Purpose:To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design: Comparisons in vitro and in vivo were carried out between nont hermosensitive liposomes (NTSL) and low temperature^sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42jC for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.The dose of drug required to achieve clinically effective cytotoxicity in tumors often causes severe damage to actively propagating nonmalignant cells, resulting in a variety of undesirable side effects (1). Abnormal and heterogeneous distribution of inefficient vasculature (2), high interstitial fluid pressures (3), and fibrillar collagen in the extracellular matrix (4) are some of the barriers that further complicate effective and uniform drug delivery to tumors. Novel paradigms to overcome these barriers with new drug and device combinations may present fertile ground for continued research.Employing drug delivery strategies, such as liposomal encapsulation, can optimize and enhance the delivery of different agents with lower systemic toxicity and better drug cell internalization compared with free drug (5). A smaller volume of distribution and prolonged clearance time may also be achieved by incorporating lipid-conjugated polyethylene glycol into the liposomal membrane. This polyethylene glycolylation provides a protective barrier against interactions with plasma proteins and the reticuloendothelial system, allowing for enhanced accumulation of the chemotherapeutic agent into tumors (6). Polyethylene glycolylated liposomes containing doxorubicin, or Doxil, have bee...

Purpose:To evaluate the influence of subtotal radiofrequency (RF) ablation on a tumor-specific immune response in a murine tumor model and to explore the role of intratumoral dendritic cells (ITDCs) in mediating this effect. Materials and Methods:Animal work was performed according to an approved protocol and in compliance with the National Cancer Institute Animal Care and Use Committee guidelines and regulations. A murine urothelial carcinoma (MB49) model expressing the male minor histocompatibility (HY) antigen was inoculated subcutaneously in female mice. Fourteen days later, splenic T cells were analyzed with enzymelinked immunosorbent spot for HY immune response (n ϭ 57). In subsequent experiments, mice were randomized into control (n ϭ 7), RF ablation, ITDC (n ϭ 9), and RF ablation ϩ ITDC (n ϭ 9) groups and monitored for tumor growth. Eleven days after treatment, tumors were harvested for histologic and immunohistochemical analysis. Animals demonstrating complete tumor regression were rechallenged in the contralateral flank. Results:Animals treated with subtotal RF ablation showed significant increases in tumor-specific class I and II responses to HY antigens and tumor regression. RF ablation, ITDC, and combined groups demonstrated similar levels of antigenpresenting cell infiltration; all groups demonstrated greater levels of infiltration compared with untreated controls. ITDC injection also resulted in tumor regression. However, combination therapy did not enhance tumor regression when compared with either treatment alone. Rechallenged mice in RF ablation, ITDC, and combination groups demonstrated significant tumor growth inhibition compared with controls. Conclusion:Subtotal RF ablation treatment results in enhanced systemic antitumor T-cell immune responses and tumor regression that is associated with increased dendritic cell infiltration. ITDC injection mimics the RF ablation effect but does not increase immune responses when injected immediately after RF ablation.

Changes in tumor metabolic activity have been shown to be an early indicator of treatment effectiveness for breast cancer, mainly in the neoadjuvant setting. The histopathologic response at the completion of chemotherapy has been used as the reference standard for assessment of the accuracy of 18F-FDG PET in predicting a response during systemic treatment. Although a pathologic complete response (pCR) remains an important positive prognostic factor for an individual patient, a recent metaanalysis could validate pCR as a surrogate marker for patient outcomes only in aggressive breast cancer subtypes. For establishment of the clinical application of metabolic treatment response studies, larger series of specific breast cancer subtypes—including hormone receptor–positive, human epidermal growth factor receptor 2–positive, and triple-negative breast cancers—are necessary. In addition, thresholds for relative changes in 18F-FDG uptake to distinguish between responding and nonresponding tumors need to be validated for different systemic treatment approaches, with progression-free survival and overall survival as references. A PET-based treatment stratification is applicable clinically only if valid alternative therapies are available. Of note, patients who do not achieve a pCR might still benefit from neoadjuvant therapy enabling breast-conserving surgery. In the metastatic setting, residual tumor metabolic activity after the initiation of systemic therapy is an indicator of active disease, whereas a complete resolution of metabolic activity is predictive of a successful treatment response.

Purpose: To investigate whether combining pulsed high-intensity focused ultrasound (HIFU) with the chemotherapeutic drug bortezomib could improve antitumor activity against murine squamous cell carcinoma (SCC) tumors. Materials and Methods: All experiments were conducted with animal care and use committee approval. Murine SCC cells were implanted subcutaneously in C3H mice. When tumors reached 100 mm3, mice were randomized to one of three groups for twice weekly intraperitoneal injections of 1.5 mg of bortezomib per kilogram of body weight, a proteasome inhibitor (n = 10); 1.0 mg/kg bortezomib (n = 11); or a control vehicle (n = 12). Within each group, half of the mice received pulsed HIFU exposure to their tumors immediately prior to each injection. The time for tumors to reach 650 mm3 was compared among groups. Additional tumors were stained with terminal deoxynucledotidyl transferase-mediated dUTP nick end labeling and CD31 to assess apoptotic index and blood vessel density, respectively. Results: Tumors in the control group, pulsed HIFU and control group, and 1.0 mg/kg of bortezomib alone group reached the size end point in 5.2 days ± 0.8 (standard deviation), 5.3 days ± 0.8, and 5.6 days ± 1.1, respectively. However, pulsed HIFU and 1.0 mg/kg bortezomib increased the time to end point to 9.8 days ± 2.9 (P < .02), not significantly different from the 8.8 days ± 2.1 in tumors treated with 1.5 mg/kg bortezomib alone (P > .05). Combination therapy was also associated with a significantly higher apoptotic index (P < .05). Conclusion: Treatment of tumors with pulsed HIFU lowered the threshold level for efficacy of bortezomib, resulting in significant tumor cytotoxicity and growth inhibition at lower dose levels.

Purpose: MR-based pseudo-CT has an important role in MR-based radiation therapy planning and PET attenuation correction. The purpose of this study is to establish a clinically feasible approach, including image acquisition, correction, and CT formation, for pseudo-CT generation of the brain using a single-acquisition, undersampled ultrashort echo time (UTE)-mDixon pulse sequence. Methods: Nine patients were recruited for this study. For each patient, a 190-s, undersampled, single acquisition UTE-mDixon sequence of the brain was acquired (TE = 0.1, 1.5, and 2.8 ms). A novel method of retrospective trajectory correction of the free induction decay (FID) signal was performed based on point-spread functions of three external MR markers. Two-point Dixon images were reconstructed using the first and second echo data (TE = 1.5 and 2.8 ms). R2 * images (1/T2 * ) were then estimated and were used to provide bone information. Three image features, i.e., Dixon-fat, Dixon-water, and R2 * , were used for unsupervised clustering. Five tissue clusters, i.e., air, brain, fat, fluid, and bone, were estimated using the fuzzy c-means (FCM) algorithm. A two-step, automatic tissue-assignment approach was proposed and designed according to the prior information of the given feature space. Pseudo-CTs were generated by a voxelwise linear combination of the membership functions of the FCM. A low-dose CT was acquired for each patient and was used as the gold standard for comparison. Results: The contrast and sharpness of the FID images were improved after trajectory correction was applied. The mean of the estimated trajectory delay was 0.774 µs (max: 1.350 µs; min: 0.180 µs). The FCM-estimated centroids of different tissue types showed a distinguishable pattern for different tissues, and significant differences were found between the centroid locations of different tissue types. Pseudo-CT can provide additional skull detail and has low bias and absolute error of estimated CT numbers of voxels (−22 ± 29 HU and 130 ± 16 HU) when compared to low-dose CT. Conclusions: The MR features generated by the proposed acquisition, correction, and processing methods may provide representative clustering information and could thus be used for clinical pseudo-CT generation. C 2015 American Association of Physicists in Medicine.

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Purpose The purpose of this study was to compare and correlate standardized uptake values (SUV) derived from magnetic resonance attenuation correction (MRAC) with those derived from computed tomography attenuation correction (CTAC) in an oncology patient population. Procedures The HIPAA-compliant study was approved by the Internal Review Board and all subjects gave written informed consent prior to inclusion in the study. Forty patients (mean age 61±15.1; 20 male) referred for clinically indicated 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) scans also underwent a PET/magnetic resonance imaging (MRI) examination. MRAC was performed using an automatic three-segment model. Regions of interest were drawn over eight normal structures in order to obtain SUVmax and SUVmean values. Spearman rank correlation coefficients (r) were calculated and two-tailed paired t tests were performed to compare the SUVmax and SUVmean values obtained from CTAC with those from MRAC. Results The mean time after FDG injection was 66±7 min for PET/CT and 117±15 min for PET/MRI examination. MRAC SUV values were significantly lower than the CTAC SUV values in mediastinal blood pool (p<0.001 for both SUVmax and SUVmean) and liver (p=0.01 for SUVmean). The MRAC SUV values were significantly higher in bone marrow (p<0.001 for both SUVmax and SUVmean), psoas major muscle (p<0.001 for SUVmax), and left ventricular myocardium (p<0.001 for SUVmax and p=0.01 for SUVmean). For the other normal structures, no significant difference was observed. When comparing SUV values generated from CTAC versus MRAC, high correlations between CTAC and MRAC were observed in myocardium (r=0.96/ 0.97 for SUVmax/mean), liver (r=0.68 for SUVmax), bone marrow (r=0.80/0.83 for SUVmax/mean), lung tissue (r=0.70 for SUVmax), and mediastinal blood pool (r=0.0.68/.069 for SUVmax/mean). Moderate correlations were found in lung tissue (r=0.67 for SUV mean), liver (r=0.66 for SUVmean), fat (r=0.48/0.53 for SUVmax/mean), psoas major muscle (r=0.54/0.58 for SUVmax/mean), and iliacus muscle (r=0.41 for SUVmax). Low correlation was found in iliacus muscle (r=0.32 for SUVmean). Conclusions Using the automatic three-segment model, our study showed high correlation for measurement of SUV values obtained from MRAC compared to those from CTAC, as the reference standard. Differences observed between MRAC and CTAC derived SUV values may be attributed to the time-delay between the PET/CT and PET/MRI scans or biologic clearance of radiotracer. Further studies are required to assess SUV measurements when performing different MR attenuation correction techniques.