Clinical Outcomes of Thermal Ablation Re-Treatment of Benign Thyroid Nodules: A Multicenter Study from the Italian Minimally Invasive Treatments of the Thyroid Group.

Background: Thermal ablation (TA) is an established therapeutic option alternative to surgery in patients with solid benign thyroid nodules causing local symptoms. However, a variable part of thyroid nodules remain viable after these nonsurgical treatments, and as many as 15% of nodules treated with TA may require a second treatment over time. This study aimed to evaluate the outcomes of TA re-treatment on symptomatic benign thyroid nodules where the volume decreased by <50% after the first procedure ( = technique inefficacy). Methods: We performed a multicenter retrospective cohort study including patients who underwent re-treatment with TA for benign thyroid nodules, whose volume decreased by <50% after initial treatment. The primary aim was to evaluate volume and volume reduction ratio (VRR) over time and compare the 6- and 12-month VRR after first versus second treatment. The secondary aim was to identify protective or risk factors for technique inefficacy, regrowth, and further treatments, expressed as adjusted hazard ratios (HRs) and confidence interval [CI], after adjustment for sex, age, nodule volume, structure and function, nodule regrowth or symptom relapse, technique used and if the same technique was used for the first and second TA and time between them. Results: We included 135 patients. Re-treatment led to VRR of 50% and 52.2% after 6 and 12 months. VRR after re-treatment was greater than after first treatment in small and medium size nodules (<30 mL), while there were no differences for large nodules (>30 mL). After re-treatment technique inefficacy rate was 51.9%, regrowth rate was 12.6%, and further treatment rate was 15.6%. Radiofrequency ablation (RFA) was protective toward technique inefficacy (HR = 0.40 [CI 0.24-0.65]) and need of further treatments (HR = 0.30 [CI 0.12-0.76]). Large nodule volume (>30 mL) was associated with increased risk of re-treatment (HR = 4.52 [CI 1.38-14.82]). Conclusions: This is the first study evaluating the outcomes of re-treatment on symptomatic benign thyroid nodules with a VRR <50% after the initial TA treatment. Best results were seen in small and medium nodules (<30 mL) and after RFA. Prospective confirmatory studies are needed.

A Multi-centre, Single Arm, Non-randomized, Prospective European Trial to Evaluate the Safety and Efficacy of the HistoSonics System in the Treatment of Primary and Metastatic Liver Cancers (#HOPE4LIVER).

PURPOSE: Image-guided thermal ablation are established treatment options for non-surgical patients with primary and metastatic liver cancers. However, there are limitations with nonuniformity of cancer tissue destruction, heat sink effect and the risk of thermal ablative injury. The current non-thermal ablative techniques have high risk of local recurrence and are not widely adopted. Histotripsy is a treatment technology that destroys targeted tissue under ultrasound visualization via mechanical destruction through the precise application of acoustic cavitation and can offer the potential of non-invasive, non-thermal and non-ionizing radiation cancer treatment. The aim of this multi-centre non-randomized phase I/II trial is to assess the initial safety and efficacy of the prototype investigational 'System' in the treatment of primary and metastatic liver cancers. METHODS/DESIGN: All non-surgical patients with primary/metastatic liver cancers having had previous liver directed therapy, radiation therapy or image-guided ablation may be offered image-guided Histotripsy as per trial protocol. The co-primary endpoints are technical success and procedural safety. Technical success is determined, at ≤ 36 h post procedure, by evaluating the histotripsy treatment size and coverage. The procedural safety is defined by procedure related major complications, defined as Common Terminology Criteria for Adverse Events (CTCAE version 5) grade 3 or higher toxicities, up to 30 days post procedure. This phase I/II trial has intended to recruit up to 45 patients to show safety and efficacy of image-guided histotripsy in liver cancers. TRAIL REGISTRATION: Clinicaltrials.gov identifier-NCT04573881; NIHR CRN CPMS-ID 47572.

Navigation and Robotics in Interventional Oncology: Current Status and Future Roadmap.

Interventional oncology (IO) is the field of Interventional Radiology that provides minimally invasive procedures under imaging guidance for the diagnosis and treatment of malignant tumors. Sophisticated devices can be utilized to increase standardization, accuracy, outcomes, and "repeatability" in performing percutaneous Interventional Oncology techniques. These technologies can reduce variability, reduce human error, and outperform human hand-to-eye coordination and spatial relations, thus potentially normalizing an otherwise broad diversity of IO techniques, impacting simulation, training, navigation, outcomes, and performance, as well as verification of desired minimum ablation margin or other measures of successful procedures. Stereotactic navigation and robotic systems may yield specific advantages, such as the potential to reduce procedure duration and ionizing radiation exposure during the procedure and, at the same time, increase accuracy. Enhanced accuracy, in turn, is linked to improved outcomes in many clinical scenarios. The present review focuses on the current role of percutaneous navigation systems and robotics in diagnostic and therapeutic Interventional Oncology procedures. The currently available alternatives are presented, including their potential impact on clinical practice as reflected in the peer-reviewed medical literature. A review of such data may inform wiser investment of time and resources toward the most impactful IR/IO applications of robotics and navigation to both standardize and address unmet clinical needs.

Stereotactic Radiotherapy after Incomplete Transarterial (Chemo-) Embolization (TAE\TACE) versus Exclusive TAE or TACE for Treatment of Inoperable HCC: A Phase III Trial (NCT02323360).

Background: Hepatocellular carcinoma (HCC) is the most frequent liver malignancy and a leading cause of cancer death in the world. In unresectable HCC patients, transcatheter arterial (chemo-) embolization (TAE/TACE) has shown a disease response in 15-55% of cases. Though multiple TAE/TACE courses can be administered in principle, Stereotactic Body Radiotherapy (SBRT) has emerged as an alternative option in the case of local relapse following multiple TAE/TACE courses. Methods: This is a single-center, prospective, randomized, controlled, parallel-group superiority trial of SBRT versus standard TAE/TACE for the curative treatment of the intermediate stage of HCC after an incomplete response following TAE/TACE (NCT02323360). The primary endpoint is 1-year local control (LC): 18 events were needed to assess a 45% difference (HR: 0.18) in favor of SBRT. The secondary endpoints are 1-year Progression-Free Survival (PFS), Distant Recurrence-Free Survival (DRFS), Overall Survival (OS) and the incidence of acute and late complications. Results: At the time of the final analysis, 40 patients were enrolled, 19 (49%) in the TAE/TACE arm and 21 (51%) in the SBRT arm. The trial was prematurely closed due to slow accrual. The 1- and 2-year LC rates were 57% and 36%. The use of SBRT resulted in superior LC as compared to TAE/TACE rechallenge (median not reached versus 8 months, p = 0.0002). PFS was 29% and 16% at 1 and 2 years, respectively. OS was 86% and 62% at 1 year and 2 years, respectively. In the TAE arm, PFS was 13% and 6% at 1 and 2 years, respectively. In the SBRT arm, at 1 and 2 years, PFS was 37% and 21%, respectively. OS at 1 and 2 years was 75% and 64% in the SBRT arm and 95% and 57% in the TACE arm, respectively. No grade >3 toxicity was recorded. Conclusions: SBRT is an effective treatment option in patients affected by inoperable HCC experiencing an incomplete response following ≥1 cycle of TAE/TAC.

Functional Investigation of the Tumoural Heterogeneity of Intrahepatic Cholangiocarcinoma by In Vivo PET-CT Navigation: A Proof-of-Concept Study.

Intra-tumoural heterogeneity (IH) is a major determinant of resistance to therapy and outcomes but remains poorly translated into clinical practice. Intrahepatic cholangiocarcinoma (ICC) often presents as large heterogeneous masses at imaging. The present study proposed an innovative in vivo technique to functionally assess the IH of ICC. Preoperative 18F-FDG PET-CT and intraoperative ultrasonography were merged to perform the intraoperative navigation of functional tumour heterogeneity. The tumour areas with the highest and the lowest metabolism (SUV) at PET-CT were selected, identified during surgery, and sampled. Three consecutive patients underwent the procedure. The areas with the highest uptake at PET-CT had higher proliferation index (KI67) values and higher immune infiltration compared to areas with the lowest uptake. One of the patients showed a heterogeneous presence of FGFR2 translocation within the samples. Tumour heterogeneity at PET-CT may drive biopsy to sample the most informative ICC areas. Even more relevant, these preliminary data show the possibility of achieving a non-invasive evaluation of IH in ICC, paving the way for an imaging-based precision-medicine approach.

Interventional oncology of liver tumors: how it all started and where are we now.

Liver was the very first organ for which interventional procedures were applied for the local treatment of primary and secondary malignancies. In this paper, the history of Interventional Oncology of liver, from the very beginning to the current situation, is summarized, including both percutaneous and intravascular procedures, and together with the evolution of the techniques for image guidance. The main ongoing developments, such as new techniques, combined interventional treatments and association of local interventions with new drugs are briefly described, too.

Thermal Ablation of Liver Tumors Guided by Augmented Reality: An Initial Clinical Experience.

Background: Over the last two decades, augmented reality (AR) has been used as a visualization tool in many medical fields in order to increase precision, limit the radiation dose, and decrease the variability among operators. Here, we report the first in vivo study of a novel AR system for the guidance of percutaneous interventional oncology procedures. Methods: Eight patients with 15 liver tumors (0.7−3.0 cm, mean 1.56 + 0.55) underwent percutaneous thermal ablations using AR guidance (i.e., the Endosight system). Prior to the intervention, the patients were evaluated with US and CT. The targeted nodules were segmented and three-dimensionally (3D) reconstructed from CT images, and the probe trajectory to the target was defined. The procedures were guided solely by AR, with the position of the probe tip was subsequently confirmed by conventional imaging. The primary endpoints were the targeting accuracy, the system setup time, and targeting time (i.e., from the target visualization to the correct needle insertion). The technical success was also evaluated and validated by co-registration software. Upon completion, the operators were assessed for cybersickness or other symptoms related to the use of AR. Results: Rapid system setup and procedural targeting times were noted (mean 14.3 min; 12.0−17.2 min; 4.3 min, 3.2−5.7 min, mean, respectively). The high targeting accuracy (3.4 mm; 2.6−4.2 mm, mean) was accompanied by technical success in all 15 lesions (i.e., the complete ablation of the tumor and 13/15 lesions with a >90% 5-mm periablational margin). No intra/periprocedural complications or operator cybersickness were observed. Conclusions: AR guidance is highly accurate, and allows for the confident performance of percutaneous thermal ablations.

Cranial sonolucent prosthesis: a window of opportunity for neuro-oncology (and neuro-surgery).

INTRODUCTION: Ultrasound (US) is a versatile technology, able to provide a real-time and multiparametric intraoperative imaging, and a promising way to treat neuro-oncological patients outside the operating room. Anyhow, its potential is limited both in imaging and therapeutic purposes by the existence of the bone shielding. To enhance the spectrum of uses, our group has designed a dedicated US-translucent cranial prosthesis. Herein, we provide the proof of concept of a long-term US-based follow-up and a potential bedside therapeutic exploitation of US. METHODS: The prosthesis was first implanted in a cadaveric specimen to record any issue related to the cranioplasty procedure. Hence, the device was implanted in a patient undergoing surgery for a multi-recurrent anaplastic oligodendroglioma. US multiparametric scans through the device were acquired at 3, 6, 9, and 30 months after the procedure. RESULTS: The prosthesis could be modeled and implanted through ordinary instruments, with no concerns over safety and feasibility. Trans-prosthesis multiparametric US imaging was feasible, with image quality comparable to intraoperative US. Long-term follow-up in an outpatient setting was possible with no adverse events. Trans-prosthesis mechanical interaction with microbubbles was also feasible during follow-up. CONCLUSIONS: This report provides the first proof of concept for a potential breakthrough in the management of neuro-oncological patients. Indeed, through the implantation of an artificial acoustic window, the road is set to employ US both for a more dynamic long-term follow-up, and for US-guided therapeutic applications.

Image-guided thermal ablation in autonomously functioning thyroid nodules. A retrospective multicenter three-year follow-up study from the Italian Minimally Invasive Treatment of the Thyroid (MITT) Group.

OBJECTIVES: To report the results of a multicenter retrospective evaluation of the clinical outcomes of thermal ablation (TA) in a large series of autonomously functioning thyroid nodules (AFTN) with a follow-up protracted up to 3 years. METHODS: Patients treated with single TA for an AFTN in Italy were included. Changes in nodule volume, TSH values, and ongoing anti-thyroid therapy were assessed at the 2-, 6-, 12-, 24-, and 36-month follow-up controls. Complications and need of any additional therapy after TA were also registered. RESULTS: A total of 361 patients (244 females, 117 males, median age 58 years, IQR 46-70 years) were included. Nodule volume was significantly reduced at all time points (p < 0.001) (median volume reduction 58% at 6-month and 60% at 12-month). Serum TSH values increased significantly at all time points. After TA, anti-thyroid therapy was withdrawn in 32.5% of patients at 2 months, in 38.9% at 6 months, and in 41.3% at 12 months. A significant difference in the rate of patients who withdrawn medical therapy at 12 months was registered between small (< 10 mL) (74%), medium (49%), or large (> 30 mL) nodules (19%). A single major complication occurred (0.25%). Additional treatments were needed in 34/361 (9.4%) of cases including 4 (1.1%) surgical treatment. CONCLUSIONS: Image-guided thermal ablation offers a further safe and effective therapeutic option in patients with AFTN. Clinical outcomes are significantly more favorable in small than in large size AFTN. KEY POINTS: • Thermal ablations (TA) can be safely and effectively used in patients with autonomously functioning thyroid nodules (AFTN). • TA results in a clinically significant nodule volume reduction that is paralleled by TSH level normalization and anti-thyroid drug therapy discontinuation (after TA anti-thyroid therapy was withdrawn in 41.3% at 12 months). • Clinical outcomes after TA are more favorable in small nodules, and when a large amount of thyroid nodule tissue is ablated.

How to Perform Intra-Operative Contrast-Enhanced Ultrasound of the Brain-A WFUMB Position Paper.

Intra-operative ultrasound has become a relevant imaging modality in neurosurgical procedures. While B-mode, with its intrinsic limitations, is still considered the primary ultrasound modality, intra-operative contrast-enhanced ultrasound (ioCEUS) has more recently emerged as a powerful tool in neurosurgery. Though still not used on a large scale, ioCEUS has proven its utility in defining tumor boundaries, identifying lesion vascular supply and mapping neurovascular architecture. Here we propose a step-by-step procedure for performing ioCEUS analysis of the brain, highlighting its neurosurgical applications. Moreover, we provide practical advice on the use of ultrasound contrast agents and review technical ultrasound parameters influencing ioCEUS imaging.

Real-Time US-CT fusion imaging for guidance of thermal ablation in of renal tumors invisible or poorly visible with US: results in 97 cases.

PURPOSE: To assess the capability of ultrasound-computed tomography (US-CT) fusion imaging to guide a precise targeting of renal tumors invisible or poorly visible with US. MATERIALS AND METHODS: From 2016 renal tumors poorly visible or inconspicuous/invisible at US were treated at our institution with the guidance of US/CT fusion in a room equipped with CT scanner. Feasibility of the procedure, accuracy of targeting, complications, and technique efficacy were evaluated. RESULTS: Of 227 patients treated from 2016 to March 2020, 91 patients (65 males and 26 females, mean age 68.5 ± 10.1 years) with 97 renal lesions (mean maximum diameter 21.6 ± 9.4 mm) inconspicuous/invisible (29/97, 29.9%) or poorly visible (68/97, 70.1%) at US underwent treatment under US-CT fusion guidance. US-CT fusion imaging guidance was always technically feasible and enabled correct targeting in 97/97/(100%) of cases. Technical success was achieved in 93/97 lesions (95.9%). Three lesions were retreated during the same ablative session, while 1 was retreated in a subsequent session. Thus, primary efficacy was achieved in one session in 96/97 (98.9%) cases and secondary efficacy in 97/97 (100%) cases. CONCLUSION: US-CT image fusion guidance allows for a correct tumor targeting of renal tumors poorly visible or inconspicuous/invisible with US alone, with a high rate of technical success and technique efficacy.

Real-time US/cone-beam CT fusion imaging for percutaneous ablation of small renal tumours: a technical note.

INTRODUCTION: Fusion imaging is gaining attention as an imaging technique to assist minimally invasive tumour ablation. Ultrasound (US) and computed tomography (CT) are the most common imaging modalities to guide thermal ablation of renal tumours, yet cone-beam CT (CBCT) has recently been described to successfully assist percutaneous renal interventions. Our goal was to evaluate primary technical success and correct lesion targeting of US/CBCT fusion imaging to guide the ablation of kidney masses < 2 cm in a small group of patients. MATERIAL AND METHODS: Six renal lesions (maximum diameter 11-17 mm) were treated with RFA in 5 different patients using real-time US/CBCT. Fusion imaging was used to identify and monitor tumour ablation. Demographics, tumour characteristics and mean serum creatinine levels were recorded before and after the procedure. Primary technical success and correct lesion targeting represented the main endpoints of the study. Primary technique efficacy was confirmed at 1-month and 3-month contrast-enhanced CT follow-ups. RESULTS: In all cases, a confident US/CBCT synchronisation was reached and allowed for a correct targeting and a successful percutaneous ablation. Primary technique efficacy was 100%. No recurrence was observed at the follow-up that ranged from 8 to 26 months (mean 16 months). CONCLUSIONS: US/CBCT fusion proved to be a viable method to precisely guide safe and effective percutaneous thermal ablation in patients with small renal tumours, especially when hardly detectable on US. KEY POINTS: • US/CBCT fusion imaging for renal ablation is safe and feasible. • US/CBCT fusion imaging allows for an improved targeting and complete ablation of small RCC with poor US-conspicuity.

Percutaneous ablation of post-surgical solitary early recurrence of colorectal liver metastases is an effective "test-of-time" approach.

Standard treatment of early recurrence of colorectal liver metastases (CLM) after liver resection (LR) is chemotherapy followed by loco-regional therapy. We reviewed the outcome of a different strategy ("test-of-time" approach): upfront percutaneous ablation without chemotherapy. Twenty-six consecutive patients with early solitary liver-only recurrence amenable to both resection and ablation (< 30 mm, distant from vessels) undergone "test-of-time" approach were analyzed. Early recurrence had a median size of 17 mm and occurred after a median interval from LR of 4 months. Primary efficacy rate of ablation was 100%. Five patients are alive and disease-free after a mean follow-up of 46 months. Five patients had local-only recurrence; all had repeat treatment (LR = 4; Ablation = 1) without chemotherapy. Local recurrence risk was associated with incomplete ablation of 1-cm thick peritumoral margin. The remaining 16 patients had non-local recurrence, 13 early after ablation. Overall, six (23%) patients had ablation as unique treatment and 13 (50%) avoided or postponed chemotherapy (mean chemotherapy-free interval 33.5 months). Ablation without chemotherapy of early liver-only recurrence is a reliable "test-of-time" approach. It minimized the invasiveness of treatment with good effectiveness and high salvageability in case of local failure, avoided worthless surgery, and saved chemotherapy for further disease progression.

Volumetric assessment of the periablational safety margin after thermal ablation of colorectal liver metastases.

OBJECTIVES: To retrospectively assess the periablational 3D safety margin in patients with colorectal liver metastases (CRLM) referred for stereotactic radiofrequency ablation (RFA) and to evaluate its influence on local treatment success. METHODS: Forty-five patients (31 males; mean age 64.5 [range 31-87 years]) with 76 CRLM were treated with stereotactic RFA and retrospectively analyzed. Image fusion of pre- and post-interventional contrast-enhanced CT scans using a non-rigid registration software enabled a retrospective assessment of the percentage of predetermined periablational 3D safety margin and CRLM successfully ablated. Periablational safety zones (1-10 mm) and percentage of periablational zone ablated were calculated, analyzed, and compared with subsequent tumor growth to determine an optimal safety margin predictive of local treatment success. RESULTS: Mean overall follow-up was 36.1 ± 18.5 months. Nine of 76 CRLMs (11.8%) developed local tumor progression (LTP) with mean time to LTP of 18.3 ± 11.9 months. Overall 1-, 2-, and 3-year cumulative LTP-free survival rates were 98.7%, 90.6%, and 88.6%, respectively. The periablational safety margin assessment proved to be the only independent predictor (p < 0.001) of LTP for all calculated safety margins. The smallest safety margin 100% ablated displaying no LTP was 3 mm, and at least 90% of a 6-mm circumscribed 3D safety margin was required to achieve complete ablation. CONCLUSIONS: Volumetric assessment of the periablational safety margin can be used as an intraprocedural tool to evaluate local treatment success in patients with CRLM referred to stereotactic RFA. Ablations achieving 100% 3D safety margin of 3 mm and at least 90% 3D safety margin of 6 mm can predict treatment success. KEY POINTS: • Volumetric assessment of the periablational safety margin can be used as an intraprocedural tool to evaluate local treatment success following thermal ablation of colorectal liver metastases. • Ablations with 100% 3D periablational safety margin of 3 mm and ablations with at least 90% 3D safety margin of 6 mm can be considered indications of treatment success. • Image fusion of pre- and post-interventional CT scans with the software used in this study is feasible and could represent a useful tool in daily clinical practice.

Percutaneous radiofrequency ablation of HCC: reduced ablation duration and increased ablation size using single, internally cooled electrodes with an optimized pulsing algorithm.

PURPOSE: To assess the use of optimized radiofrequency (RF) to achieve larger, spherical ablation volumes with short application duration for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty-two patients (M:F = 17:5, median age 69.6 year, range 63-88) with 28 HCCs due to HCV + liver cirrhosis underwent RFA. 20/28 (71.4%) were tumors ≤3cm diameter, and 8/28 (28.6%) ranged from 3.2 to 4.2 cm. RF was applied using up to 2500mA via an optimized pulsing algorithm with real-time ultrasound monitoring to detect hyperechogenic changes. Single insertions of an internally cooled electrode were performed using exposed tips of 2 or 3 cm for 13 HCCs and 4 cm for 15 HCCs. All patients were followed-up for a minimum of 5 years with contrast-enhanced computed tomography (CECT). RESULTS: Technical success was achieved without adverse events in all cases. The mean ablation time was 8.5 ± 2.6 min. In 21/28 (75%), ablation duration ranged from 3 to 9 min, with 12 min duration applied in only 7/28 (25%). Mean coagulation diameters were 2.4 ± 0.14, 3.3 ± 0.62, and 4.4 ± 1.0, for 2, 3 and 4 cm electrodes, respectively (p < 0.01). The sphericity index was 74.9 ± 12.8 for 4 cm electrodes and 81.9 ± 8.0 for shorter electrodes (p = 0.091). At 5-year follow-up, no tumor ≤3 cm had recurrence and only 2/8 (25%) >3 cm tumors developed local progression. One patient had multifocal disease with no local progression. CONCLUSION: Efficient delivery of RF energy can considerably decrease the ablation time in many instances while achieving larger, relatively spherical, and reproducible areas of ablation with extremely low rates of local tumor progression and adverse events.