Nanoknife for HCC

1. Irreversible Electroporation (IRE)
By
Mohammed Ezz El-din
Assistant Lecturer of Tropical Medicine & Gastroenterology
Faculty of Medicine, Assiut University
Email: squint_2008@yahoo.com

2. Irreversible Electroporation,
what does it mean???

3. Irreversible Electroporation
• Irreversible electroporation (IRE) is a new ablative technology that
uses high-voltage, low-energy direct current to create nanopores in the
cell membrane, disrupting the homeostasis mechanism and inducing
cell death by initiating apoptosis.
• It is a minimally invasive procedure that uses electrical probes to
permeate through the cell membrane of a tumor and kill the cancer
cells inside it.
• It is just beginning to be used in the medical field as a possible
replacement for chemotherapy, radiation treatment, as well as electro
chemotherapy.

4. Electroporation
• “Reversible”
• Electric pulses create tiny holes in
the cell
• Temporary as long as the energy is
low (360 V/cm)
• Chemotherapy and Genetic
therapy delivery
• “Irreversible”
• Higher energy (680 V/cm)
• Create permanent holes in the cell
• Cell loses essential molecules and
internal signals tell the cell to die
• Ablative therapy for tumors

5. The Origins of Electroporation
• Electroporation originated with two men, Okino and Mohri in 1987
who independently discovered that the permeability of cell membrane
can be increased by the use of reversible electric pulses, combined
with anticancer drugs.
• This process is referred to as reversible electroporation or electro
chemotherapy.
• The problem with this particular procedure is that it combines the use
of an electric field along with combinations of chemical agents.

6. • Ultimately , irreversible electroporation was derived from reversible
electroporation.
• This discussion of this new method was described by Davalos et al. in
2005.
• This group of engineers discovered that electrical pulse treatment can
be applied to a tumor without the use of cytotoxic cancer drugs.
• They conducted tests with models of the liver and found that the tumor
size is greatly reduced due to the applied electric field.
• They also stated in their research that a unique aspect of irreversible
electroporation is that the affected area can be controlled and
monitored with electrical impedance tomography.

10. Safety and Efficacy in Animal Models
• The safety of IRE has been evaluated in several animal models.
• Bile ducts and vessels integrity was completely preserved. The
treatment areas were sharply demarcated.
• The vessel-preserving effect of IRE is believed to be due to the fact
that the vessel wall contains a higher proportion of collagenous
connective tissue and elastic fiber, and it lacks a normal cellular
membrane. This belief was supported by the finding of mild
inflammatory changes that were seen in vessels in the IRE-treated
zone. This finding could be seen due to the fact that the inner most
layer of the vessels lacks collagenous and elastic fibrous tissue.

11. • Another explanation for preservation of the blood vessels following
IRE is the presence of gap junctions in the smooth muscle cells of the
blood vessels that may facilitate the passage of the electrical pulses of
IRE without damaging the cell membrane, thereby preserving the
integrity of the smooth muscle cell membrane.

15. Safety and Efficacy in Human Subjects
• The first human experience of IRE was published by Thomson et al. in
2011which described a single-center prospective non randomized
cohort study performed to investigate the safety of IRE.
• Thirty-eight volunteers with advanced malignancy of the liver, kidney,
or lung (69 separate tumors) unresponsive to standard treatment
underwent IRE under general anesthesia.
• No mortalities occurred at 30 days. Transient ventricular arrhythmia
occurred in four patients; electrocardiographically (ECG)
synchronized delivery was used subsequently in the remaining 30
patients.

16. • The authors concluded that IRE
appeared to be safe for human
clinical use, provided EKG
synchronized delivery is used.
• When energy is applied, the
ECG trigger monitor
automatically detects the rising
slope of the R wave and sends a
signal to the NanoKnife
generator, which delivers an
energy pulse after a 50 ms (0.05
second) delay.
• The energy pulse is delivered
during (or just before) the
ventricular refractory period.

17. Irreversible Electroporation: How It Works
• In IRE it begins with the electric probes that are used as needles in the
procedure.
• These electrical probes emit electrical pulses across the membrane of a
tumor.
• The electrical pulses create an electric field across the membrane.
• The voltage generated from this electric field targets the cancer cells
and destroys them.

19. NanoKnife® System
• The Nanoknife® system created by Angiodynamics was granted
approval by the FDA for surgical ablation of soft tissue in 2009.
• The Nanoknife system applies the methods of irreversible
electroporation to permanently open cell membranes of tumors.
• Healthy tissue then has the opportunity to grow and populate the area
where the dead tissue now lies.

21. • A treatment procedure with the NanoKnife device requires the use of
monopolar or bipolar probes.
• Monopolar probes are currently available in 15- and 20-cm lengths.
• When using the monopolar probes, a minimum of two probes are
required to create an appropriate treatment zone.
• A maximum of six probes can be used for a single treatment, and the
treatment zone at any given time is the tissue between two probes.

22. • The NanoKnife generator has a treatment planning algorithm software
that enables the user to evaluate different combinations with the
number of needles required to create an adequate treatment zone.
• The only limitation is that the machine does not actually know
precisely where the lesion is in relation to the needle placements, a
factor that the operator must determine. The ideal spacing between two
monopolar electrodes should be between 1.5 and 2 cm.

23. • The exposure length of the active tip is determined by the depth of the
lesion and by the type of the tissue treated, and treatments in the liver
can be safely performed with an exposure between 1.5 and 3 cm.
• If the depth of the tumor is greater than the exposure (i.e., 4 cm), when
the needle exposure is 2 cm then a pull back of the probes followed by
a second treatment will be required to cover the depth of 4 cm while
obtaining an appropriate treatment margin.

24. • Bipolar electrodes have the two poles on the same needle separated by
an insulated region, and they can ablate larger areas up to 2.0 x 2.0 x
2.5 cm.
• Typically, 90 high-voltage (1500 to 3000 V) direct current (25 to 45 A)
electrical pulses are delivered between paired unipolar electrodes or a
single bipolar electrode. With the revision of the treatment guidelines,
the number of pulses for a successful treatment between a pair of
monopolar electrodes has been reduced from 90 to 70.
• The voltage setting is determined by the distance between each pair of
electrodes with the intent to generate at least 1000 V between the
electrodes.

25. • The generator is programmed to stop delivery and recharge if the
current flow exceeded 48 A.
• The electrodes are placed percutaneously under imaging (computed
tomography [CT] or ultrasound) guidance, with the maximum
separation between the electrodes 2.2 cm.

27. Summary of the procedure
• Minimum of two electrodes:
Direct current
90 pulses of 1500 V/cm
70 Nano seconds per pulse
• Field generates pores
• Up to 6 electrodes can be connected:
19 gauge needle
Max. distance between two needle is 2 Cm
• Ablation time for 4 electrodes is 9 minutes

28. Primary tissue sites for uses of IRE
• Irreversible electroporation will mainly be applied to areas of soft
tissue.
• These areas include the pancreas, liver, kidneys, prostate and lungs.
• These areas are the main target areas of irreversible electroporation
because these areas are located near blood vessels.

29. Precautions before IRE procedure
• A detailed cardiac history is crucial for IRE because patients with a
known history of cardiac arrhythmias are not ideal candidates due to
the risk of inducing dangerous rhythms during the procedure.
• IRE is approved by the FDA in the United States under a 510 (k) for
surgical ablation of soft tissue; use of the technology in the liver is
considered off label and should be discussed with the patient.
• Consultation with anesthesia is required because all IRE procedures
are performed under general anesthesia.

30. Precautions during the procedure
• During treatment, a neuromuscular blockade is necessary to counteract
the high electrical voltage generated during treatment.
• The patient’s electrocardiograph tracing, heart rate, oxygen saturation,
respiratory rate, blood pressure, bispectral index, end tidal carbon
dioxide, temperature, and urine output is continuously monitored by
an anesthesiologist.
• The number of electrodes used in treatment and the number of
treatment sessions are both based on tumor size.

31. Follow up after the procedure
• Following completion of the IRE treatment, we perform a post
procedure CT scan the same day or the following day to evaluate for
any immediate complications and to evaluate if the lesion has been
entirely treated. Contrast is administered if renal function permits.
• Successful treatment is signified by a lack of contrast enhancement in
the ablation zone and complete coverage of the lesion by the ablation
zone.

32. Follow up after the procedure
• Following ablation, patients are transferred to recovery room and, if
stable and/or not scheduled to receive additional therapies, discharged
home the following day.
• Follow-up contrast-enhanced CT scans and/or magnetic resonance
imaging are generally obtained 1, 3, and 6 months, and 1 year after
treatment.

35. Advantages and Disadvantages of Irreversible Electroporation
Advantages
• It is minimally invasive surgery
that allows for quicker recovery
time.
• The destruction of the tumor is
monitored throughout the
procedure to assure the target area
is being tended to.
• IRE does substantial less harm to
the body than chemotherapy or
radiation.
Disadvantages
• Nanoknife system costs $300,000,
and each electric probe costs
$2,000 making for expensive
treatment.
• The Nanoknife system is designed
mainly for small tumors, and would
be rather ineffective with larger
tumors.

36. Contraindications of IRE
• Inability to tolerate general anesthesia via neuromuscular blockade
• Implanted pacemaker or cardiac defibrillator
• Symptomatic heart artery disease, cardiac arrhythmia or cardiac failure
• Presence of metal in vicinity of tumor
• Coagulopathy
• Recent seizures

37. Adverse Effects of Irreversible Electroporation
• Like any other local ablative therapy, IRE is also associated with a few
other adverse effects, be they general or procedure-related.
• General intra-operative complications
As with all operations, IRE carries the risk of general anesthesia and
positional neuropraxia. In two retrospective studies, such effects
occurred in an isolated number of patients but were transient and self-
limiting, and resolved without any long-term disability.

38. • Specific intra-operative complications:
 Unintended injury to other organs and structures during manipulation
of the electrodes
Pneumothorax
 Cardiac arrhythmia
 Muscle contraction
 Hyperkalemia
• Postoperative complications
Postoperative pain

39. Summary
• Irreversible electroporation is a tremendous step for the treatment of cancer.
• It is far less painful that the current treatments that are employed now, and
is quite effective in eliminating the cell membrane of the cancer cells.
• t is a very benign procedure because it only destroys the bad tissue, leaving
healthy tissue unharmed.
• Patients can have quick recovery times with little scarring or pain following
the surgery.
• Treatment of tumors greater than 3–4 cm in maximal diameter with IRE
results in decreased rates of complete ablation and higher likelihood of
recurrence.
• With further research the Nanoknife system will be able to destroy larger
tumors on a wider variety of areas on the body.

40. Waiting for Egyptian Experience
• National Hepatology & Tropical Medicine Research Institute
(NHTMRI), Cairo, Interventional ultrasonography Unit.
• National Cancer Institute (NCI), Cairo, Interventional Radiology Unit.
• Assiut ?????????????????????????????????????????????????????

41. References
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1987;78(12):1319–1321
• Mir LM, Orlowski S, Belehradek J Jr, Paoletti C. Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric
pulses. Eur J Cancer 1991;27(1):68–72
• Davalos RV, Mir IL, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng 2005;33(2):223–231
• Rubinsky B, Onik G, Mikus P. Irreversible electroporation: a new ablation modality—clinical implications. Technol Cancer Res Treat
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• Lee EW, Chen C, Prieto VE, Dry SM, Loh CT, Kee ST. Advanced hepatic ablation technique for creating complete cell death: irreversible
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• Thomson KR, Cheung W, Ellis SJ, et al. Investigation of the safety of irreversible electroporation in humans. J Vasc Interv Radiol
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• Kingham TP, Karkar AM, D’Angelica MI, et al. Ablation of perivascular hepatic malignant tumors with irreversible electroporation.
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• Narayanan G, Hosein P, Arora G, Barbery KJ, Yrizarry J. Percutaneous irreversible electroporation (ire) in the treatment of HCC and
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