Antiglycolytic therapy combined with an image-guided minimally invasive delivery strategy for the treatment of breast cancer.

PURPOSE: The antiglycolytic agent 3-bromopyruvate (3-BrPA) promotes anticancer effects in multiple tumor models. This study evaluated the therapeutic efficacy of ultrasound (US)-guided intratumoral delivery of 3-BrPA in an orthotopic tumor model of breast cancer. MATERIALS AND METHODS: Human breast cancer cell line MDA MB 231 was used for in vitro and in vivo studies. The anticancer effect of 3-BrPA was evaluated by viability assay, quantification of adenosine triphosphate (ATP) and lactate levels, and activity of matrix metalloproteinase (MMP)-9. In animal experiments, 15 nude mice with MDA MB 231 breast tumors were divided into three groups for US-guided intratumoral treatment with 1.75 mM 3-BrPA (group 1), 5 mM 3-BrPA (group 2), and saline solution (group 3). Tumor size was measured and subjected to histopathologic examination. RESULTS: In vitro, treatment with 3-BrPA resulted in a dose-dependent decrease in cell viability. A decrease in ATP and lactate levels, invasion, and MMP9 activity and expression was observed after treatment with concentrations of 3-BrPA that did not affect cell viability. In vivo, a significant difference in tumor volume was observed between 3-BrPA-treated and control animals. At the end of the study, tumor volumes in the 3-BrPA groups were 1,876 mm(3)±346 and 426 mm(3)±180 in the 1.75-mM and 5-mM 3-BrPA groups, respectively, versus 4,447 mm(3)±571 in the control group (P< .05). CONCLUSIONS: US-guided intratumoral injection of 3-BrPA effectively blocks breast cancer progression in an orthotopic mouse tumor model.

Spontaneous tumor regression in a syngeneic rat model of liver cancer: implications for survival studies.

PURPOSE: To characterize tumor growth of N1S1 cells implanted into the liver of Sprague-Dawley rats to determine if this model could be used for survival studies. These results were compared with tumor growth after implantation with McA-RH7777 cells. MATERIALS AND METHODS: N1S1 or McA-RH7777 cells were implanted into the liver of Sprague-Dawley rats (n = 20 and n = 12, respectively) using ultrasound (US) guidance, and tumor growth was followed by using US. Serum profiles of 19 cytokines were compared in naive versus tumor-bearing rats. RESULTS: Both types of tumors were visible on US 1 week after tumor implantation, but the mean tumor volume of N1S1 tumors was larger compared to McA-RH7777 tumors (231 mm(3) vs 82.3 mm(3), respectively). Tumor volumes in both groups continued to increase, reaching means of 289 mm(3) and 160 mm(3) in N1S1 and McA-RH7777 groups, respectively, 2 weeks after tumor implantation. By week 3, tumor volumes had decreased considerably, and six tumors (50%) in the McA-RH7777 had spontaneously regressed, versus two (10%) in the N1S1 group. Tumor volumes continued to decrease over the following 3 weeks, and complete tumor regression of all tumors was seen 5 weeks and 6 weeks after tumor implantation in the McA-RH7777 and N1S1 groups, respectively. In an N1S1-implanted rat, multiple cytokines that have been shown to correlate with the ability of the tumor to survive in a hostile environment were increased by as much as 50%, whereas the average increase in cytokine levels was 90%. These findings suggest that the net cytokine environment favors an antitumor immune response. A similar trend was observed in a rat with a McA-RH7777 tumor, and the increase in cytokine levels was considerably more pronounced, with an average increase of 320%. CONCLUSIONS: The model of N1S1 cell implantation in the liver of Sprague-Dawley rats is not ideal for survival studies and should only be used with great caution in short-term studies that involve cancer therapies.

Trans-arterial (90)yttrium radioembolization for patients with unresectable tumors originating from the biliary tree.

Patients with malignant tumors originating from the biliary tree have a poor prognosis, since only a minority of tumors can be resected and most palliative regimens have shown only limited success. We present two patients with unresectable tumors, who were treated with trans-arterial (90)yttrium radioembolization: a patient with an infiltrating gallbladder carcinoma and a patient with an extensive intrahepatic cholangiocarcinoma. In both cases the treatment was technically feasible, effective in controlling tumor growth, and without significant side effects. In conclusion, the presented cases demonstrate the potential of (90)yttrium radioembolization as a palliative treatment option for malignant tumors of the biliary tree.

Procedural sedation and analgesia for respiratory-gated MR-HIFU in the liver: a feasibility study.

BACKGROUND: Previous studies demonstrated both pre-clinically and clinically the feasibility of magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablations in the liver. To overcome the associated problem of respiratory motion of the ablation area, general anesthesia (GA) and mechanical ventilation was used in conjunction with either respiratory-gated energy delivery or energy delivery during induced apnea. However, clinical procedures requiring GA are generally associated with increased mortality, morbidity, and complication rate compared to procedural sedation and analgesia (PSA). Furthermore, PSA is associated with faster recovery and an increased eligibility for non- and mini-invasive interventions. METHODS: In this study, we investigate both in an animal model and on a small patient group the kinetics of the diaphragm during free-breathing, when a tailored remifentanil/propofol-based PSA protocol inducing partial respiratory depression is used. Subsequently, we demonstrate in an animal study the compatibility of the resulting respiratory pattern of the PSA protocol with a gated HIFU ablation in the liver by direct comparison with gated ablations conducted under GA. Wilcoxon signed-rank tests were performed for statistical analysis of non-perfused and necrosed tissue volumes. Duty cycles (ratio or percentage of the breathing cycle with the diaphragm in its resting position, such that acoustic energy delivery with MR-HIFU was allowed) were statistically compared for both GA and PSA using student's t tests. RESULTS: In both animal and human experiments, the breathing frequency was decreased below 9/min, while maintaining stable vital functions. Furthermore an end-exhalation resting phase was induced by this PSA protocol during which the diaphragm is virtually immobile. Median non-perfused volumes, non-viable volumes based on NADH staining, and duty cycles were larger under PSA than under GA or equal. CONCLUSIONS: We conclude that MR-HIFU ablations of the liver under PSA are feasible and potentially increase the non-invasive nature of this type of intervention.

A clinically feasible treatment protocol for magnetic resonance-guided high-intensity focused ultrasound ablation in the liver.

OBJECTIVES: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) allows for noninvasive thermal ablation under real-time temperature imaging guidance. The purpose of this study was to assess the feasibility and safety of MR-HIFU ablation of liver tissue in a clinically acceptable setting. The experimental protocol was designed with a clinical ablation procedure of a small malignant tumor in mind; the procedures were performed within a clinically feasible time frame and care was taken to avoid adverse events. The main outcome was the size and quality of the ablated liver tissue volume on imaging and histology. Secondary outcomes were safety and treatment time. MATERIALS AND METHODS: Healthy pigs (n = 10) under general anesthesia were positioned on a clinical MR-HIFU system, which consisted of an HIFU tabletop with a skin cooling system integrated into a 1.5-T MR scanner. A liver tissue volume was ablated with multiple sonication cells (4 × 4 × 10 mm, 450 W). Both MR thermometry and sonication were respiratory-gated using a pencil beam navigator on the diaphragm. Contrast-enhanced T1-weighted (CE-T1w) imaging was performed for treatment evaluation. Targeted total treatment time was 3 hours. The abdominal wall, liver, and adjacent organs were inspected postmortem for thermal damage. Ablated tissue volumes were processed for cell viability staining. The ablated volumes were analyzed using MR imaging, MR thermometry, and cell viability histology. RESULTS: Eleven volume ablations were performed in 10 animals, resulting in a median nonperfused volume (NPV) on CE-T1w imaging of 1.6 mL (interquartile range [IQR], 0.8-2.3; range, 0.7-3.0). Cell viability histology showed a damaged volume of 1.5 mL (IQR, 1.1-1.8; range, 0.7-2.3). The NPV was confluent in 10 of the 11 cases. The ablated tissue volume on cell viability histology was confluent in all 9 available cases. In all cases, there was a good correspondence between the aspects of the NPV on CE-T1w and the ablated volume on cell viability histology. Two treatment-related adverse events occurred: 1 animal had a 7-mm skin burn and 1 animal showed evidence of thermal damage on the surface of the spleen. Median ablation time was 108 minutes (IQR, 101-120; range, 96-181 minutes) and median total treatment time was 180 minutes (IQR, 165-224; 130-250 minutes). CONCLUSIONS: Our results demonstrate the feasibility and safety of MR-HIFU ablation of liver tissue volumes. The imaging data and cell viability histology show, for the first time, that confluent ablation volumes can be achieved with motion-gated ablation and MR guidance. These results were obtained using a readily available MR-HIFU system with only minor modifications, within a clinically acceptable time frame, and with only minor adverse events. This shows that this technique is sufficiently reliable and safe to initiate a clinical trial.

Non-invasive magnetic resonance-guided high intensity focused ultrasound ablation of a vascular malformation in the lower extremity: a case report.

INTRODUCTION: Therapy of choice for symptomatic vascular malformations consists of surgery, sclerotherapy, or embolization. However, these techniques are invasive with possible complications and require hospitalization. We present a novel non-invasive technique, i.e., magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation, for the treatment of a vascular malformation in a patient. This technique applies high-intensity sound waves transcutaneously to the body and is fully non-invasive. MRI guidance is the novel aspect of HIFU treatments and is used for exquisite delineation and localization of the lesion and accurate real-time temperature monitoring during tissue ablation. MR-HIFU is a well-established treatment option for uterine fibroids and is currently being investigated for, e.g., bone tumors, breast cancer, prostate cancer, and liver cancer. MR-HIFU of vascular malformations has not been a topic of research yet. CASE DESCRIPTION: Volumetric MR-HIFU ablation of a vascular malformation in the lower extremity of an 18-year-old male patient was performed. Temperatures of 62-80 °C were reached in the target lesion with sonications of 4 × 4 × 8 mm using powers of 200 W for <20 s. At 1-month follow-up, the patient reported qualitatively sustained reduction of pain and normal motor function. Three-month follow-up imaging indicated successful nidus destruction, which resulted in reduction of >30 % of the tumor volume. After 13 months, pain score was reduced to <2 after extreme exertion for several hours and to 0 for daily activities. DISCUSSION AND EVALUATION: Radiofrequency ablation and cryoablation are minimally invasive techniques that have been tried on low-flow vascular malformations with inconsistent results. Furthermore, both techniques require probe insertion, which is associated with risks of wound infection and hospitalization. Since MR-HIFU is truly non-invasive, these risks are negligible. CONCLUSIONS: In conclusion, we reported a successful non-invasive treatment of a vascular malformation with MR-HIFU in a clinical patient including long-term follow-up data for the first time. The patient reported qualitatively sustained pain reduction up to 13 months post treatment.

Intrapleural fluid infusion for MR-guided high-intensity focused ultrasound ablation in the liver dome.

RATIONALE AND OBJECTIVES: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation of tumors in the liver dome is challenging because of the presence of air in the costophrenic angle. In this study, we used a porcine liver model and a clinical MR-HIFU system to assess the feasibility and safety of using intrapleural fluid infusion (IPI) to create an acoustic window for MR-HIFU ablation in the liver dome. MATERIALS AND METHODS: Healthy adult Dalland land pigs (n = 6) under general anesthesia were used with animal committee approval. Degassed saline (200-800 mL) was infused into the intrapleural space under ultrasound guidance. A clinical 1.5-T MR-HIFU system was used to perform sonications (4-mm treatment cells, 300-450 W, 20-30 seconds) in the liver dome under real-time MR thermometry. An intercostal firing technique was used to prevent rib heating in one experiment. Technical success was defined as a temperature increase (>10°C) in the target area. After termination, the animal was examined for thermal damage to liver, diaphragm, pleura, lung, or intercostal muscle. RESULTS: An acoustic window was established in all animals. A temperature increase in the target area was achieved in all animals (max. 47°C-67°C). MR thermometry showed no heating outside the target area. Intercostal firing effectively reduced rib heating (55°C vs. 42°C). Postmortem examination revealed no unwanted thermal damage. One complication occurred, in the first experiment, because of an ill-suited needle (displacement of the needle). CONCLUSIONS: The results indicate that IPI may be used safely to assist MR-HIFU ablation of tumors in the liver dome. For reliable tissue coagulation, IPI must be combined with an intercostal sonication technique. Considering the proportion of patients with tumors in the liver dome, IPI widens the applicability of MR-HIFU ablation for liver tumors considerably.

Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer.

Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer.

Evolution of the ablation region after magnetic resonance-guided high-intensity focused ultrasound ablation in a Vx2 tumor model.

OBJECTIVES: Volumetric magnetic resonance (MR)-guided high-intensity focused ultrasound (HIFU) is a completely noninvasive image-guided thermal ablation technique. Recently, there has been growing interest in the use of MR-HIFU for noninvasive ablation of malignant tumors. Of particular interest for noninvasive ablation of malignant tumors is reliable treatment monitoring and evaluation of response. At this point, there is limited evidence on the evolution of the ablation region after MR-HIFU treatment. The purpose of the present study was to comprehensively characterize the evolution of the ablation region after volumetric MR-HIFU ablation in a Vx2 tumor model using MR imaging, MR temperature data, and histological data. MATERIALS AND METHODS: Vx2 tumors in the hind limb muscle of New Zealand White rabbits (n = 30) were ablated using a clinical MR-HIFU system. Twenty-four animals were available for analyses. Magnetic resonance imaging was performed before and immediately after ablation; MR temperature mapping was performed during the ablation. The animals were distributed over 7 groups with different follow-up lengths. Depending on the group, animals were reimaged and then killed on day 0, 1, 3, 7, 14, 21, or 28 after ablation. For all time points, the size of nonperfused areas (NPAs) on contrast-enhanced T1-weighted (CE-T1-w) images was compared with lethal thermal dose areas (ie, the tissue area that received a thermal dose of 240 equivalent minutes or greater [EM] at 43°C) and with the necrotic tissue areas on histology sections. RESULTS: The NPA on CE-T1-w imaging showed an increase in median size from 266 ± 148 to 392 ± 178 mm(2) during the first day and to 343 ± 170 mm(2) on day 3, followed by a gradual decrease to 113 ± 103 mm(2) on day 28. Immediately after ablation, the NPA was 1.6 ± 1.4 times larger than the area that received a thermal dose of 240 EM or greater in all animals. The median size of the necrotic area on histology was 1.7 ± 0.4 times larger than the NPA immediately after ablation. After 7 days, the size of the NPA was in agreement with the necrotic tissue area on histology (ratio, 1.0 ± 0.2). CONCLUSIONS: During the first 3 days after MR-HIFU ablation, the ablation region increases in size, after which it gradually decreases in size. The NPA on CE-T1-w imaging underestimates the extent of tissue necrosis on histology in the initial few days, but after 1 week, the NPA is reliable in delineating the necrotic tissue area. The 240-EM thermal dose limit underestimates the necrotic tissue area immediately after MR-HIFU ablation. Reliable treatment evaluation techniques are particularly important for noninvasive, image-guided tumor ablation. Our results indicate that CE-T1-w imaging is reliable for MR-HIFU treatment evaluation after 1 week.

Effectiveness of reirradiation for painful bone metastases: a systematic review and meta-analysis.

PURPOSE: Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases. METHODS AND MATERIALS: A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated for overall pain response for reirradiation of metastatic bone pain. RESULTS: Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49-0.67). There was a substantial between-study heterogeneity (I² = 63.3%, p = 0.01) because of clinical and methodological differences between studies. CONCLUSIONS: Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date.