Irreversible Electroporation: Implications for Prostate Ablation

Center for Bioengineering in the Service of Humanity and Society, School of Engineering and Computer Science, Hebrew University of Jerusalem, Givaat Ram Campus, Jerusalem, Israel 91904.
Technology in cancer research & treatment (Impact Factor: 1.73). 09/2007; 6(4):295-300. DOI: 10.1177/153303460700600405
Source: PubMed
ABSTRACT
Percutaneous prostate cryo-ablation has become an accepted treatment for primary prostate cancer. Thermal tissue ablation based on cold, however, does have some distinct limitations. These include, variable damage at the cryo lesions margin, injury to adjacent structures such as rectum, urethra and NVB (neurovascular bundle), and long procedure time due to the need for multiple freeze thaw cycles, that have limited the acceptance of this modality. Irreversible electroporation IRE, is a new non-thermal ablation modality that uses short pulses of DC electric current to create irreversible pore in the cell membrane, thus, causing cell death. This method theoretically should have significant advantages in ablating prostate tissue. Six males dogs had their prostates treated using IRE. Pulses were applied using a DC generator that delivered pulses in the microsecond range of duration, with a variable pulse interval and voltage range. IRE probes were placed percutaneously or trans-rectally using trans-rectal ultrasound guidance. In one of the dogs, the lesions were made purposely to include the rectum, urethra, and neurovascular bundle (NVB). Subjects were followed for 1 to 14 days before sacrifice. IRE lesions in the prostate had unique characteristics compared to thermal lesions. The margins of the IRE lesions was very distinct with a narrow zone of transition from normal to complete necrosis, there was complete destruction within the IRE lesion, and rapid resolution of the lesions with marked shrinkage within two weeks. Structures such as urethra, vessels, nerves, and rectum were unaffected by the IRE application. IRE lesions have characteristics that are distinctly different than thermal lesions. The differences could be very advantageous in a clinical setting, improving the results and acceptance of prostate ablation.

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Available from: Boris Rubinsky
Technology in Cancer Research and Treatment
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Volume 6, Number 4, August 2007
©Adenine Press (2007)
Irreversible Electroporation:
Implications for Prostate Ablation
www.tcrt.org
Percutaneous prostate cryo-ablation has become an accepted treatment for primary prostate
cancer. Thermal tissue ablation based on cold, however, does have some distinct limitations.
These include, variable damage at the cryo lesions margin, injury to adjacent structures such
as rectum, urethra and NVB (neurovascular bundle), and long procedure time due to the
need for multiple freeze thaw cycles, that have limited the acceptance of this modality. Irre-
versible electroporation IRE, is a new non-thermal ablation modality that uses short pulses of
DC electric current to create irreversible pore in the cell membrane, thus, causing cell death.
This method theoretically should have signicant advantages in ablating prostate tissue.
Six males dogs had their prostates treated using IRE. Pulses were applied using a DC
generator that delivered pulses in the microsecond range of duration, with a variable pulse
interval and voltage range. IRE probes were placed percutaneously or trans-rectally using
trans-rectal ultrasound guidance. In one of the dogs, the lesions were made purposely to
include the rectum, urethra, and neurovascular bundle (NVB). Subjects were followed for
1 to 14 days before sacrice.
IRE lesions in the prostate had unique characteristics compared to thermal lesions. The
margins of the IRE lesions was very distinct with a narrow zone of transition from normal to
complete necrosis, there was complete destruction within the IRE lesion, and rapid resolu-
tion of the lesions with marked shrinkage within two weeks. Structures such as urethra,
vessels, nerves, and rectum were unaffected by the IRE application.
IRE lesions have characteristics that are distinctly different than thermal lesions. The dif-
ferences could be very advantageous in a clinical setting, improving the results and ac-
ceptance of prostate ablation.
Introduction
Percutaneous prostate cryo-ablation has become an accepted treatment for primary
prostate cancer (1). Cryoablative lesions, however, have some distinct limitations,
such as variable damage at the cryo lesions margin, injury to adjacent structures
such as rectum, urethra and neurovascular bundle (NVB), and long procedure
time due to the need for multiple freeze thaw cycles. These characteristics have
limited the widespread acceptance of this modality despite certain demonstrated
advantages over the more traditional treatments of radiation and radical prostatec-
tomy (2). Irreversible electroporation (IRE), is a new non-thermal ablation mo-
dality that uses short pulses of DC electric current to create irreversible pores in
the cell membrane, thus, causing cell death. This method has been shown to have
signicant advantages in ablating hepatic tissue, such as rapid lesion creation, rap-
id lesion resolution, sparing of structures such as vessels and bile ducts, and uni-
Gary Onik, M.D.
3,2
Paul Mikus, B.Sc.
2
Boris Rubinsky, Ph.D.
1,2,4
1
Center for Bioengineering in the
Service of Humanity and Society
School of Engineering and
Computer Science
Hebrew University of Jerusalem
Givaat Ram Campus
Jerusalem, Israel 91904
2
Oncobionic Inc.
30211 Avenida De las Banderas Suite 200
Rancho Santa Margarita, CA 92679, USA
3
Department of Radiology
Celebration Health/Florida Hospital
Suite A-280, 400 Celebration Place
Celebration, Florida 34747, USA
4
Department of Mechanical Engineering
Department of Bioengineering
University of California at Berkeley
Berkeley, CA 94720
*
Corresponding Author:
Gary Onik, DEGREE
Email: OnikCryo@aol.com
295
Open Access Article
The authors, the publisher, and the right
holders grant the right to use, reproduce, and
disseminate the work in digital form to all users.
Page 1
296 Onik et al.
Technology in Cancer Research & Treatment, Volume 6, Number 4, August 2007
form destruction throughout the IRE lesion (3). In addition
IRE is extension of an already successful cancer treatment
electro-chemotherapy in which reversible electroporation is
accomplished (opening of the cell membrane that then closes
allowing chemotherapy into the cell resulting in it’s death)
(5). It is postulated that IRE advantages could be directly ap-
plied to the prostate as well with out the use of chemotherapy
as needed in electrochemotherapy. In this paper, we will de-
scribe the rst application of IRE to prostate tissue.
Methods
This study was conducted in accordance with Good Labo-
ratory Practice regulations as set forth by the 21 Code of
Federal Regulations (CFR) Part 58 and was approved by the
animal use committee. Each procedure started with anes-
thetization of the animal under general anesthesia per SOP
#33156. In addition, pancuronium (0.1 mg/kg,) was ad-
ministered through an IV prior to the procedure, to reduce
muscle contractions during the application of the electrical
pulses. Pancuronium (0.05 mg/ml at 1 mg/ml) was adminis-
tered throughout the procedure as needed.
Six male beagle dogs had their prostates treated using IRE.
Using trans-rectal US 18 gauge electrodes were placed trans-
perennially into the prostate in three dogs. One to four probes
were placed into one lobe of the prostate in ve dogs. In two
dogs, four probes were placed in order to create a hemi-abla-
tion of the prostate. The probes were used in pairs of two, and
each pair applied 80 pulses of 1500, with a pulse length of 100
microseconds. In the sixth dog pairs of probes were placed to
purposely create a lesion in certain sensitive structures such
as the urethra, rectum, and neurovascular bundles. Pulses ap-
plied in the safety study at each anatomical structure were 80
pulses of 2000 V with a pulse length of 100 microseconds.
Pulses were applied using a DC generator (Oncobionic Inc.)
that delivered pulses in the microsecond range of duration,
with a variable pulse interval and voltage range. IRE was de-
livered in a bipolar manner between two probes, separated by
between 1 and 1.5 cm. In three subjects a single probe with
both electrodes incorporated into it and separated by 5mm was
placed trans-rectally using ultrasound guidance. Treatment
parameters of the single probe were 1 or 8 pulses of 1000 V
with a pulse length of 100 microseconds. Pulses delivered per
lesion varied in number. Three animals sacriced at one day
had 8 pulse delivered at 1 kV and two animals sacriced at 2
weeks had 80 pulses delivered per pair of electrodes using 1.5
kV. The duration of the pulses was 100 microsecond with an
interval between pulses of 100-200 milliseconds.
Results
All animals survived the procedure. Upon application of
the IRE pulse a variable degree of generalized muscle con-
traction occurred in each animal, from no contraction to
mild to moderate contraction. The degree of contraction ap-
peared to be related to the level of anesthesia of the animal,
the degree of muscle blocking agents given, if any, and the
voltage of the pulse used, with the higher voltages causing
greater contractions. In previously reported experiments
(3) we found that when Pancuronium was administered to
the animals at the doses reported earlier, the contractions
were manageable even when a maximal voltage of 3kV was
applied to the electrodes. It appears that voltages lower
than 1.5 kV as used in these experiments, produced little to
no contraction in anesthetized animals and paralyzed ani-
mals. This is important because potential major movement
of the animal could potentially cause damage to unwanted
structures due to needle movement.
The study is limited by the small number of animals and vari-
ance of the parameters used; therefore, a comparison of the
various voltages and pulse sequences and the effect that they
might have on the histology, both immediate and delayed,
cannot be made form this study. At 1 day the lesion made at
1 kV with 8 pulses appeared grossly to be hemorrhagic (Fig-
ure 1). Histology showed the ablated area to have diffuse
necrotic glandular tissue with no obvious viable tissue within
the ablated zone (Figure 2). The ablated zone was well de-
marcated from the immediately adjacent unaffected prostate
parenchyma with an abrupt transition between necrotic glan-
dular tissue in the ablation area and adjacent normal glan-
dular tissue (Figure 3). Necrotic glandular tissue was noted
adjacent to the urethra; however, the urethral structural integ-
rity remained intact without evidence for necrosis within the
sub-mucosa (Figure 4), even when the urethra was subjected
to direct ablation during the safety portion of the study. In
the neurovascular bundle areas, including the neurovascular
bundle that was directly ablated during the safety portion of
the study, vessels had variable loss of endothelium and were
surrounded by scattered red blood cells (hemorrhage), neuro-
phils, and edematous stroma. In some areas the vessel walls
were hyper eosinophilic and homogenous consistent with -
brinoid necrosis. The lumen of affected vessels remained
patent however without evidence for thrombosis (Figure 5).
In addition, no heat sink effect was evident adjacent to ves-
sels with complete necrosis adjacent and often surrounding
patent vasculature. Nerves within the neurovascular bundles
appeared to be intact and unaffected (Figure 6). Even gan-
glion cells showed no evidence of cells death.
The regional lymph nodes were enlarged in the drainage area.
There was mild cortical reactivity and expansion of medul-
lary sinuses consistent with a drainage reaction. Medullary
sinuses are expanded by red blood cells, eosinophils, neutro-
phils, and macrophages. Para-cortical regions are expanded
by increased lymphocytes. Occasional lymphoid follicles
have reactive germinal centers.
Page 2
Technology in Cancer Research & Treatment, Volume 6, Number 4, August 2007
Irreversible Electroporation of the Prostate 297
At two weeks the hemorrhagic changes had mostly resolved
within the ablated tissue. The volume of tissue had already
been markedly reduced compared to the untreated tissue.
The contracted region of the previous lesion consisted pri-
marily of collagenous tissue consistent with early scar for-
mation (Figure 6). Once again, the urethral wall adjacent to
the lesion showed no evidence of necrosis and the urethral
mucosa was intact. The nerves and vessels within the NVB
on the side of the lesion were intact and patent.
All layers of the rectum adjacent to the lesion appeared to be
viable with no evidence for stula formation.
Figure 1: Gross pathology of the IRE lesion at 24 hrs. The right side of the
gland is hemorrhagic (Pulses=8, kV =1).
Figure 2: Photomicrograph of prostate tissue that has been electroporated
at 24 hrs. No glandular elements are visible (Pulses=8, kV=1).
Figure 3: Photomicrograph at the margin of the IRE lesion. A very narrow
zone of transition between normal and necrotic tissue is noted at the margin
(Pulses=8, kV=1).
Urethra
Figure 4: The urethra is noted at the center of the micrograph as the open
space at 24 hrs. Sub-mucosal hemorrhage is noted but the integrity of the
urethra is still intact Pulses=8, kV=1.
Nerve trunk
Vessel
Figure 5: Photomicrograph of the neurovascular bundle after electropora-
tion at two weeks (Pulses=80, kV=1.5). It can be seen that both the vessel
and the nerve trunk show no evidence for necrosis.
Figure 6: Whole mount slide of a prostate where the right side of the gland
was electroporated two weeks prior. There is marked shrinkage of the lobe
with replacement by brous tissue (Pulses=80, kV=1.5).
Page 3
298 Onik et al.
Technology in Cancer Research & Treatment, Volume 6, Number 4, August 2007
Discussion
IRE as described in this paper has a number of demonstrat-
ed advantages over the well known thermal based ablation
methods. Many of these advantages stem from the mecha-
nism of cell destruction used by IRE. IRE rather than causing
destruction through coagulative necrosis such as in RFA or
through cellular and micro-vascular disruption as in cryo-ab-
lation, IRE causes cell death by the mechanism of irreversible
electroporation (IRE). When cells are exposed to a pulsed
electrical eld with the proper parameters, holes are created
in the cell membrane increasing it’s permeability. Depending
mainly on the magnitude of the trans-membrane potential the
cell is exposed to, the holes may close, i.e., reversible electro-
poration, or remain open, irreversible electroporation.
Reversible electroporation occurs within a narrow range of
parameters roughly between 300 V/cm
2
and 600 V/cm
2
al-
though cell size, pulse duration and number of pulses can
affect these ranges. The application of reversible electro-
poration to tissues has found important applications in bio-
technology and medicine. Electrogenetherapy (EGT) is the
in vivo insertion of genes into cells in tissue through revers-
ible electroporation and presents an alternative to viral vec-
tors (4). Electrochemotherapy is accomplished by injecting
drugs or macromolecules into a targeted area. Electrodes
are placed into or around that area to generate a reversible
permeabilizing electric eld in the tissue, thereby, intro-
ducing the drugs or macromolecules into the cells of the
affected area (5). In addition, potent but normally imper-
meable anti-cancer drugs such as bleomycin are used with
electroporation to ablate tissue.
In the above applications the electroporation has to be revers-
ible and irreversible electroporation is consciously avoided.
Therefore, the electrical parameters that induce irreversible
electroporation where studied only as an upper limit to the
range of electrical parameters that induce reversible elec-
troporation. Irreversible electroporation, however, has been
studied extensively in in vitro cellular systems. For instance
IRE has been considered an effective means for killing both
gram negative and positive bacteria responsible for water
contamination. Davalos et al. (6) were the rst to suggest
that irreversible electroporation could be used for surgical
tissue ablation without the inherent limitations of chemother-
apeutic injection or the narrow window of parameters associ-
ated with reversible electroporation. They speculated that
this could result in signicant advantages over the currently
used thermal ablation methods. This was later conrmed
with the rst animal study creating liver lesions (3).
A major limitation to the monitoring of the efcacy of thermal
ablation procedures is the many months both heat and cold
based lesions take to show decrease in size and years to show
complete resolution. The determination of an adequate treat-
ment by imaging, therefore, becomes a matter of assessing
continued tumor growth at the margins of the treated lesion
or stability of the size of the lesion, signs of which take time
to determine treatment failures. Previous work in liver has
shown that IRE lesion have very rapid resolution with the le-
sion resolving to a minimal scar in approximately two weeks
(3). The underlying basis for this phenomena we believe is the
preservation of the microvasculature, down to the arteriolar
level, throughout IRE lesion. IRE lesions are, therefore, able
to heal throughout their volume where as cryo and RFA lesions,
which are completely de-vascularized shortly after lesion cre-
ation, must resolve from the edges of the lesion inwards. Our
present study shows that this phenomena occurs with the pros-
tate as well, with the affected side showing marked dimunition
in size two weeks after the creation of the lesion.
The preservation of the microvasculature raises the possibil-
ity that there could possibly be tissue regeneration in the
area of ablation. With correct targeting of the tumor with it’s
complete destruction regeneration of the tumor should not
be an issue. The possibility that normal tissue might regen-
erate within the previously made lesion, in organs such as
the liver where normal tissue regeneration is a well known
phenomena, is a possibility that would have to be studied in
longer term animal models.
In the prostate this has major implications other than just le-
sion monitoring. Many of the older patients with prostate
cancer have some measure of BPH causing signicant uri-
nary ow symptoms. The immediate and mid-term effect
of cryo-ablation, therefore, can often be to initially increase
the patients urinary ow problems. With an IRE lesion and
it’s rapid decrease in the volume of the prostate in a mat-
ter of weeks we might expect actually an improvement in
symptoms over the short and long term. This also raises the
possibility that IRE might be an excellent treatment for BPH
where cryo-ablation has not been used with success due to
the unfavorable characteristics of its lesion resolution.
How this will translate clinically into tumor resolution once
again is open to speculation. It would be expected that since
both prostate cancer and BPH are often associated with in-
creased vascularity, we might have very rapid resolution of
the cancers themselves as seen in this early experience with
normal prostate tissue.
Other pathologic characteristics of the IRE lesions we pro-
duced, could have signicant clinical implications. For
instance, IRE produces a lesion within the prostate with
uniform necrosis throughout and to the very margin of the
lesion. Since the pulse occurs in microseconds the variabil-
ity of blood ow has no effect on the destruction within the
lesion. The eld effect is uniform within the lesion and,
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Technology in Cancer Research & Treatment, Volume 6, Number 4, August 2007
Irreversible Electroporation of the Prostate 299
therefore, the necrosis is uniform, making a distinct margin
where the magnitude of the eld falls below the irreversible
electroporation range. This is in marked contrast to cryo
lesions, which have a zone of variable destruction as the le-
sion margin is approached. In the prostate, where so many
important structures are packed closely together, this creates
a situation in which greater freezing may have to be car-
ried out, in order to insure tumor destruction than is desir-
able, leading to either under treatment (when the freezing
is stopped prematurely due to the rectum) or complications
such as impotence, when the NVB is included in the cryo le-
sion in order to assure destruction of a cancer near by.
All thermal ablation methods have a signicant limitation
due to the vessel heat sink effect. This vessel heat sink effect
protects cancer adjacent to major vessels resulting in high
local recurrence rates in this clinical setting. In contrast,
pathology demonstrated that IRE lesions, showed complete
destruction of tissue extended directly up to the vessel wall,
without sparing of tissue adjacent to the vessel. In addition,
this was accomplished without vessel destruction or occlu-
sion. This characteristic has major implications, particularly
in the prostate, where preservation of blood ow is a critical
component of maintaining potency. Based on this charac-
teristic, tumor inltrating the NVB area should be treatable
without damage to the associated vessels.
Another major limitation of thermal ablation technologies has
been the non-selective nature of the destructive process. RFA,
and to a somewhat lesser extent cryo-ablation, cause compli-
cations to normal structures that are encompassed within the
ablation zone. Gross and microscopic pathology of IRE le-
sions, however, have previously demonstrated intact bile ducts
created within liver lesions and our experience in the prostate
demonstrated a similar effect in relation to the prostatic urethra
as well as the peri-prostatic nerves. Unlike thermal ablation
technologies IRE will destroy the cellular components of a tis-
sue such as the mucosal cells of the urethra but does not affect
the underlying collagen network of tissue, thereby preserving
the basic tissue structure. This allows certain tissue with re-
generative capacities such as the urethra to replace its mucosal
cells over time. If successfully translated into clinical practice
this lack of effect on the supporting collagen network of tis-
sue could have major implications by markedly decreasing the
incidence of urethral and rectal complications associated with
prostate cryoablation. The nding that both nerves and ves-
sels appear to survive IRE raises the possibility of a treatment
for prostate cancer with minimal effect of patient potency.
Another unique and unexpected pathologic nding with IRE
lesions was evidence for an immunologic reaction in the
lymph nodes draining the area of the ablation. With the rapid
resolution of large areas of ablated tissue, reaction in draining
lymph nodes would be understandable particularly since there
is no denaturing of proteins associated with IRE. In relation
to tumor ablation this raises the possibility of whether there
might be a tumor specic immunological reaction to be har-
nessed associated with IRE. Such a reaction has been found to
occur in association with cryoablation (7), another modality in
which proteins are not denatured by the ablation process and
are theoretically still able to be recognized by the hosts im-
mune system. If a tumor specic reaction in draining lymph
nodes can be harnessed it could have tremendous implications
for patients who at the time of diagnosis already demonstrate
lymph node involvement or that are diagnosed with it after
failed radiation therapy. Such a reaction in lymph nodes drain-
ing an area of cancer could result in destruction of micro-me-
tastasis in the effected lymph nodes, which could signicantly
effect survival in patients at high risk for recurrence.
From a technical point of view IRE has some interesting dif-
ferences compared to previous thermal ablation techniques.
For instance, the speed of the procedure is impressive with
the ablation occurring in seconds rather than minutes. There-
fore, the time needed to complete an IRE procedure is almost
solely determined by the time needed to properly place the
ablation probes. In the majority of our experiments, ablations
were carried out in a bipolar fashion with a least two needles
needed for lesion generation. IRE, however, is a rather ex-
ible technology allowing both elements, active and ground
electrodes to be placed on a single probe. We demonstrated
this potential in our by using such a probe through a trans-
rectal approach. Such an approach uses the skills gained
from the large experience with trans-rectal biopsy and could
form the foundation of a unique BPH procedure.
Another difference with thermal ablations is the size of the
ablation probes needed to create adequate size lesions. Un-
like both cryo and RF the size of the probes have little effect
on the ability to create an IRE lesion. In our experiment an
18 gauge needle was used. Calculations indicate, however,
that very little capability would be lost by using an even
smaller 20 or 22 gauge needle.
In these experiments we did not try to optimize the capabili-
ties of IRE to completely ablate the whole prostate. Some
of the parameters that can be manipulated with IRE to cre-
ate larger tailored ablation zones include the use of multiple
needle arrays as in cryosurgical ablation, increased exposure
of the active zone to increase lesion length, increasing the
pulse number, and an increase in pulse voltage. Much work
remains to be carried out in determining what approach is
best for creating and shaping the ablation zones needed for a
whole gland prostate ablation.
In addition, since blood ow is not a factor in determining
the size and shape of an IRE lesion, IRE is particularly ame-
nable to predictive modeling. Previous experiments in liver
Page 5
300 Onik et al.
Technology in Cancer Research & Treatment, Volume 6, Number 4, August 2007
has shown lesion size and shape to have a close correlation
with predictions made by a method of mathematical modeling
previously described (3). We anticipate that this will be true
for the prostate although these experiments were not designed
to conrm this. Practically speaking, incorporation of these
models into clinical application software, to be used for proce-
dure planning, could add a greater degree of procedure repro-
ducibility than that is seen with thermal ablation techniques.
Of course ablating normal prostate tissue is not equivalent to
ablating tumors. It is very possible that the parameters need-
ed to destroy tumor cells may be different than that needed to
destroy normal prostate. In addition, it is very likely that dif-
ferent tumor cells will have lesser or greater sensitivity to de-
struction by electroporation. Rather than a single parameter,
i.e., temperature, that determines cell destruction in the ther-
mal ablation techniques, IRE has multiple parameters that
can be manipulated to optimize cell death including: voltage
gradient, pulse duration, pulse number, and pulse polarity.
Rubinsky et al. (8) has shown that in vitro testing can be a
valuable tool in determining the optimal IRE protocol for a
given tumor type. Using an in vitro IRE testing technique
Rubinsky et al. was able to quickly determine an optimal IRE
protocol, which resulted in 100% destruction of a highly ma-
lignant hepatocellular carcinoma cell line.
Lastly, experience has to be gained with the radiographic im-
aging and monitoring of IRE. In the liver, there appears to
be excellent correlation of the ultrasound image post IRE, as
evidenced by a hypo-echoic zone corresponding to the IRE
lesion. This needs to be conrmed in the prostate as well.
Other modality such as CT and MRI also need to be investi-
gated as possible monitoring modalities for IRE.
Conclusions
When considered as a whole, the pathologic data now avail-
able indicates that the advantages IRE has over thermal ab-
lation technologies in the prostate is signicant. Improved
procedure planning, monitoring, and lesion resolution could
have a signicant impact on the eld of tumor ablation. The
ability to do in vitro testing for various cell types should al-
low the development of optimal procedure protocols from
the outset of patient treatment. The improved safety prole
should facilitate physician acceptance and the possibility of
harnessing a positive immunologic reaction offers numerous
research and development opportunities.
Conict of Interest
The authors are afliated with Oncobionic Inc. a company
in the eld of irreversible electroporation and may benet
nancially from this study.
References
1.
2.
3.
4.
5.
6.
7.
8.
Health Care Financing Administration. Medicare Coverage Policy:
Decisions. Bagley, G. P. Cryosurgery ablation of the prostate (#CAG-
00031). Available at: http://www.hcfa.gov/coverage/8b3-f1.htm. Ac-
cessed November 7, 2001.
Bahn, D. K., Lee, F., Bandalament, R., et al. Targeted cryoablation
of the prostate: 7-year outcomes in the primary treatment of prostate
cancer. Urology 60 (2 Suppl 1), 3-11 (2002).
Rubinsky, B., Onik, G., Mikus, P. Irreversible electroporation: a new
ablation modality -- clinical implications. Technol Cancer Res Treat
6, 37-48 (2007).
Neumann, E., Schaefer-Ridder, M., Wang, Y., Hofschneider, P. H. et
al. Gene transfer into mouse lyoma cells by electroporation in high
electric elds. J EMBO 1, 841-845 (1982).
Mir, L. M., Belehradek, M., Domenge, C., Luboniski, B., Orlowski,
S. Belehradek, J., Schwaab, B., Luboniski, B., Paoletti, C. Electro-
chemotherapy, a novel antitumor treatment: rst clinical trial. C R
Acad Sci III 313, 613-618 (1991).
Davalos, R. V., Mir, L. M., and Rubinsky, B. Tissue ablation with
irreversible electroporation. Annals of Biomedical Engineering 33,
223-231 (2005).
Tanaka, S. Immunological aspects of cryosurgery in general surgery.
Cryobiology 19, 247-262 (1982).
Miller, L., Leor, J., and Rubinsky, B. Cancer cells ablation with irre-
versible electroporation. Technology in Cancer Research and Treat-
ment 4, 699-705 (2005).
Received: April 11, 2007; Revised: June 16, 2007;
Accepted: June 25, 2007
Page 6
  • Source
    • "Since pathological assessment following IRE showed fibrosis without glandular prostatic ducts and necrotic tissue and no skip lesions within the ablated zone, we believe IRE effectively ablates all PCa foci within the target zone. Tumour ablation experiments in animals and humans have shown the potential to preserve connective tissue structures within the target zone and limit damage to associated blood vessels, neural tissue or other vital structures [16][17][18]. However, this may not apply to current thorough clinical treatment protocols [14, 40]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Current surgical and ablative treatment options for prostate cancer (PCa) may result in a high incidence of (temporary) incontinence, erectile dysfunction and/or bowel damage. These side effects are due to procedure related effects on adjacent structures including blood vessels, bowel, urethra and/or neurovascular bundle. Ablation with irreversible electroporation (IRE) has shown to be effective and safe in destroying PCa cells and also has the potential advantage of sparing surrounding tissue and vital structures, resulting in less impaired functional outcomes and maintaining men's quality of life. Methods/Design: In this randomized controlled trial (RCT) on IRE in localized PCa, 200 patients with organ-confined, unilateral (T1c-T2b) low- to intermediate-risk PCa (Gleason sum score 6 and 7) on transperineal template-mapping biopsies (TTMB) will be included. Patients will be randomized into focal or extended ablation of cancer foci with IRE. Oncological efficacy will be determined by multiparametric Magnetic Resonance Imaging, Contrast-Enhanced Ultrasound imaging if available, TTMP and Prostate Specific Antigen (PSA) follow-up. Patients will be evaluated up to 5 years on functional outcomes and quality of life with the use of standardized questionnaires. Discussion: There is critical need of larger, standardized RCTs evaluating long-term oncological and functional outcomes before introducing IRE and other focal therapy modalities as an accepted and safe therapeutic option for PCa. This RCT will provide important short- and long-term data and elucidates the differences between focal or extended ablation of localized, unilateral low- to intermediate-risk PCa with IRE. Trial registration: Clinicaltrials.gov database registration number NCT01835977. The Dutch Central Committee on Research Involving Human Subjects registration number NL50791.018.14.
    Full-text · Article · Dec 2016 · BMC Cancer
    • "No evidence has as yet been obtained on the application of IRE as an alternative curative PCA treatment. The following are available at present: mathematical simulations, experimental investigations (Table 1, [11][12][13][14][15][16][17]) and first clinical phase 1–2 results on focal IRE of PCA (Table 2, [18][19][20][21][22][23][24][25][26]). It should be noted in this context that more than half the experimental investigations were not carried out using the NanoKnife (AngioDynamics). "
    [Show abstract] [Hide abstract] ABSTRACT: Irreversible electroporation (IRE), a new tissue ablation procedure available since 2007, could meet the requirements for ideal focal therapy of prostate cancer with its postulated features, especially the absence of a thermal ablation effect. Thus far, there is not enough evidence of its effectiveness or adverse effects to justify its use as a definitive treatment option for localized prostate cancer. Moreover, neither optimal nor individual treatment parameters nor uniform endpoints have been defined thus far. No advantages over established treatment procedures have as yet been demonstrated. Nevertheless, IRE is now being increasingly applied for primary prostate cancer therapy outside clinical trials, not least through active advertising in the lay press. This review reflects the previous relevant literature on IRE of the prostate or prostate cancer and shows why we should not adopt IRE as a routine treatment modality at this stage.
    No preview · Article · May 2016 · World Journal of Urology
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    • "Electroporation-based techniques, like electrochemotherapy (ECT), gene electrotransfection and non-thermal irreversible electroporation, are becoming a viable option for treatment of internal, deep-seated tumors and tissues (e.g., in bones, brain, liver, lung, prostate, kidney, colon and esophagus). In such cases, surgical, percutaneous or endoscopic procedures are used to gain access to the treatment area123456789101112131415161718. These advanced treatment procedures thus provide new possibilities for restoring, correcting or modifying physiological functions but, at the same time, because of their novelty, complexity and technical specificity, may also introduce new risks to patients. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Electrochemotherapy (ECT) is a combined treatment in which high voltage electroporation (EP) pulses are used to facilitate the uptake of a chemotherapeutic drug into tumor cells, thus increasing antitumor effectiveness of the drug. The effect of ECT of deep-seated tumors located close to the heart on functioning of the heart has not been previously investigated. In this study, we investigate the effects of intra-abdominal ECT of colorectal liver metastases on functioning of the heart during the early post-operative care period. Methods: For ECT high voltage EP pulses with amplitudes of up to 3000 V and 30 A were delivered in synchronization with electrical activity of the heart. Holter electrocardiographic (ECG) signals were obtained from 10 patients with colorectal liver metastases treated with ECT. ECG was recorded during the periods of 24 hours before and after the surgical procedure involving ECT. Four-hour long night-time ECG segments from both periods exhibiting the highest level of signal stationarity were analyzed and compared. Changes in several ECG and heart rate variability (HRV) parameters were evaluated. Results: No major heart rhythm changes (i.e., induction of extrasystoles, ventricular tachycardia or fibrillation) or pathological morphological changes (i.e., ST segment changes) indicating myocardial ischemia were found. However, we found several minor statistically significant but clinically irrelevant changes in HRV parameters after ECT procedures: a decrease in median values of the mean NN interval, a decrease in the low-frequency and in the normalized low-frequency component, and an increase in the normalized high-frequency component. Conclusions: Only minor effects of intra-abdominal ECT treatment on functioning of the heart were found. They were expressed as statistically significant but clinically irrelevant changes in heart rate and long-term HRV parameters and were as such not life-threatening to the patients. The nature of these changes is such that they can be attributed to the known effects of the drugs given to the patients in the post-operative care. Further investigation is still warranted to unambiguously resolve whether ECT with high voltage EP pulses applied in immediate vicinity of the heart is responsible for the observed effects.
    Full-text · Article · Sep 2015 · BioMedical Engineering OnLine
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