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Hu Q, Zuo H, Hsu JC, Zeng C, Zhou T, Sun Z, Cai W, Tang Z, Chen W. The Emerging Landscape for Combating Resistance Associated with Energy-Based Therapies via Nanomedicine. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2308286. [PMID: 37971203 PMCID: PMC10872442 DOI: 10.1002/adma.202308286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 11/07/2023] [Indexed: 11/19/2023]
Abstract
Cancer represents a serious disease with significant implications for public health, imposing substantial economic burden and negative societal consequences. Compared to conventional cancer treatments, such as surgery and chemotherapy, energy-based therapies (ET) based on athermal and thermal ablation provide distinct advantages, including minimally invasive procedures and rapid postoperative recovery. Nevertheless, due to the complex pathophysiology of many solid tumors, the therapeutic effectiveness of ET is often limited. Nanotechnology offers unique opportunities by enabling facile material designs, tunable physicochemical properties, and excellent biocompatibility, thereby further augmenting the outcomes of ET. Numerous nanomaterials have demonstrated the ability to overcome intrinsic therapeutic resistance associated with ET, leading to improved antitumor responses. This comprehensive review systematically summarizes the underlying mechanisms of ET-associated resistance (ETR) and highlights representative applications of nanoplatforms used to mitigate ETR. Overall, this review emphasizes the recent advances in the field and presents a detailed account of novel nanomaterial designs in combating ETR, along with efforts aimed at facilitating their clinical translation.
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Affiliation(s)
- Qitao Hu
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Huali Zuo
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Jessica C. Hsu
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Wisconsin 53705, United States
| | - Cheng Zeng
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Tian Zhou
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Zhouyi Sun
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
| | - Weibo Cai
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Wisconsin 53705, United States
| | - Zhe Tang
- Department of Surgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiyu Chen
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
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Spiliopoulos S, Reppas L, Filippiadis D, Delvecchio A, Conticchio M, Memeo R, Inchingolo R. Irreversible electroporation for the management of pancreatic cancer: Current data and future directions. World J Gastroenterol 2023; 29:223-231. [PMID: 36687122 PMCID: PMC9846938 DOI: 10.3748/wjg.v29.i2.223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/13/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Pancreatic cancer is currently the seventh leading cause of cancer death (4.5% of all cancer deaths) while 80%-90% of the patients suffer from unresectable disease at the time of diagnosis. Prognosis remains poor, with a mean survival up to 15 mo following systemic chemotherapy. Loco-regional thermal ablative techniques are rarely implemented due to the increased risk of thermal injury to the adjacent structures, which can lead to severe adverse events. Irreversible electroporation, a promising novel non-thermal ablative modality, has been recently introduced in clinical practice for the management of inoperable pancreatic cancer as a safer and more effective loco-regional treatment option. Experimental and initial clinical data are optimistic. This review will focus on the basic principles of IRE technology, currently available data, and future directions.
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Affiliation(s)
- Stavros Spiliopoulos
- Second Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Athens 12461, Attiki, Greece
| | - Lazaros Reppas
- Second Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Athens 12461, Attiki, Greece
| | - Dimitrios Filippiadis
- Second Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Athens 12461, Attiki, Greece
| | - Antonella Delvecchio
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” Regional General Hospital, Acquaviva delle Fonti 70021, Bari, Italy
| | - Maria Conticchio
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” Regional General Hospital, Acquaviva delle Fonti 70021, Bari, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” Regional General Hospital, Acquaviva delle Fonti 70021, Bari, Italy
| | - Riccardo Inchingolo
- Interventional Radiology Unit, “F. Miulli” Regional General Hospital, Acquaviva delle Fonti 70021, Italy
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Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. Sci Rep 2022; 12:22336. [PMID: 36572706 PMCID: PMC9792528 DOI: 10.1038/s41598-022-25258-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 11/28/2022] [Indexed: 12/28/2022] Open
Abstract
As a non-thermal ablation method, irreversible electroporation (IRE) has been widely investigated in the treatment of prostate cancer. However, no consensus has been achieved on the optimal parameters of IRE for prostate cancer. Since high voltage is known to carry risks of muscle contraction and patient discomfort, it is crucial to identify the minimum but effective and safer applied voltage to inhibit tumor growth. In this study, the effect of different applied voltages of IRE on prostate cancer was evaluated in BALB/c nude mice. Mathematical simulation and measurement of the actual ablation area revealed a larger ablation area at a higher voltage. In in vivo experiment, except for the three different voltages applied, all groups received identical electrical conditions: pulse number, 180 (20 groups × 9 pulses/group); pulse width, 100 µs; pulse interval, 2 ms; distance between the electrodes, 5 mm; and electrode exposure length, 15 mm. Whilst the tumor volume initially decreased in the 500 V (1000 V/cm) and 700 V (1400 V/cm) groups and subsequently increased, only a transient increase followed by a continuous decrease until the sacrifice was observed in the 900 V (1800 V/cm) group. This result demonstrated a lasting effect of a higher applied voltage on tumor growth inhibition. The histological, immunohistochemical, and western blot findings all confirmed IRE-induced apoptosis in the treatment groups. Taken together, 900 V seemed to be the minimum applied voltage required to reduce tumor growth, though subsequent studies are anticipated to further narrow the voltage intervals and lower the minimum voltage required for tumor inhibition.
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Fujimori M, Kimura Y, Ueshima E, Dupuy DE, Adusumilli PS, Solomon SB, Srimathveeravalli G. Lung Ablation with Irreversible Electroporation Promotes Immune Cell Infiltration by Sparing Extracellular Matrix Proteins and Vasculature: Implications for Immunotherapy. Bioelectricity 2021; 3:204-214. [PMID: 34734168 DOI: 10.1089/bioe.2021.0014] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background: This study investigated the sparing of the extracellular matrix (ECM) and blood vessels at the site of lung irreversible electroporation (IRE), and its impact on postablation T cell and macrophage populations. Materials and Methods: Normal swine (n = 8) lung was treated with either IRE or microwave ablation (MWA), followed by sacrifice at 2 and 28 days (four animals/timepoint) after treatment. En bloc samples of ablated lung were stained for blood vessels (CD31), ECM proteins (Collagen, Heparan sulfate, and Decorin), T cells (CD3), and macrophages (Iba1). Stained slides were analyzed with an image processing software (ImageJ) to count the number of positive staining cells or the percentage area of tissue staining for ECM markers, and the statistical difference was evaluated with Student's t-test. Results: Approximately 50% of the blood vessels and collagen typically seen in healthy lung were evident in IRE treated samples at Day 2, with complete destruction within MWA treated lung. These levels increased threefold by Day 28, indicative of post-IRE tissue remodeling and regeneration. Decorin and Heparan sulfate levels were reduced, and it remained so through the duration of observation. Concurrently, numbers of CD3+ T cells and macrophages were not different from healthy lung at Day 2 after IRE, subsequently increasing by 2.5 and 1.5-fold by Day 28. Similar findings were restricted to the peripheral inflammatory rim of MWA samples, wherein the central necrotic regions remained acellular through Day 28. Conclusion: Acute preservation of blood vessels and major ECM components was observed in IRE treated lung at acute time points, and it was associated with the increased infiltration and presence of T cells and macrophages, features that were spatially restricted in MWA treated lung.
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Affiliation(s)
- Masashi Fujimori
- Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Department of Radiology, Mie University, Mie, Japan
| | - Yasushi Kimura
- Department of Mechanical & Industrial Engineering, University of Massachusetts, Amherst, Massachusetts, USA
| | | | - Damian E Dupuy
- Department of Radiology, Cape Cod Healthcare, Hyannis, Massachusetts, USA
| | - Prasad S Adusumilli
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Stephen B Solomon
- Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Department of Radiology, Mie University, Mie, Japan
| | - Govindarajan Srimathveeravalli
- Department of Mechanical & Industrial Engineering, University of Massachusetts, Amherst, Massachusetts, USA.,Institute for Applied Life Sciences, University of Massachusetts, Amherst, Massachusetts, USA
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Batista Napotnik T, Polajžer T, Miklavčič D. Cell death due to electroporation - A review. Bioelectrochemistry 2021; 141:107871. [PMID: 34147013 DOI: 10.1016/j.bioelechem.2021.107871] [Citation(s) in RCA: 227] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/12/2021] [Accepted: 06/03/2021] [Indexed: 12/15/2022]
Abstract
Exposure of cells to high voltage electric pulses increases transiently membrane permeability through membrane electroporation. Electroporation can be reversible and is used in gene transfer and enhanced drug delivery but can also lead to cell death. Electroporation resulting in cell death (termed as irreversible electroporation) has been successfully used as a new non-thermal ablation method of soft tissue such as tumours or arrhythmogenic heart tissue. Even though the mechanisms of cell death can influence the outcome of electroporation-based treatments due to use of different electric pulse parameters and conditions, these are not elucidated yet. We review the mechanisms of cell death after electroporation reported in literature, cell injuries that may lead to cell death after electroporation and membrane repair mechanisms involved. The knowledge of membrane repair and cell death mechanisms after cell exposure to electric pulses, targets of electric field in cells need to be identified to optimize existing and develop of new electroporation-based techniques used in medicine, biotechnology, and food technology.
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Affiliation(s)
- Tina Batista Napotnik
- University of Ljubljana, Faculty of Electrical Engineering, Tržaška cesta 25, 1000 Ljubljana, Slovenia
| | - Tamara Polajžer
- University of Ljubljana, Faculty of Electrical Engineering, Tržaška cesta 25, 1000 Ljubljana, Slovenia
| | - Damijan Miklavčič
- University of Ljubljana, Faculty of Electrical Engineering, Tržaška cesta 25, 1000 Ljubljana, Slovenia.
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Is irreversible electroporation safe and effective in the treatment of hepatobiliary and pancreatic cancers? Hepatobiliary Pancreat Dis Int 2019; 18:117-124. [PMID: 30655073 DOI: 10.1016/j.hbpd.2019.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 12/21/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Irreversible electroporation (IRE) is a novel ablative technique for hepatobiliary and pancreatic cancers. This review summarizes the data regarding the safety and efficacy of IRE in the treatment of hepatobiliary and pancreatic cancers. DATA SOURCES Studies were identified by searching PubMed and Embase for articles published in English from database inception through July 31, 2017. For inclusion, each clinical study had to report morbidity and survival data on hepatobiliary and pancreatic cancers treated with IRE and contain at least 10 patients. Studies that met these criteria were included for analysis. Two authors assessed each clinical study for data extraction. The controversial parts were resolved through discussion with seniors. RESULTS A total of 24 clinical studies were included. Fourteen focused on hepatic ablation with IRE comprising 437 patients with 666 lesions of different tumor types. Two patients (0.5%) died after the IRE procedure. Morbidity of hepatic ablation with IRE ranged from 7% to 35%. Most complications were mild. Complete response for hepatic tumors was reported as 57%-97%. Ten studies with 455 patients focused on pancreatic IRE. The overall mortality of IRE in pancreatic cancer was 2%. Overall severe morbidity of IRE in pancreatic cancer ranged from 0 to 20%. The median overall survival after IRE ranged from 7 to 23 months. Patients treated with IRE combined with surgical resection showed a longer overall survival. CONCLUSIONS IRE significantly improves the prognosis of advanced hepatobiliary and pancreatic malignances, and companied with less complications. Hence, IRE is a relatively safe and effective non-thermal ablation strategy and potentially recommended as an option for therapy of patients with hepatobiliary and pancreatic malignances.
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Su JJ, Xu K, Wang PF, Zhang HY, Chen YL. Histological analysis of human pancreatic carcinoma following irreversible electroporation in a nude mouse model. World J Gastrointest Oncol 2018; 10:476-486. [PMID: 30595801 PMCID: PMC6304300 DOI: 10.4251/wjgo.v10.i12.476] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 10/15/2018] [Accepted: 11/24/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To determine changes in the morphology and function of pancreatic cancer cells after irreversible electroporation (IRE) treatment, and to explore the clinical significance of IRE treatment for pancreatic cancer providing an experimental basis for the clinical application of IRE treatment.
METHODS IRE was carried out in an athymic nude mouse model of pancreatic carcinoma generated with human pancreatic cancer cells 1. In therapy groups, IRE electrodes were inserted with 90 pulses per second at 800 V/cm applied to ablate the targeted tumor tissues. Histological assessment of the affected tissue was performed by hematoxylin and eosin staining (HE). Quantification of cell proliferation and apoptosis was performed by evaluating Ki67 and caspase-3 levels, respectively. Flow cytometry was used to assess cell apoptosis. Ultrasound imaging was carried out to evaluate IRE treatment results. Pathological correlation studies showed IRE is effective for the targeted ablation of pancreatic tumors in an orthotopic mouse model.
RESULTS IRE was efficacious in removing tumors in the orthotopic mouse model. The IRE-ablated zone displays characteristics of nude mouse models at different time-points as assessed by hematoxylin and eosin staining. Immunohistochemical analysis of samples from the pancreatic cancer models showed significantly enhanced caspase-3 cleavage and Ki67. Flow cytometry data corroborated the above findings that apoptosis in tumor cells was observed immediately on the first postoperative day, and with time the middle and late stages of apoptosis were observed. For ultrasound imaging studies, the IRE ablation zone became a hyperechoic area due to increasing inflammatory and immunologic cellular contents.
CONCLUSION IRE is a promising new approach for pancreatic cancer, with many potential advantages over conventional ablation techniques.
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Affiliation(s)
- Jun-Jun Su
- Department of Hepatobiliary Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
- Division of Gastroenterological Surgery, Department of Surgery, Shanxi Provincial People’s Hospital, Taiyuan 030012, Shanxi Province, China
| | - Kai Xu
- Department of Hepatobiliary Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Peng-Fei Wang
- Department of Hepatobiliary Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Hao-Yun Zhang
- Department of Hepatobiliary Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Yong-Liang Chen
- Department of Hepatobiliary Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
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Nano-Pulse Stimulation for the Treatment of Pancreatic Cancer and the Changes in Immune Profile. Cancers (Basel) 2018; 10:cancers10070217. [PMID: 29954062 PMCID: PMC6070875 DOI: 10.3390/cancers10070217] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/21/2018] [Accepted: 05/21/2018] [Indexed: 12/25/2022] Open
Abstract
A Pancreatic cancer is a notorious malignant neoplasm with an extremely poor prognosis. Current standard of care is rarely effective against late-stage pancreatic cancer. In this study, we assessed nanopulse stimulation (NPS) as a local treatment for pancreatic cancer in a syngeneic mouse Pan02 pancreatic cancer model and characterized corresponding changes in the immune profile. A single NPS treatment either achieved complete tumor regression or prolonged overall survival in animals with partial tumor regression. While this is very encouraging, we also explored if this local ablation effect could also result in immune stimulation, as was observed when NPS led to the induction of immune-mediated protection from a second tumor challenge in orthotopic mouse breast and rat liver cancer models. In the Pan02 model, there were insufficient abscopal effects (1/10) and vaccine-like protective effects (1/15) suggesting that NPS-induced immune mechanisms in this model were limited. To evaluate this further, the immune landscape was analyzed. The numbers of both T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSCs) in blood were significantly reduced, but memory (CD44+) T-cells were absent. Furthermore, the numbers of Tregs and MDSCs did not reduce in spleens compared to tumor-bearing mice. Very few T-cells, but large numbers of MDSCs were present in the NPS treated tumor microenvironment (TME). The number of dendritic cells in the TME was increased and multiple activation markers were upregulated following NPS treatment. Overall, NPS treatments used here are effective for pancreatic tumor ablation, but require further optimization for induction of immunity or the need to include effective combinational NPS therapeutic strategy for pancreatic cancer.
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Ansari D, Kristoffersson S, Andersson R, Bergenfeldt M. The role of irreversible electroporation (IRE) for locally advanced pancreatic cancer: a systematic review of safety and efficacy. Scand J Gastroenterol 2017; 52:1165-1171. [PMID: 28687047 DOI: 10.1080/00365521.2017.1346705] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 06/19/2017] [Accepted: 06/19/2017] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Irreversible electroporation (IRE) is a new modality for tumor ablation. Electrodes are placed around the tumor, and a pulsed, direct current with a field strength of 2000 V/cm is delivered. The direct current drives cells into apoptosis and cell death without causing significant heating of the tissues, which spares the extracellular matrix and proteins. The purpose of this review was to evaluate current experience of IRE for the ablation of pancreatic cancer. MATERIAL AND METHODS We searched PubMed for all studies of IRE in human pancreatic cancer in English reporting at least 10 patients. RESULTS The search yielded 10 studies, comprising a total of 446 patients. Percutaneous IRE was done in 142 patients, while 304 patients were treated during laparotomy. Tumor sizes ranged from median 2.8 to 4.5 cm. Post-procedural complications occurred in 35% of patients, most of them were less severe. Nine patients (2.0%) died after the procedure. The technical success rate was 85-100%. The median recurrence-free survival was 2.7-12.4 months after IRE treatment. The median overall survival was 7-23 months postoperatively. The longest overall survival was noted when IRE was used in conjunction with pancreatic resection. CONCLUSIONS IRE seems feasible and safe with a low post-procedural mortality. Further efforts are needed to address patient selection and efficacy of IRE, as well as the use of IRE for 'margin accentuation' during surgical resection.
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Affiliation(s)
- Daniel Ansari
- a Department of Surgery, Clinical Sciences Lund , Lund University, Skåne University Hospital , Lund , Sweden
| | - Stina Kristoffersson
- a Department of Surgery, Clinical Sciences Lund , Lund University, Skåne University Hospital , Lund , Sweden
| | - Roland Andersson
- a Department of Surgery, Clinical Sciences Lund , Lund University, Skåne University Hospital , Lund , Sweden
| | - Magnus Bergenfeldt
- a Department of Surgery, Clinical Sciences Lund , Lund University, Skåne University Hospital , Lund , Sweden
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Zhang W, Wang W, Chai W, Luo X, Li J, Shi J, Bi L, Niu L. Breast tissue ablation with irreversible electroporation in rabbits: A safety and feasibility study. PLoS One 2017; 12:e0181555. [PMID: 28732031 PMCID: PMC5521795 DOI: 10.1371/journal.pone.0181555] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 07/03/2017] [Indexed: 12/11/2022] Open
Abstract
Background and aim Irreversible electroporation (IRE) was confirmed to control several solid tumors effectively in vivo. Our preclinical study aimed to assess the feasibility and safety of IRE in the breast of rabbit. Methods Thirty New Zealand white rabbits were randomly divided into 3 groups of 10 rabbits (control group, IRE group A, and B). Two mono-electrode needles were inserted into the breast tissue by percutaneous puncture. Electrocardiogram and vital signs were monitored before, during, and after ablation. Histopathology, immunohistochemistry, and transmission electron microscopy were examined at 0 hours, 12 hours, 24 hours, 4 days, 7 days, 14 days, and 28 days after ablation. Results All the rabbits survived the procedure with no significant adverse effects. Intra-operative ventricular arrhythmias occurred in 1 rabbit from IRE group B and was immediately relieved after ablation. Reversible subcutaneous hemorrhage was observed in 8 rabbits from IRE group A and 7 rabbits from IRE group B. No skin was burnt, however, pectoralis major muscle injuries were found in all rabbits. Histopathological and ultrastructural examination revealed the coexistence of cell necrosis and apoptosis. HE, TUNEL, and Masson staining revealed breast tissue injury and the recovery of damage by fibrous tissue and granulation tissue. Notably, the structures of mammary gland lobules and interstitial components of the breasts were well preserved. Conclusions Our study suggests that IRE destroys breast cancer while effectively preserving the skin, the structure of mammary gland lobules, and interstitial components. IRE may be a promising technique to locally control breast cancer and to maintain the esthetic of the breast.
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Affiliation(s)
- Wenlong Zhang
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wanning Wang
- Department of Nephrology, First Hospital of Jilin University, Changchun, China
| | - Wei Chai
- Department of Gynecology and Obstetrics, The First Hospital of Jilin University, Changchun, China
| | - Xiaomei Luo
- School of Medicine, Jinan University, Guangdong Province, Guangzhou, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jian Shi
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Liqi Bi
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China
- * E-mail: (LB); (LN)
| | - Lizhi Niu
- Fuda Cancer Hospital, Jinan University School of Medicine (Guangzhou Fuda Cancer Hospital), Guangzhou, China
- * E-mail: (LB); (LN)
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Yan L, Chen YL, Su M, Liu T, Xu K, Liang F, Gu WQ, Lu SC. A Single-institution Experience with Open Irreversible Electroporation for Locally Advanced Pancreatic Carcinoma. Chin Med J (Engl) 2016; 129:2920-2925. [PMID: 27958223 PMCID: PMC5198526 DOI: 10.4103/0366-6999.195476] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Locally advanced pancreatic carcinoma (LAPC) is characterized by poor prognosis despite recommended concurrent chemoradiotherapy. Irreversible electroporation (IRE) has emerged as a potential option for the management of unresectable pancreatic cancer. This study was conducted to evaluate the safety and short-term efficacy of open IRE for the treatment of LAPC. METHODS Retrospective data of 25 consecutive patients receiving IRE for T3 lesions from July 2015 to June 2016 at a single center were analyzed. The perioperative and long-term IRE-related complications were reviewed to evaluate the safety of the procedure. The tumor reduction and biological response were analyzed through computed tomography/magnetic resonance imaging; the serum level of CA19-9 was measured as a secondary endpoint to evaluate the short-term efficacy of IRE. RESULTS All patients were successfully treated; the median tumor size was 4.2 cm and the median IRE time was 36 min. Four intraoperative procedure-related complications were observed (16%): two transient hypertensive episodes, one hypotension case, and one transient supraventricular tachycardia case. Nine postoperative complications were described, including three Grade A pancreatic fistulas, three delayed gastric emptying, one acute pancreatitis, one upper gastrointestinal hemorrhage, and one portal vein thrombosis. The overall rate of stable disease was 28%, 36% achieved partial response, and lower serum CA19-9 levels were recorded in all patients at discharge. CONCLUSIONS IRE is feasible for the treatment of LAPC and is a reasonable intervention strategy owing to its combined attributes of safety and efficacy.
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Affiliation(s)
- Li Yan
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Yong-Liang Chen
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Ming Su
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Tian Liu
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Kai Xu
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Feng Liang
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
- Department of General Surgery, People's Hospital of Rizhao, Rizhao, Shandong 276800, China
| | - Wan-Qing Gu
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Shi-Chun Lu
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
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Tasu JP, Vesselle G, Herpe G, Richer JP, Boucebci S, Vélasco S, Carretier M, Debeane B, Tougeron D. Irreversible electroporation for locally advanced pancreatic cancer. Diagn Interv Imaging 2016; 97:1297-1304. [PMID: 27856215 DOI: 10.1016/j.diii.2016.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 10/04/2016] [Indexed: 12/18/2022]
Abstract
Pancreatic adenocarcinoma is one of the solid cancers associated with the poorest prognosis; the only curative treatment remains surgical resection but in most cases, this treatment is not possible because of distant metastasis or local extension. Irreversible electroporation is a new tumor ablation technique, which provides cellular apoptosis without any thermal coagulation effect. This technique helps preserve the ducts, vessels or nerves located in the treatment area. This article reviews the current knowledge regarding the use of electroporation for the treatment of pancreatic adenocarcinoma.
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Affiliation(s)
- J-P Tasu
- Department of Imaging, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France.
| | - G Vesselle
- Department of Imaging, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France
| | - G Herpe
- Department of Imaging, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France
| | - J-P Richer
- Laboratory of Simulations and Anatomy Department, University of Poitiers, rue de la Milétrie, 86000 Poitiers, France; Abdominal Surgery Department, University of Poitiers, rue de la Milétrie, 86000 Poitiers, France
| | - S Boucebci
- Department of Imaging, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France
| | - S Vélasco
- Department of Imaging, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France
| | - M Carretier
- Abdominal Surgery Department, University of Poitiers, rue de la Milétrie, 86000 Poitiers, France
| | - B Debeane
- Anaesthesiology Department, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France
| | - D Tougeron
- Abdominal Oncology Department, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France
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14
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Li J, Liu F, Gupta S, Li C. Interventional Nanotheranostics of Pancreatic Ductal Adenocarcinoma. Am J Cancer Res 2016; 6:1393-402. [PMID: 27375787 PMCID: PMC4924507 DOI: 10.7150/thno.15122] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 05/19/2016] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of all pancreatic cancer. Nanoparticles (NPs) offer new opportunities for image-guided therapy owing to the unique physicochemical properties of the nanoscale effect and the multifunctional capabilities of NPs. However, major obstacles exist for NP-mediated cancer theranostics, especially in PDAC. The hypovascular nature of PDAC may impede the deposition of NPs into the tumor after systemic administration, and most NPs localize predominantly in the mononuclear phagocytic system, leading to a relatively poor tumor-to-surrounding-organ uptake ratio. Image guidance combined with minimally invasive interventional procedures may help circumvent these barriers to poor drug delivery of NPs in PDAC. Interventional treatments allow regional drug delivery, targeted vascular embolization, direct tumor ablation, and the possibility of disrupting the stromal barrier of PDAC. Interventional treatments also have potentially fewer complications, faster recovery, and lower cost compared with conventional therapies. This work is an overview of current image-guided interventional cancer nanotheranostics with specific attention given to their applications for the management of PDAC.
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15
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Bimonte S, Leongito M, Granata V, Barbieri A, Del Vecchio V, Falco M, Nasto A, Albino V, Piccirillo M, Palaia R, Amore A, Giacomo RD, Lastoria S, Setola SV, Fusco R, Petrillo A, Izzo F. Electrochemotherapy in pancreatic adenocarcinoma treatment: pre-clinical and clinical studies. Radiol Oncol 2016; 50:14-20. [PMID: 27069445 PMCID: PMC4825336 DOI: 10.1515/raon-2016-0003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 12/13/2015] [Indexed: 12/18/2022] Open
Abstract
Background Pancreatic adenocarcinoma is currently one of the deadliest cancers with high mortality rate. This disease leads to an aggressive local invasion and early metastases, and is poorly responsive to treatment with chemotherapy or chemo-radiotherapy. Radical resection is still the only curative treatment for pancreatic cancer, but it is generally accepted that a multimodality strategy is necessary for its management. Therefore, new alternative therapies have been considered for local treatment. Conclusions Chemotherapeutic resistance in pancreatic cancer is associated to a low penetration of drugs into tumour cells due to the presence of fibrotic stroma surrounding cells. In order to increase the uptake of chemotherapeutic drugs into tumour cells, electrochemotherapy can be used for treatment of pancreatic adenocarcinoma leading to an increased tumour response rate. This review will summarize the published papers reported in literature on the efficacy and safety of electrochemotherapy in pre-clinical and clinical studies on pancreatic cancer.
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Affiliation(s)
- Sabrina Bimonte
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Maddalena Leongito
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Vincenza Granata
- Division of Radiology, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Antonio Barbieri
- S.S.D Sperimentazione Animale, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Vitale Del Vecchio
- S.S.D Sperimentazione Animale, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Michela Falco
- S.S.D Sperimentazione Animale, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Aurelio Nasto
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Vittorio Albino
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Mauro Piccirillo
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Raffaele Palaia
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Alfonso Amore
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Raimondo di Giacomo
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Secondo Lastoria
- Division of Nuclear Medicine, Department of Diagnostic Imaging and Radiotherapy, Istituto Nazionale Tumori "Fondazione G.Pascale" IRCCS, Naples, Italy
| | - Sergio Venanzio Setola
- Division of Radiology, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Roberta Fusco
- Division of Radiology, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Antonella Petrillo
- Division of Radiology, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Francesco Izzo
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
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16
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Paiella S, Salvia R, Ramera M, Girelli R, Frigerio I, Giardino A, Allegrini V, Bassi C. Local Ablative Strategies for Ductal Pancreatic Cancer (Radiofrequency Ablation, Irreversible Electroporation): A Review. Gastroenterol Res Pract 2016; 2016:4508376. [PMID: 26981115 PMCID: PMC4770121 DOI: 10.1155/2016/4508376] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/28/2015] [Accepted: 01/13/2016] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Locally advanced pancreatic cancer (LAPC) accounts for the 40% of the new diagnoses. Current treatment options are based on chemo- and radiotherapy regimens. Local ablative techniques seem to be the future therapeutic option for stage-III patients with PDAC. Radiofrequency Ablation (RFA) and Irreversible Electroporation (IRE) are actually the most emerging local ablative techniques used on LAPC. Initial clinical studies on the use of these techniques have already demonstrated encouraging results in terms of safety and feasibility. Unfortunately, few studies on their efficacy are currently available. Even though some reports on the overall survival are encouraging, randomized studies are still required to corroborate these findings. This study provides an up-to-date overview and a thematic summary of the current available evidence on the application of RFA and IRE on PDAC, together with a comparison of the two procedures.
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Affiliation(s)
- Salvatore Paiella
- Unit of General Surgery B, The Pancreas Institute, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy
| | - Roberto Salvia
- Unit of General Surgery B, The Pancreas Institute, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy
| | - Marco Ramera
- Unit of General Surgery B, The Pancreas Institute, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy
| | - Roberto Girelli
- Pancreatic Surgical Unit, Casa di Cura Pederzoli, Peschiera del Garda, Verona, Italy
| | - Isabella Frigerio
- Pancreatic Surgical Unit, Casa di Cura Pederzoli, Peschiera del Garda, Verona, Italy
| | - Alessandro Giardino
- Pancreatic Surgical Unit, Casa di Cura Pederzoli, Peschiera del Garda, Verona, Italy
| | - Valentina Allegrini
- Unit of General Surgery B, The Pancreas Institute, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy
| | - Claudio Bassi
- Unit of General Surgery B, The Pancreas Institute, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy
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17
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Svatoň R, Hlavsa J, Kala Z, Procházka V, Gašparová K, Crha M, Nečas A, Raušer P, Andrašina T, Válek V, Svobodová I. Selective effect of irreversible electroporation on parenchyma of the pancreas and its vascular structures - an in vivo experiment on a porcine model. ACTA VET BRNO 2016; 85:133-137. [DOI: 10.2754/avb201685020133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
Irreversible electroporation is a local, non-thermal ablation method, where short electrical pulses of high voltage lead to changes in cell membrane permeability and cell death. Recent experimental studies have shown that it does not lead to damage of blood vessels, nerves, bile duct or ureters. The aim of our experimental study was to evaluate the negative effect of irreversible electroporation regarding damage to the vascular wall and porcine pancreatic tissue. Irreversible electroporation of the pancreas was performed in 6 pigs after medial laparotomy. Irreversible electroporation was applied to each pig to the splenic lobe of the pancreas in order to assess damage to the pancreatic tissue and to the duodenal lobe of the pancreas to assess damage to the vascular structure of the pancreatic tissue. Higher ablation electric intensity (minimum 500 V/cm – maximum 1,750 V/cm, step 250 V/cm) in 90 μs pulses was utilized on each pig. After 7 days, macroscopic and microscopic evaluations of en bloc resected specimen (pancreas with duodenum) were performed. During 7 post-ablation days, no deaths or clinical worsening occurred in any of the pigs. Necrotic changes in the pancreatic tissue were recorded at an electric intensity of 750 V/cm. Changes in the outer layers of the wall of the arteries and veins occurred at 1,000 V/cm. Transmural vascular wall damage was not recorded in any case. Irreversible electroporation allows for relatively efficient cell death in the target tissues. Our independent experimental work confirms the safety of this method towards vascular structures located in the ablation zone.
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18
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Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg 2015; 262:486-94; discussion 492-4. [PMID: 26258317 DOI: 10.1097/sla.0000000000001441] [Citation(s) in RCA: 292] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Ablative therapies have been increasingly utilized in the treatment of locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) is an energy delivery system, effective in ablating tumors by inducing irreversible membrane destruction of cells. We aimed to demonstrate efficacy of treatment with IRE as part of multimodal treatment of LAPC. METHODS From July 2010 to October 2014, patients with radiographic stage III LAPC were treated with IRE and monitored under a multicenter, prospective institutional review board-approved registry. Perioperative 90-day outcomes, local failure, and overall survival were recorded. RESULTS A total of 200 patients with LAPC underwent IRE alone (n = 150) or pancreatic resection plus IRE for margin enhancement (n = 50). All patients underwent induction chemotherapy, and 52% received chemoradiation therapy as well for a median of 6 months (range, 5-13 months) before IRE. IRE was successfully performed in all patients. Thirty-seven percent of patients sustained complications, with a median grade of 2 (range, 1-5). Median length of stay was 6 days (range, 4-36 days). With a median follow-up of 29 months, 6 patients (3%) have experienced local recurrence. Median overall survival was 24.9 months (range: 4.9-85 months). CONCLUSIONS For patients with LAPC (stage III), the addition of IRE to conventional chemotherapy and radiation therapy results in substantially prolonged survival compared with historical controls. These results suggest that ablative control of the primary tumor may prolong survival.
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