Majid Maybody

Irreversible Electroporation Near the Heart: Ventricular Arrhythmias Can Be Prevented With ECG Synchronization

OBJECTIVE Irreversible electroporation is a nonthermal ablative tool that uses direct electrical pulses to create irreversible membrane pores and cell death. The ablation zone is surrounded by a zone of reversibly increased permeability; either zone can cause cardiac arrhythmias. Our purpose was to establish a safety profile for the use of irreversible electroporation close to the heart. MATERIALS AND METHODS The effect of unsynchronized and synchronized (with the R wave on ECG) irreversible electroporation in swine lung and myocardium was studied in 11 pigs. Twelve lead ECG recordings were analyzed by an electrophysiologist for the presence of arrhythmia. Ventricular arrhythmias were categorized as major events. Minor events included all other dysrhythmias or ECG changes. Cardiac and lung tissue was submitted for histopathologic analysis. Electrical field modeling was performed to predict the distance from the applicators over which cells show electroporation-induced increased permeability. RESULTS At less than or equal to 1.7 cm from the heart, fatal (major) events occurred with all unsynchronized irreversible electroporation. No major and three minor events were seen with synchronized irreversible electroporation. At more than 1.7 cm from the heart, two minor events occurred with only unsynchronized irreversible electroporation. Electrical field modeling correlates well with the clinical results, revealing increased cell membrane permeability up to 1.7 cm away from the applicators. Complete lung ablation without intervening live cells was seen. No myocardial injury was seen. CONCLUSION Unsynchronized irreversible electroporation close to the heart can cause fatal ventricular arrhythmias. Synchronizing irreversible electroporation pulse delivery with absolute refractory period avoids significant cardiac arrhythmias.

Percutaneous Radiofrequency Ablation of Colorectal Cancer Liver Metastases: Factors Affecting Outcomes—A 10-year Experience at a Single Center

PURPOSE To identify predictors of oncologic outcomes after percutaneous radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLMs) and to describe and evaluate a modified clinical risk score (CRS) adapted for ablation as a patient stratification and prognostic tool. MATERIALS AND METHODS This study consisted of a HIPAA-compliant institutional review board-approved retrospective review of data in 162 patients with 233 CLMs treated with percutaneous RFA between December 2002 and December 2012. Contrast material-enhanced CT was used to assess technique effectiveness 4-8 weeks after RFA. Patients were followed up with contrast-enhanced CT every 2-4 months. Overall survival (OS) and local tumor progression-free survival (LTPFS) were calculated from the time of RFA by using the Kaplan-Meier method. Log-rank tests and Cox regression models were used for univariate and multivariate analysis to identify predictors of outcomes. RESULTS Technique effectiveness was 94% (218 of 233). Median LTPFS was 26 months. At univariate analysis, predictors of shorter LTPFS were tumor size greater than 3 cm (P < .001), ablation margin size of 5 mm or less (P < .001), high modified CRS (P = .009), male sex (P = .03), and no history of prior hepatectomy (P = .04) or hepatic arterial infusion chemotherapy (P = .01). At multivariate analysis, only tumor size greater than 3 cm (P = .01) and margin size of 5 mm or less (P < .001) were independent predictors of shorter LTPFS. Median and 5-year OS were 36 months and 31%. At univariate analysis, predictors of shorter OS were tumor size larger than 3 cm (P = .005), carcinoembryonic antigen level greater than 30 ng/mL (P = .003), high modified CRS (P = .02), and extrahepatic disease (EHD) (P < .001). At multivariate analysis, tumor size greater than 3 cm (P = .006) and more than one site of EHD (P < .001) were independent predictors of shorter OS. CONCLUSION Tumor size of less than 3 cm and ablation margins greater than 5 mm are essential for satisfactory local tumor control. Tumor size of more than 3 cm and the presence of more than one site of EHD are associated with shorter OS.

Acute and Subacute Effects of Irreversible Electroporation on Nerves: Experimental Study in a Pig Model

PURPOSE To evaluate whether irreversible electroporation (IRE) has the potential to damage nerves in a porcine model and to compare histopathologic findings after IRE with histopathologic findings after radiofrequency ablation (RFA). MATERIALS AND METHODS This study was approved by the institutional animal care and use committee. Computed tomography (CT)-guided IRE of 11 porcine sciatic nerves was performed in nine pigs, and histopathologic analysis was performed on the day of ablation or 3, 6, or 14 days after ablation. In addition, acute RFA of six porcine sciatic nerves was performed in six pigs that were harvested on the day of ablation. All nerves and associated muscles and tissues were assessed for histopathologic findings consistent with athermal or thermal injury, respectively, such as axonal swelling, axonal fragmentation and loss, Wallerian degeneration, inflammatory infiltrates, Schwann cell proliferation, and coagulative necrosis. The percentage of fascicles affected was recorded. RESULTS All nerves had an axonal injury. The percentage of affected nerve fascicles after IRE was 50%-100%. Axonal swelling and perineural inflammatory infiltrates were detectable at every time point after ablation. Axonal fragmentation and loss, macrophage infiltration, and Schwann cell proliferation were found 6 and 14 days after ablation. Distal Wallerian axonal degeneration was observed 14 days after ablation. The endoneurium and perineurium architecture remained intact in all cases. RFA specimens at the day of ablation revealed acute coagulative necrosis associated with intense basophilic staining of extracellular matrix, including collagen of the perineurium and epineurium consistent with thermal injury. CONCLUSION IRE has the potential to damage nerves and may result in axonal swelling, fragmentation, and distal Wallerian degeneration. However, preservation of endoneurium architecture and proliferation of Schwann cells may suggest the potential for axonal regeneration. In contrast, RFA leads to thermal nerve damage, causing protein denaturation, and suggests a much lower potential for regeneration.

Polyorchidism Report of 3 Cases and Review of the Literature

Objective. To describe the embryologic, clinical, sonographic, and magnetic resonance imaging features of polyorchidism and to review the literature on similar cases. Methods. Over a 5‐year period, we encountered 3 patients who were found to have polyorchidism on scrotal sonography. All 3 patients had a painless scrotal mass. Two patients also had magnetic resonance imaging of the scrotum, and the results were correlated with the sonograms. We also performed a literature search for other reports of polyorchidism. Results. One patient had 2 right testicles and a single left testicle. The second patient had 3 left testicles and 1 right testicle. In the third patient, who had 2 left testicles and 1 right testicle, microlithiasis was found in all 3 testes. The supernumerary testes were within the scrotum in all cases. All testicles were identified by sonography. Magnetic resonance imaging in 2 cases provided confirmatory data regarding the presence of an extra testicle but did not add other relevant information. Conservative treatment was chosen in all cases. Conclusions. Polyorchidism is a rare congenital anomaly. There are characteristic sonographic features of polyorchidism, and the diagnosis is often made on the basis of sonography. Magnetic resonance imaging can be used for confirmation but may be more helpful in cases complicated by cryptorchism or neoplasia. Conservative treatment is advised in uncomplicated cases.

Image-guided Thermal Ablation of Tumors Increases the Plasma Level of Interleukin-6 and Interleukin-10

PURPOSE To identify changes in plasma cytokine levels after image-guided thermal ablation of human tumors and to identify the factors that independently predict changes in plasma cytokine levels. MATERIALS AND METHODS Whole-blood samples were collected from 36 patients at three time points: before ablation, after ablation (within 48 hours), and at follow-up (1-5 weeks after ablation). Plasma levels of interleukin (IL)-1α, IL-2, IL-6, IL-10, and tumor necrosis factor (TNF)-α were measured using a multiplex immunoassay. Univariate and multivariate analyses were performed using cytokine level as the dependent variable and sample collection, time, age, sex, primary diagnosis, metastatic status, ablation site, and ablation type as the independent variables. RESULTS There was a significant increase in the plasma level of IL-6 after ablation compared with before ablation (9.6-fold ± 31-fold, P<.002). IL-10 also showed a significant increase after ablation (1.9-fold ± 2.8-fold, P<.02). Plasma levels of IL-1α, IL-2, and TNF-α were not significantly changed after ablation. Cryoablation resulted in the largest change in IL-6 level (>54-fold), whereas radiofrequency ablation and microwave ablation showed 3.6-fold and 3.4-fold changes, respectively. Ablation of melanomas showed the largest change in IL-6 48 hours after ablation (92×), followed by ablation of kidney (26×), liver (8×), and lung (6×) cancers. Multivariate analysis revealed that ablation type (P<.0003) and primary diagnosis (P<.03) were independent predictors of changes to IL-6 after ablation. Age was the only independent predictor of IL-10 levels after ablation (P< .019). CONCLUSIONS Image-guided thermal ablation of tumors increases plasma levels of IL-6 and IL-10, without increasing plasma levels of IL-1α, IL-2, or TNF-α.

A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women with Early-Stage Breast Cancer with Comprehensive Immune Profiling

Purpose: To assess the safety and tolerability of preoperative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. Experimental Design: In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy. Exploratory studies of immune activation were performed on peripheral blood and tumor. Results: Preoperative cryoablation and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery. Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab). Combination therapy was associated with sustained peripheral elevations in: Th1-type cytokines, activated (ICOS+) and proliferating (Ki67+) CD4+ and CD8+ T cells, and posttreatment proliferative T-effector cells relative to T-regulatory cells within tumor. Conclusions: Preoperative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intratumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy. Clin Cancer Res; 22(23); 5729–37. ©2016 AACR.

Deep Sequencing of T-Cell Receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy

Tumor cryoablation plus immune checkpoint blockade facilitates antitumor T-cell responses (TCRs) and improves survival in mice. Deep sequencing of TCRs in human early-stage breast cancer tumors revealed T-cell clonality and density and served as a biomarker after cryo-immunotherapy. In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti–CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 106 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared with monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T-cell responses to therapy and for the study of cryoimmunotherapy in early-stage breast cancer. Cancer Immunol Res; 4(10); 835–44. ©2016 AACR.

Factors Affecting Periprocedural Morbidity and Mortality and Long-term Patient Survival after Arterial Embolization of Hepatic Neuroendocrine Metastases

PURPOSE To identify factors affecting periprocedural morbidity and mortality and long-term survival following hepatic artery embolization (HAE) of hepatic neuroendocrine tumor (NET) metastases. MATERIALS AND METHODS This single-center, institutional review board-approved retrospective review included 320 consecutive HAEs for NET metastases performed in 137 patients between September 1996 and September 2007. Forty-seven HAEs (15%) were performed urgently to manage refractory symptoms in inpatients (urgent group), and 273 HAEs (85%) were elective (elective group). Overall survival (OS) was estimated by Kaplan-Meier methodology. Complications were categorized per Common Terminology Criteria for Adverse Events, version 4.0. Univariate and multivariate analyses were performed to determine independent predictors for OS, complications, and 30-day mortality. The independent factors were combined to develop clinical risk score groups. RESULTS Urgent HAE (P = .007), greater than 50% liver replacement by tumor (P < .0001), and extrahepatic metastasis (P = .007) were independent predictors for shorter OS. Patients with all three risk factors had decreased OS versus those with none (median, 8.5 vs 86 mo; P < .001). Thirty-day mortality was significantly lower in the elective (1%) versus the urgent group (8.5%; P = .0009). There were eight complications (3%) in the elective group and five (10.6%) in the urgent group (P = .03). Male sex and urgent group were independent factors for higher 30-day mortality rate (P = .023 and P =.016, respectively) and complications (P = .012 and P =.001, respectively). CONCLUSIONS Urgent HAE, replacement of more than 50% of liver by tumor, and extrahepatic metastasis are strong independent predictors of shorter OS. Male sex and urgent HAE carry higher 30-day mortality and periprocedural morbidity risks.

Cystic Artery Localization with a Three-dimensional Angiography Vessel Tracking System Compared with Conventional Two-dimensional Angiography

PURPOSE During transcatheter hepatic therapy, the cystic artery feeding the gallbladder may inadvertently be exposed to tumor therapy. Localization of the cystic artery may help prevent exposure. The objective of this study was to compare the application of a vessel tracking system software based on three-dimensional (3D) angiography versus standard two-dimensional (2D) angiography for identifying the cystic artery and its origin. MATERIALS AND METHODS A software system that can rapidly localize the cystic artery from a 3D common hepatic angiogram was applied in 25 patients and was compared with manual localization of the cystic artery with conventional 2D digital subtraction common hepatic angiograms. RESULTS With the vessel tracking software prototype, 28 cystic arteries were retrogradely tracked in 25 of 25 cases. The origin sites were correctly located by the software in 27 of 28 cystic arteries, with one mistracked as a result of streak artifact. By contrast, on standard 2D hepatic angiography, the cystic artery was deemed visible with certainty in 12 of 25 cases (P < .001). The vessel tracking system revealed a 56% prevalence of extraanatomic distribution by the cystic artery, with the most common supply going to segment 5 liver parenchyma. CONCLUSIONS The 3D vessel rapid tracking system has advantages over conventional 2D hepatic angiography in revealing the cystic artery and its origin site. It is also an important tool to identify the complete distribution of the cystic artery without superselective angiography. Supply to adjacent hepatic parenchyma or tumor by the cystic artery is not insignificant and should be considered during hepatic therapies.

An overview of image-guided percutaneous ablation of renal tumors.

Although nephron-sparing surgery remains the gold standard treatment for small renal tumors, minimally invasive image-guided percutaneous ablation is becoming a viable alternative to operative resection. Percutaneous radiofrequency ablation (RFA) and cryoablation show high technical success rates, a relatively low incidence of residual or recurrent tumor, and competitive rates of patient survival. In this review, an overview of the current status of image-guided percutaneous ablation of renal tumors is presented, with a focus on procedure indications and patient selection, technical aspects of ablation procedures, and treatment outcomes and patient follow-up.