Haruyuki Takaki

Thermal ablation and immunomodulation: From preclinical experiments to clinical trials

Accumulating evidence has shown that thermal ablation can induce spontaneous distant tumor regression, which is also known as abscopal effect. Abscopal effect might depend upon the activation of antitumor immune response. However, such responses induced by thermal ablation had been thought to be usually weak and that they rarely induce distant tumor regression. Recently, results of several preclinical and clinical studies have suggested that thermal ablation can induce therapeutically effective systemic antitumor immune response if appropriate immunomodulators are combined. To elucidate the mechanisms of these promising strategies, effects of thermal ablation on the immune system are overviewed. Furthermore, recent promising preclinical and clinical studies examining enhancement of systemic antitumor immune response by combining thermal ablation and immunomodulation are summarized.

Changes in liver stiffness on real-time tissue elastography before and after occlusion of spontaneous portosystemic shunts

PURPOSE This study was conducted to evaluate changes in liver stiffness, volume, and function before and after occlusion of spontaneous portosystemic shunt. MATERIALS & METHODS Twenty-four patients (13 men and 11 women) with a mean age of 68.2 years±10.1 (SD) (age range, 49-82 years) underwent percutaneous occlusion of spontaneous portosystemic shunt because of gastric varices (n=17) or hepatic encephalopathy (n=7) from March 2011 to June 2013. The liver fibrosis index indicating liver stiffness was calculated by using ultrasound elastography before and after shunt occlusion. Liver volume and liver profile were also evaluated. RESULTS Spontaneous portosystemic shunt occlusion was uneventfully performed in all patients. The mean liver fibrosis index was significantly decreased from 2.7±1.0 before shunt occlusion to 2.0±0.9 (P<0.001) at 1 month, 2.2±1.0 at 3 months (P=0.004), and 1.6±0.7 at 6 months (P=0.001) afterwards. A significant increase in the liver volume was observed from 1035.3±340.1mL before shunt occlusion to 1116.8±298.4mL (P=0.006) at 1 month and 1174.2±354.1mL (P<0.001) at 3 months afterwards. Significant improvement in the Child-Pugh score was also found at 1 month (6.2±1.4, P<0.001), 3 months (6.5±1.1, P=0.022), and 6 months (6.0±0.9, P=0.004) after shunt occlusion as compared with that (7.2±1.9) before. CONCLUSION The liver stiffness decreases along with an increase in liver volume and improvement in liver function after spontaneous portosystemic shunt occlusion.

Safety and Clinical Outcomes of Percutaneous Radiofrequency Ablation for Intermediate and Large Bone Tumors Using a Multiple-Electrode Switching System: A Phase II Clinical Study

PURPOSE To evaluate the safety and clinical outcomes of radiofrequency (RF) ablation using a multiple-electrode switching system in patients with bone tumors > 3 cm. MATERIALS AND METHODS This prospective study enrolled 20 subjects (15 men, 5 women; mean age 70.0 y ± 7.4 [SD]; range, 60-80 y) with malignant unresectable bone tumors. The maximum mean tumor diameter was 5.5 cm ± 2.0 (range, 3.1-10.0 cm). Two to three RF electrodes were placed into each bone tumor. Real-time CT fluoroscopic guidance was used with a multiple-electrode switching system. The primary endpoint was safety, as evaluated by Common Terminology Criteria for Adverse Events, until 12 months after bone RF ablation. As secondary endpoints, pain relief was evaluated by visual analog scale (VAS) scores before and 1 week after RF ablation; tumor response, by contrast-enhanced magnetic resonance imaging studies until 4 weeks after bone RF ablation; and survival, by Kaplan-Meier method. RESULTS No adverse event was found in 19 of 20 patients (95%). Grade 2 fever occurred in 1 patient (5%; 1/20). VAS scores decreased by ≥ 2 in 11 of 13 patients (84.6%) who had painful bone tumors. Tumor response (complete or partial response) was achieved in 16 of 18 patients (88.9%) who underwent follow-up imaging studies. The 1-year overall survival rate was 60.9%, and the median survival time was 14.1 months. CONCLUSIONS Bone RF ablation using this system is safe and achieves local tumor control and pain relief in patients with large bone tumors.

Changes in peripheral blood T-cell balance after percutaneous tumor ablation

Abstract Purpose: To evaluate the changes in T-cell balance in peripheral blood following percutaneous tumor ablation. Material and methods: Patients underwent thermal ablation including radiofrequency (n = 9) and microwave ablation (n = 5), or cryoablation (n = 5). Target tumors were located in the lung (n = 7), soft tissue (n = 5), liver (n = 4), and bone (n = 3). Patient peripheral blood samples were collected before and within 14 days after ablation. Peripheral blood populations of cytotoxic T-cells (CTL), type-1 (Th1) and type-2 helper T-cells (Th2), and regulatory T-cells (Treg) were measured using flow cytometry. Changes in CTL/Treg and Th1/Th2 ratios before and after ablation therapy were compared using paired t-tests. Results: Peripheral blood CTL population (27.5 ± 2.1% to 30.2 ± 2.5%, p < .03) and CTL/Treg ratios (18.8 ± 3.7% to 21.6 ± 3.6%, p < .05) increased significantly after ablation. Although a significant increase in CTL/Treg ratios was found after heat-based ablation (18.0 ± 4.4% to 21.6 ± 4.7%, p < .02), it remained unchanged after cryoablation (21.0 ± 7.0% to 21.5 ± 4.3%, p = .92). Th1/Th2 ratio (13.7 ± 3.0% to 17.2 ± 3.5%, p = .12) remained unchanged after ablation. Conclusion: Ablation therapy alters the T-cell balance by increasing the systemic CTL/Treg, ratio. Heat-based ablation might be a more effective approach than cryoablation to enhance systemic anti-tumor immunity.

Balloon-occluded retrograde transvenous obliteration of varices: focusing on the portal hemodynamics and the recent techniques

PurposeTo evaluate the recent topics of Ballloon-occluded retrograde trasnvenous obliteration(B-RTO).MethodWe overviewed the recent scientific papers regarding B-RTO.ResultB-RTO is a treatment method for occluding varices retrogradely using a sclerosing agent under balloon occlusion of a major draining vein. It has been recognized as an effective treatment method for gastric varices. Hepatic function reserve is improved and liver volume is increased after B-RTO. In recent years, various technical options, such as plug-assisted retrograde transvenous obliteration, coil-assisted retrograde transvenous obliteration, or foam B-RTO, have also been reported. In performing B-RTO, portal hemodynamics must be thoroughly examined radiologically. Judging the classification of the grade of collateral venous hemodynamics is important to select the appropriate embolization technique of B-RTO and to successfully occlude varices. Finally, the word “portosystemic shunt syndrome” has been proposed and the condition should be considered while selecting a treatment for gastric varices.ConclusionB-RTO is effective for gastrointestinal varices and portosystemic shunts.

Radiofrequency Ablation Effectively Treated Focal Recurrence of Mesothelioma

A 55-year-old man with malignant pleural mesothelioma underwent multimodality treatment comprising induction chemotherapy followed by extrapleural pneumonectomy and radiation therapy. After 2.5 years, focal recurrence occurred, with computed tomography revealing a tumor in the left cardiophrenic angle. Surgery was considered a problem for the patient because of the previous extrapleural pneumonectomy and difficult tumor location. Radiofrequency ablation was therefore performed; the course was uneventful, and there was no recurrence. Radiofrequency ablation should be considered an option to treat recurrence of malignant pleural mesothelioma.

Reversible Electroporation–Mediated Liposomal Doxorubicin Delivery to Tumors Can Be Monitored With 89Zr-Labeled Reporter Nanoparticles:

Reversible electroporation (RE) can facilitate nanoparticle delivery to tumors through direct transfection and from changes in vascular permeability. We investigated a radiolabeled liposomal nanoparticle (89Zr-NRep) for monitoring RE-mediated liposomal doxorubicin (DOX) delivery in mouse tumors. Intravenously delivered 89Zr-NRep allowed positron emission tomography imaging of electroporation-mediated nanoparticle uptake. The relative order of 89Zr-NRep injection and electroporation did not result in significantly different overall tumor uptake, suggesting direct transfection and vascular permeability can independently mediate deposition of 89Zr-NRep in tumors. 89Zr-NRep and DOX uptake correlated well in both electroporated and control tumors at all experimental time points. Electroporation accelerated 89Zr-NRep and DOX deposition into tumors and increased DOX dosing. Reversible electroporation–related vascular effects seem to play an important role in nanoparticle delivery to tumors and drug uptake can be quantified with 89Zr-NRep.

Transportal Embolization of Intrahepatic Arterioportal Fistulae Refractory to Arterial Embolization

avoided as primary embolization agents because of the presence of multiple feeding vessels and risk of nontarget embolization. Angiography performed after embolization demonstrated no flow into the aneurysm sac (Fig 2b). The pelvic drainage catheter was removed after the output decreased to o 5 mL/d. The patient was discharged from the hospital 3 days after the procedure. A follow-up CT scan performed at 9 months demonstrated complete occlusion of the aneurysm and no signs of recanalization with a patent intrahepatic and extrahepatic portal vein (Fig 3). PVAs are the most common visceral venous aneurysm, although still extremely rare with a reported prevalence of up to 0.43% (1). Extrahepatic PVAs (defined as 4 2 cm) are more common than intrahepatic PVAs (defined as 4 9 mm) (1). PVAs can be congenital or acquired. Common etiologies of PVA include chronic liver disease (with or without portal hypertension), pancreatitis, trauma, and malignant invasion. Most patients are asymptomatic or present with unrelated abdominal pain, and the PVA is usually diagnosed incidentally (1–3). In our case, although the diagnosis was incidental, the PVA may have been related to hematogenous spread of infection from a diverticular abscess eroding into the mesenteric veins. Rupture of a rapidly growing PVA is rare. Most PVAs require no treatment and are monitored with imaging (commonly vascular ultrasound). Surgical treatment of a PVA is recommended if the patient is symptomatic or if the aneurysm enlarges (2). Surgical interventions include aneurysmorrhaphy for saccular aneurysms and aneurysmectomy for fusiform aneurysms (3). Portocaval or mesocaval shunts may be placed to prevent aneurysm

Ablation protocols and ancillary procedures in tumor ablation therapy: consensus from Japanese experts

PurposeA panel of Japanese experts on tumor ablation therapy gathered to reach a general consensus on topics surrounding ablation therapy.Materials and methodsQuestionnaires relating to ablation protocols for radiofrequency ablation (RFA) and cryoablation, as well as ancillary procedures required for safe and secure ablation therapy, were sent to seven institutions. Experts from these institutions discussed each topic based on the evidence and the questionnaire data, and a consensus was reached at an annual meeting of the Japan Image-guided Ablation Group in Maebashi, Japan, in October 2015.ResultsA consensus was reached on each of six topics, including “management of antiplatelet and anticoagulation drug therapy”; “pain control in the perioperative period”; “arterial embolization combined with ablation therapy”; “protection of non-target organs”; “RFA and cryoablation protocols”; and “ablative margins.”ConclusionsThe consensus achieved here will serve as the framework for tumor ablation therapies in Japan.