Research Article

Rapid dramatic alterations to the tumor microstructure in pancreatic cancer following irreversible electroporation ablation

Department of Radiology, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Robert H Lurie Comprehensive Cancer Center, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Search for more papers by this author

Weiguo Li

Department of Radiology, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Search for more papers by this author

Daniel Procissi

Department of Radiology, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Search for more papers by this author

Patrick Tyler

Department of Radiology, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Search for more papers by this author

Reed A Omary

Department of Radiology, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Robert H Lurie Comprehensive Cancer Center, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA

Search for more papers by this author

Andrew C Larson

* Author for correspondence:

E-mail Address: a-larson@northwestern.edu

Department of Radiology, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Robert H Lurie Comprehensive Cancer Center, Northwestern University, 737 N. Michigan Avenue, 16th Floor, Chicago, IL 60611, USA

Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA

Search for more papers by this author

Published Online:14 Aug 2014https://doi.org/10.2217/nnm.13.72

View article

Abstract

Aim: NanoKnife^® (Angiodynamics, Inc., NY, USA) or irreversible electroporation (IRE) is a newly available ablation technique to induce the formation of nanoscale pores within the cell membrane in targeted tissues. The purpose of this study was to elucidate morphological alterations following 30 min of IRE ablation in a mouse model of pancreatic cancer. Materials & methods: Immunohistochemistry markers were compared with diffusion-weighted MRI apparent diffusion coefficient measurements before and after IRE ablation. Results: Immunohistochemistry apoptosis index measurements were significantly higher in IRE-treated tumors than in controls. Rapid tissue alterations after 30 min of IRE ablation procedures (structural and morphological alterations along with significantly elevated apoptosis markers) were consistently observed and well correlated to apparent diffusion coefficient measurements. Discussion: This imaging assay offers the potential to serve as an in vivo biomarker for noninvasive detection of tumor response following IRE ablation.

Original submitted 2 October 2012; Revised submitted 12 March 2013

Keywords:

References

1 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J. Clin.59(4),225–249 (2009).
MedlineGoogle Scholar
2 Olive KP, Jacobetz MA, Davidson CJ et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science324(5933),1457–1461 (2009).
Medline CASGoogle Scholar
3 Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology52(2),762–773 (2010).
Medline CASGoogle Scholar
4 Kulke MH, Siu LL, Tepper JE et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J. Clin. Oncol.29(7),934–943 (2011).
Medline CASGoogle Scholar
5 Willett CG, Czito BG, Bendell JC, Ryan DP. Locally advanced pancreatic cancer. J. Clin. Oncol.23(20),4538–4544 (2005).
MedlineGoogle Scholar
6 Miller L, Leor J, Rubinsky B. Cancer cells ablation with irreversible electroporation. Technol. Cancer Res. Treat.4(6),699–705 (2005).
MedlineGoogle Scholar
7 Iida N, Nakamoto Y, Baba T et al. Antitumor effect after radiofrequency ablation of murine hepatoma is augmented by an active variant of CC Chemokine ligand 3/macrophage inflammatory protein-1alpha. Cancer Res.70(16),6556–6565 (2010).
Medline CASGoogle Scholar
8 Meza-Junco J, Montano-Loza AJ, Liu DM et al. Locoregional radiological treatment for hepatocellular carcinoma; which, when and how? Cancer Treat. Rev.38(1),54–62 (2012).
MedlineGoogle Scholar
9 Goldberg SN, Grassi CJ, Cardella JF et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology235(3),728–739 (2005).
MedlineGoogle Scholar
10 Brace CL, Hinshaw JL, Lubner MG. Thermal ablation for the treatment of abdominal tumors. J. Vis. Exp.7(49),2596 (2011).
Google Scholar
11 Phillips M, Maor E, Rubinsky B. Nonthermal irreversible electroporation for tissue decellularization. J. Biomech. Eng.132(9),091003 (2010).
MedlineGoogle Scholar
12 Rubinsky B. Irreversible electroporation in medicine. Technol. Cancer Res. Treat.6(4),255–260 (2007).
MedlineGoogle Scholar
13 Rubinsky B, Onik G, Mikus P. Irreversible electroporation: a new ablation modality – clinical implications. Technol. Cancer Res. Treat.6(1),37–48 (2007).
MedlineGoogle Scholar
14 Ahmed M, Brace CL, Lee FT Jr, Goldberg SN. Principles of and advances in percutaneous ablation. Radiology258(2),351–369 (2011).
MedlineGoogle Scholar
15 Griggs JJ, Somerfield MR, Anderson H et al. American Society of Clinical Oncology endorsement of the cancer care Ontario practice guideline on adjuvant ovarian ablation in the treatment of premenopausal women with early-stage invasive breast cancer. J. Clin. Oncol.29(29),3939–3942 (2011).
MedlineGoogle Scholar
16 Davalos RV, Mir IL, Rubinsky B. Tissue ablation with irreversible electroporation. Ann. Biomed. Eng.33(2),223–231 (2005).
Medline CASGoogle Scholar
17 Lee EW, Wong D, Prikhodko SV et al. Electron microscopic demonstration and evaluation of irreversible electroporation-induced nanopores on hepatocyte membranes. J. Vasc. Interv. Radiol.23(1),107–113 (2012).
MedlineGoogle Scholar
18 Chang DC, Reese TS. Changes in membrane structure induced by electroporation as revealed by rapid-freezing electron microscopy. Biophys. J.58(1),1–12 (1990).
Medline CASGoogle Scholar
19 Lee EW, Thai S, Kee ST. Irreversible electroporation: a novel image-guided cancer therapy. Gut Liver4(Suppl. 1),S99–S104 (2010).
MedlineGoogle Scholar
20 Lee EW, Chen C, Prieto VE, Dry SM, Loh CT, Kee ST. Advanced hepatic ablation technique for creating complete cell death: irreversible electroporation. Radiology255(2),426–433 (2010).
MedlineGoogle Scholar
21 Golberg A, Rubinsky B. A statistical model for multidimensional irreversible electroporation cell death in tissue. Biomed. Eng. Online9(13),13 (2010).
MedlineGoogle Scholar
22 Edd JF, Horowitz L, Davalos RV, Mir LM, Rubinsky B. In vivo results of a new focal tissue ablation technique: irreversible electroporation. IEEE Trans. Biomed. Eng.53(7),1409–1415 (2006).
MedlineGoogle Scholar
23 Daniels CS, Rubinsky B. Cryosurgery with pulsed electric fields. PLoS ONE6(11),e26219 (2011).
Medline CASGoogle Scholar
24 Garcia PA, Rossmeisl JH, Jr, Neal RE 2nd, Ellis TL, Davalos RV. A parametric study delineating irreversible electroporation from thermal damage based on a minimally invasive intracranial procedure. Biomed. Eng. Online10(34),34 (2011).
MedlineGoogle Scholar
25 Sano MB, Neal RE 2nd, Garcia PA, Gerber D, Robertson J, Davalos RV. Towards the creation of decellularized organ constructs using irreversible electroporation and active mechanical perfusion. Biomed. Eng. Online9(83),83 (2010).
MedlineGoogle Scholar
26 Yang XJ, Li J, Sun CX, Zheng FY, Hu LN. The effect of high frequency steep pulsed electric fields on in vitro and in vivo antitumor efficiency of ovarian cancer cell line skov3 and potential use in electrochemotherapy. J. Exp. Clin. Cancer Res.28(53),53 (2009).
Medline CASGoogle Scholar
27 Spugnini EP, Arancia G, Porrello A et al. Ultrastructural modifications of cell membranes induced by ‘electroporation’ on melanoma xenografts. Microsc. Res. Tech.70(12),1041–1050 (2007).
MedlineGoogle Scholar
28 Mahmood F, Hansen RH, Agerholm-Larsen B, Jensen KS, Iversen HK, Gehl J. Diffusion-weighted MRI for verification of electroporation-based treatments. J. Membr. Biol.240(3),131–138 (2011).
Medline CASGoogle Scholar
29 Esser AT, Smith KC, Gowrishankar TR, Weaver JC. Towards solid tumor treatment by irreversible electroporation: intrinsic redistribution of fields and currents in tissue. Technol. Cancer Res. Treat.6(4),261–274 (2007).
MedlineGoogle Scholar
30 Wang Z, Vemuri BC, Chen Y, Mareci T. A constrained variational principle for direct estimation and smoothing of the diffusion tensor field from DWI. Inf. Process Med. Imaging18,660–671 (2003).
Medline CASGoogle Scholar
31 Roy SK, Chen Q, Fu J, Shankar S, Srivastava RK. Resveratrol inhibits growth of orthotopic pancreatic tumors through activation of FOXO transcription factors. PLoS ONE6(9),e25166 (2011).
Medline CASGoogle Scholar
32 Cheng G, Zhu L, Mahato RI. caspase 3 gene silencing for inhibiting apoptosis in insulinoma cells and human islets. Mol. Pharm.5(6),1093–1102 (2008).
Medline CASGoogle Scholar
33 Lahijani MS, Tehrani DM, Sabouri E. Histopathological and ultrastructural studies on the effects of electromagnetic fields on the liver of preincubated white Leghorn chicken embryo. Electromagn. Biol. Med.28(4),391–413 (2009).
Medline CASGoogle Scholar
34 Gowrishankar TR, Esser AT, Smith KC, Son RS, Weaver JC. Intracellular electroporation site distributions: modeling examples for nsPEF and IRE pulse waveforms. Conf. Proc. IEEE Eng. Med. Biol. Soc.2011,732–735 (2011).
Medline CASGoogle Scholar
35 Edd JF, Davalos RV. Mathematical modeling of irreversible electroporation for treatment planning. Technol. Cancer Res. Treat.6(4),275–286 (2007).
MedlineGoogle Scholar
36 Guo Y, Zhang Y, Klein R et al. Irreversible electroporation therapy in the liver: longitudinal efficacy studies in a rat model of hepatocellular carcinoma. Cancer Res.70(4),1555–1563 (2010).
Medline CASGoogle Scholar
37 Guo Y, Zhang Y, Nijm GM et al. Irreversible electroporation in the liver: contrast-enhanced inversion-recovery MR imaging approaches to differentiate reversibly electroporated penumbra from irreversibly electroporated ablation zones. Radiology258(2),461–468 (2011).
MedlineGoogle Scholar
38 Guo Y, Zhang Y, Jin N et al. Electroporation-mediated transcatheter arterial chemoembolization in the rabbit VX2 liver tumor model. Invest. Radiol.47(2),116–120 (2012).
MedlineGoogle Scholar
39 Zhang Y, Guo Y, Ragin AB et al. MR imaging to assess immediate response to irreversible electroporation for targeted ablation of liver tissues: preclinical feasibility studies in a rodent model. Radiology256(2),424–432 (2010).
MedlineGoogle Scholar
40 Maor E, Ivorra A, Leor J, Rubinsky B. The effect of irreversible electroporation on blood vessels. Technol. Cancer Res. Treat.6(4),307–312 (2007).
MedlineGoogle Scholar
41 Lee EW, Loh CT, Kee ST. Imaging guided percutaneous irreversible electroporation: ultrasound and immunohistological correlation. Technol. Cancer Res. Treat.6(4),287–294 (2007).
MedlineGoogle Scholar
42 Jensen LR, Garzon B, Heldahl MG, Bathen TF, Lundgren S, Gribbestad IS. Diffusion-weighted and dynamic contrast-enhanced MRI in evaluation of early treatment effects during neoadjuvant chemotherapy in breast cancer patients. J. Magn. Reson. Imaging34(5),1099–1109 (2011).
MedlineGoogle Scholar
43 Morgan VA, Riches SF, Thomas K et al. Diffusion-weighted magnetic resonance imaging for monitoring prostate cancer progression in patients managed by active surveillance. Br. J. Radiol.84(997),31–37 (2011).
Medline CASGoogle Scholar
44 Petralia G, Thoeny HC. DW-MRI of the urogenital tract: applications in oncology. Cancer Imaging10(Spec. no A),S112–S123 (2010).
MedlineGoogle Scholar
45 Pope WB, Qiao XJ, Kim HJ et al. Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi-center study. J. Neurooncol.108(3),491–498 (2012).
Medline CASGoogle Scholar
46 Tang L, Zhang XP, Sun YS et al. Gastrointestinal stromal tumors treated with imatinib mesylate: apparent diffusion coefficient in the evaluation of therapy response in patients. Radiology258(3),729–738 (2011).
MedlineGoogle Scholar
47 Bower M, Sherwood L, Li Y, Martin R. Irreversible electroporation of the pancreas: definitive local therapy without systemic effects. J. Surg. Oncol.104(1),22–28 (2011).
MedlineGoogle Scholar
48 Breton M, Mir LM. Microsecond and nanosecond electric pulses in cancer treatments. Bioelectromagnetics33(2),106–123 (2012).
MedlineGoogle Scholar

Vol. 9, No. 8

Metrics

Downloaded 255 times

History

Published online 14 August 2014

Published in print June 2014

Information

Keywords

Acknowledgements

Special thanks to D-H Kim for assistance with transmission electron microscopy studies. We also thank J Nicolai for cell culture support.

Financial & competing interests disclosure

This work was supported by American Cancer Society SP0011492 (Z Zhang), National Cancer Institute CA134719 (AC Larson), and funds from the NIH Clinical and Translational Science Awards Program (Northwestern University, IL, USA; UL1RR0254741). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

PDF download