes complete agenesis of the CC. Absence of the CSP is associated with an extremely wide spectrum of neuroanatomic malformations: these range from the lethal entities of hydranencephaly and alobar holoprosencephaly; to the potentially serious but nonlethal entities of schizencephaly, porencephaly, basilar encephaloceles, severe hydrocephalus, and the less severe prosencephalic cleavage disorders (including syntelencephaly); to the normal variant, the rare and somewhat controversial entity of isolated septal deficiency. The value of noting that the absent CSP allows diagnosis of very subtle and easily overlooked abnormalities such as septo‐optic dysplasia is presented. Conclusions. Correct recognition of the CSP provides welcome reassurance of proper development of the central forebrain.