MRI and CT in the follow-up after irreversible electroporation of small renal masses.

PURPOSE: Ablation plays a growing role in the treatment of small renal masses (SRMs) due to its nephron sparing properties and low invasiveness. Irreversible electroporation (IRE) has the potential, although still experimental, to overcome current limitations of thermal ablation. No prospective imaging studies exist of the ablation zone in the follow up after renal IRE in humans. Objectives are to assess computed tomography (CT) and magnetic resonance imaging (MRI) on the ablation zone volume (AZV), enhancement and imaging characteristics after renal IRE. METHODS: Prospective phase 2 study of IRE in nine patients with ten SRMs. MRI imaging was performed pre-IRE, 1 week, 3 months, 6 months and 12 months after IRE. CT was performed pre-IRE, perioperatively (direct after ablation), 3 months, 6 months and 12 months after IRE. AZVs were assessed by two independent observers. Observer variation was analyzed. Evolution of AZVs, and relation between the needle configuration volume (NCV; planned AZV) and CT- and MRI volumes were evaluated. RESULTS: Eight SRMs were clear cell renal cell carcinomas, one SRM was a papillary renal cell carcinoma and one patient had a non-diagnostic biopsy. On CT, median AZV increased perioperatively until 3 months post-IRE (respectively, 16.8 cm3 and 6.2 cm3) compared to the NCV (4.8 cm3). On MRI, median AZV increased 1-week post-IRE until 3 months post-IRE (respectively, 14.5 cm3 and 4.6 cm3) compared to the NCV (4.8 cm3). At 6 months the AZV starts decreasing (CT 4.8 cm3; MRI 3.0 cm3), continuing at 12 months (CT 4.2 cm3, MRI 1.1 cm3). Strong correlation was demonstrated between the planning and the post-treatment volumes. Inter-observer agreement between observers was excellent (CT 95% CI 0.82-0.95, MRI 95% CI 0.86-0.96). All SRMs appeared non-enhanced immediately after ablation, except for one residual tumour. Subtraction images confirmed non-enhancement on MRI in unclear enhancement cases (3/9). Directly after IRE, gas bubbles, perinephric stranding and edema were observed in all cases. CONCLUSION: The AZV increases immediately on CT until 3 months after IRE. On MRI, the AZV increases at 1 week until 3 months post-IRE. At 6 months the AZV starts decreasing until 12 months post-IRE on both CT and MRI. Enhancement was absent post-IRE, except for one residual tumour. Gas bubbles, perinephric stranding and edema are normal findings directly post-IRE.

Feasibility and safety of irreversible electroporation (IRE) in patients with small renal masses: Results of a prospective study.

BACKGROUND: Irreversible electroporation (IRE) has the potential to overcome limitations of thermal ablation, enabling small renal mass (SRM) ablation near vital structures. PURPOSE: To assess feasibility and safety of percutaneous IRE for the treatment of SRMs. MATERIALS AND METHODS: This prospective study is a phase 2 trial (NCT02828709) of IRE for patients with SRMs. Primary endpoints are feasibility and safety. Device- and procedural-adverse events were assessed by Clavien-Dindo and Common Terminology Criteria for Adverse Events version 4.0 grading systems. Technical feasibility was assessed by recording the technical success of the procedures. Technical success was evaluated by performing a CT immediately after ablation where complete tumor coverage and nonenhancement were evaluated. Tumor charcateristics and patient characteristics, procedural and anesthesia details, postprocedural events, and perioperative complications were recorded. RESULTS: Ten SRMs were included with a mean tumor size of 2.2 cm (range 1.1-3.9 cm) were treated with IRE. Renal mass biopsies revealed 7 clear cell and 1 papillary renal cell carcinoma. Two renal mass biopsies were nondiagnostic. The median follow-up was 6 months (range 3-12 months). Technical success was achieved in 9 out of 10 cases. One patient had a grade 3 Clavien-Dindo complication (1/10, 95% Confidence interval (CI) 0.0179-0.4041). Mean anesthesia time was 3.7 hours (range 3-5 hours), mean procedural time was 2.1 hours (range 1 hour 45 minutes-2 hours 30 minutes) and mean ablation time was 50 minutes (range 20 minutes-1 hour 45 minutes). The creatinine preoperative and postoperative (1 week, 3 months, 6 months, and 12 months) did not significantly differ. In total, 8 out of 10 cases did not experience postoperative pain. CONCLUSION: IRE in SRMs is safe and feasible. Renal function is not affected by IRE and postoperative pain is rare. Anesthesia time and procedural time are a potential concern.

An In-vivo Prospective Study of the Diagnostic Yield and Accuracy of Optical Biopsy Compared with Conventional Renal Mass Biopsy for the Diagnosis of Renal Cell Carcinoma: The Interim Analysis.

BACKGROUND: Lack of accuracy in preoperative imaging leads to overtreatment of benign renal masses (RMs) or indolent renal cell carcinomas (RCCs). Optical coherence tomography (OCT) is real time and high resolution, enabling quantitative analysis through attenuation coefficient (µOCT, mm-1). OBJECTIVE: To determine the accuracy and diagnostic yield of OCT and renal mass biopsy (RMB) for the differentiation of benign RMs versus RCC and oncocytoma versus RCC. DESIGN, SETTING, AND PARTICIPANTS: From October 2013 to June 2016, 95 patients with solid enhancing RMs on cross-sectional imaging were prospectively included. All patients underwent subsequent excision or ablation. INTERVENTION: Percutaneous, image-guided, needle-based OCT followed by RMB in an outpatient setting under local anaesthesia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Accuracy and diagnostic yield, µOCT correlated to resection pathology or second biopsy during ablation. Tables (2×2) for RMB, receiver operating characteristic curve for OCT. Mann-Whitney test to differentiate µOCT of RMs. RESULTS AND LIMITATIONS: RMB diagnostic yield was 79% with sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of 100%, 89%, 99%, and 100%, respectively. Diagnostic yield and added value of OCT to differentiate RCC from benign was 99% and 15%, respectively. Significant difference was observed in median µOCT between benign RMs (3.2mm-1, interquartile range [IQR]: 2.65-4.35) and RCCs (4.3mm-1, IQR: 3.70-5.00), p=0.0171, and oncocytomas (3.38mm-1, IQR: 2.68-3.95) and RCCs (4.3mm-1, IQR: 3.70-5.00), p=0.0031. OCT showed sensitivity, specificity, positive predictive value. and NPV of 91%, 56%, 91%, and 56%, respectively, to differentiate benign RMs from RCCs and 92%, 67%, 95%, and 55%, respectively, to differentiate oncocytoma from RCC. Limitations include two reference standards and heterogeneity benign RMs. CONCLUSIONS: Compared with RMB, OCT has a higher diagnostic yield. OCT accurately distinguishes benign RMs from RCCs, and oncocytoma from RCCs, although specificity and NPV are lower. PATIENT SUMMARY: Optical coherence tomography, a new optical scan, exhibits similar sensitivity and positive predictive value than renal mass biopsy, although lower specificity and negative predictive value. Optical coherence tomography has a higher diagnostic yield for diagnosing renal cell carcinoma.

Irreversible electroporation for the treatment of localized prostate cancer: a summary of imaging findings and treatment feedback.

PURPOSE: Imaging plays a crucial role in ablative therapies for prostate cancer (PCa). Irreversible electroporation (IRE) is a new treatment modality used for focal treatment of PCa. We aimed to demonstrate what imaging modalities can be used by descriptively reporting contrast-enhanced ultrasonography (CEUS), multiparametric magnetic resonance imaging (mpMRI), and grey-scale transrectal ultrasound (TRUS) results. Furthermore, we aimed to correlate quantitatively the ablation zone seen on mpMRI and CEUS with treatment planning to provide therapy feedback. METHODS: Imaging data was obtained from two prospective multicenter trials on IRE for localized low- to intermediate-risk PCa. The ablation zone volume (AZV) seen on mpMRI and CEUS was 3D reconstructed to correlate with the planned AZV. RESULTS: Descriptive examples are provided using mpMRI, TRUS, and CEUS for treatment planning and follow-up after IRE. The mean AZV on T2-weighted imaging 4 weeks following IRE was 12.9 cm3 (standard deviation [SD]=7.0), 5.3 times larger than the planned AZV. Linear regression showed a positive correlation (r=0.76, P = 0.002). For CEUS the mean AZV was 20.7 cm3 (SD=8.7), 8.5 times larger than the planned AZV with a strong positive correlation (r=0.93, P = 0.001). Prostate volume is reduced over time (mean= -27.5%, SD=11.9%) due to ablation zone fibrosis and deformation, illustrated by 3D reconstruction. CONCLUSION: The role of imaging in conjunction with IRE is of crucial importance to guide clinicians throughout the treatment protocol. CEUS and mpMRI may provide essential treatment feedback by visualizing the ablation zone dimensions and volume.

Irreversible Electroporation for the Ablation of Renal Cell Carcinoma: A Prospective, Human, In Vivo Study Protocol (IDEAL Phase 2b).

BACKGROUND: Irreversible electroporation (IRE) is an emerging technique delivering electrical pulses to ablate tissue, with the theoretical advantage to overcome the main shortcomings of conventional thermal ablation. Recent short-term research showed that IRE for the ablation of renal masses is a safe and feasible treatment option. In an ablate and resect design, histopathological analysis 4 weeks after radical nephrectomy demonstrated that IRE-targeted renal tumors were completely covered by ablation zone. In order to develop a validated long-term IRE follow-up study, it is essential to obtain clinical confirmation of the efficacy of this novel technology. Additionally, follow-up after IRE ablation obliges verification of a suitable imaging modality. OBJECTIVE: The objectives of this study are the clinical efficacy and safety of IRE ablation of renal masses and to evaluate the use of cross-sectional imaging modalities in the follow-up after IRE in renal tumors. This study conforms to the recommendations of the IDEAL Collaboration and can be categorized as a phase 2B exploration trial. METHODS: In this prospective clinical trial, IRE will be performed in 20 patients aged 18 years and older presenting with a solid enhancing small renal mass (SRM) (≤4 cm) who are candidates for ablation. Magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) will be performed at 1 day pre-IRE, and 1 week post-IRE. Computed tomography (CT), CEUS, and MRI will be performed at 3 months, 6 months, and 12 months post-IRE. RESULTS: Presently, recruitment of patients has started and the first inclusions are completed. Preliminary results and outcomes are expected in 2018. CONCLUSIONS: To establish the position of IRE ablation for treating renal tumors, a structured stepwise assessment in clinical practice is required. This study will offer fundamental knowledge on the clinical efficacy of IRE ablation for SRMs, potentially positioning IRE as ablative modality for renal tumors and accrediting future research with long-term follow-up. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT02828709; https://clinicaltrials.gov/ct2/show/NCT02828709 (archived by WebCite at http://www.webcitation.org/6nmWK7Uu9). Dutch Central Committee on Research Involving Human Subjects NL56935.018.16.

Irreversible electroporation: state of the art.

The field of focal ablative therapy for the treatment of cancer is characterized by abundance of thermal ablative techniques that provide a minimally invasive treatment option in selected tumors. However, the unselective destruction inflicted by thermal ablation modalities can result in damage to vital structures in the vicinity of the tumor. Furthermore, the efficacy of thermal ablation intensity can be impaired due to thermal sink caused by large blood vessels in the proximity of the tumor. Irreversible electroporation (IRE) is a novel ablation modality based on the principle of electroporation or electropermeabilization, in which electric pulses are used to create nanoscale defects in the cell membrane. In theory, IRE has the potential of overcoming the aforementioned limitations of thermal ablation techniques. This review provides a description of the principle of IRE, combined with an overview of in vivo research performed to date in the liver, pancreas, kidney, and prostate.

Percutaneous Needle Based Optical Coherence Tomography for the Differentiation of Renal Masses: a Pilot Cohort.

PURPOSE: We determine the ability of percutaneous needle based optical coherence tomography to differentiate renal masses by using the attenuation coefficient (µOCT, mm(-1)) as a quantitative measure. MATERIALS AND METHODS: Percutaneous needle based optical coherence tomography of the kidney was performed in patients presenting with a solid renal mass. A pathology specimen was acquired in the form of biopsies and/or a resection specimen. Optical coherence tomography results of 40 patients were correlated to pathology results of the resected specimens in order to derive µOCT values corresponding with oncocytoma and renal cell carcinoma, and with the 3 main subgroups of renal cell carcinoma. The sensitivity and specificity of optical coherence tomography in differentiating between oncocytoma and renal cell carcinoma were assessed through ROC analysis. RESULTS: The median µOCT of oncocytoma (3.38 mm(-1)) was significantly lower (p=0.043) than the median µOCT of renal cell carcinoma (4.37 mm(-1)). ROC analysis showed a µOCT cutoff value of greater than 3.8 mm(-1) to yield a sensitivity, specificity, positive predictive value and negative predictive value of 86%, 75%, 97% and 37%, respectively, to differentiate between oncocytoma and renal cell carcinoma. The area under the ROC curve was 0.81. Median µOCT was significantly lower for oncocytoma vs clear cell renal cell carcinoma (3.38 vs 4.36 mm(-1), p=0.049) and for oncocytoma vs papillary renal cell carcinoma (3.38 vs 4.79 mm(-1), p=0.027). CONCLUSIONS: We demonstrated that the µOCT is significantly higher in renal cell carcinoma vs oncocytoma, with ROC analysis showing promising results for their differentiation. This demonstrates the potential of percutaneous needle based optical coherence tomography to help in the differentiation of renal masses, thus warranting ongoing research.

Low-dose endotoxin potentiates capsaicin-induced pain in man: evidence for a pain neuroimmune connection.

Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produced by intradermal capsaicin in healthy volunteers. Here we provide evidence of immune priming of this neuropathic-like pain response in humans. Specifically, in 12 healthy volunteers, activation of Toll-Like Receptor 4 by endotoxin (0.4ng/kg IV) caused significant 5.1-fold increase in the 90-min integral of areas of capsaicin-induced allodynia (95% CI 1.3-9.1), 2.2-fold increase in flare (95% CI 1.9-2.6) and 1.8-fold increase in hyperalgesia (95% CI 1.1-2.5) following 50µg intradermal capsaicin injected into the forearm 3.5h after endotoxin. These data demonstrate clinically a significant role for the neuroimmune pain connection in modifying pain, thus providing evidence that immune priming may produce pain enhancement in humans and hence offer a novel range of pharmacological targets for anti-allodynics and/or analgesics. Additionally, the simplicity of the model makes it suitable as a test-bed for novel immune-targeted pain therapeutics.