Endovascular tumor treatment devices and methods

Abstract

A method for transvascular treatment of a tumor (370) in an organ of a subject includes endovascularly advancing an electrode (304) of an applicator (301) into a blood vessel (307) adjacent the tumor. A margin of the tumor is then cleared (520) adjacent the blood vessel by driving the electrode to apply a series of electroporation pulses to the tumor from within the blood vessel. At least some of the tumor is subsequently resected (540). Other methods and devices are included herein.

Description

ENDOVASCULAR TUMOR TREATMENT DEVICES AND METHODSCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present application claims priority to:Provisional US Patent Application 63 / 748,498 to Taff et al., titled "Endovascular tumor treatment devices and methods," filed 23 January 2025; andProvisional US Patent Application 63 / 929,912 to Ekeltchik et al., titled "Endovascular tumor treatment devices and methods," filed 3 December 2025.

[0002] Each of the above is incorporated herein by reference.FIELD OF THE INVENTION

[0003] The present application relates to the field of medical devices, particularly devices for tissue ablation.BACKGROUND

[0004] Surgical resection often provides the best chance for a curable treatment for many cancer types. Unfortunately, many tumors may be deemed unresectable due to their proximity or infiltration of major blood vessels. Some examples may be pancreatic tumors, brain tumors, liver tumors, neck tumors kidney tumors, etc.

[0005] Alternative treatments such as radiation and / or chemotherapy may sometimes be used prior to surgery in an effort to reduce tumor size and improve the odds of removing the tumor at its entirety, however these treatments are not always effective.

[0006] In addition, tumor ablation may be performed in a neoadjuvant setting prior to surgical resection. Typically, percutaneous access may be used with multiple needles inserted into the vicinity of the tumor. The ablation modality may either be thermal, such as RF Ablation (RFA) or Microwave Ablation (MW A), or nonthermal such as Irreversible Electroporation (IRE). The access to the tumor site using these modalities may often be challenging, and fear of damage to sensitive structures, such as major blood vessels, may limit their use.SUMMARY OF THE INVENTION

[0007] This summary is meant to provide some examples and is not intended to be limiting of the scope of the invention in any way. For example, any feature included in an example of this summary is not required by the claims, unless the claims explicitly recite the features. Also, the features, components, steps, concepts, etc. described in examples in this summary and elsewhere in this disclosure can be combined in a variety of ways. Various features and steps as described elsewhere in this disclosure may be included in the examples summarized here.

[0008] In general, some embodiments of the present invention include an apparatus configured for endovascular ablation of tissue, for example tumors that are located in proximity to blood vessels.

[0009] Devices and methods are disclosed for utilizing electroporation to clear a margin around a blood vessel with which a tumor is associated, in order to increase the likelihood of successful subsequent resection of the tumor.

[0010] In some embodiments, the tool may be in the form of a catheter or wire with at least one electrode, applying energy for ablation of tissues in proximity to the blood vessel in which the electrode is positioned.

[0011] In some embodiments, the tool may include at least one lumen for local administration of therapeutics.

[0012] In some embodiments, the tool may include multiple electrodes and the energy may be delivered between them.

[0013] In some embodiments, the tool may be in the form of multiple catheters and / or wires with at least one electrode on each. The catheters and / or wires may be positioned in separated blood vessels such that the ablation energy is delivered between them.

[0014] In some embodiments, the surface area of one electrode may be larger than that of another.

[0015] In some embodiments, the ablation energy used may be RFA. Alternatively, or additionally, the ablation energy may be high voltage pulses required to induce IRE.

[0016] In some embodiments one or more of the electrodes may be expandable. The expandable electrode may or may not be detachable.

[0017] In some embodiments one or more of the electrodes may be mounted on a balloon.

[0018] Some embodiments of the present invention include a method for endovascular tissue ablation.

[0019] In some embodiments, the method may include positioning of one or more electrodes inside a blood vessel that is in the vicinity of the target tissue and delivering ablation energy by means of these one or more electrodes.

[0020] In some embodiments, the method may include the positioning of a first electrode inside a first blood vessel, and a second electrode in a second blood vessel and delivering the ablation energy between them.

[0021] In some embodiments, the first electrode may have a smaller surface area than the second electrode.

[0022] In some embodiments of the present method, any of the electrodes may be expandable. The expandable electrode may be in the form of the stent that may be detachable after the ablation energy has been delivered in order to maintain the blood vessels’ patency.

[0023] In some embodiments, the method may include delivering targeted therapeutics into the treated area, for example chemotherapy drugs, prior, during and / or after applying the ablation energy.

[0024] In some embodiments, the delivery of the targeted therapeutics may be using the ablation tool, a catheter used to deliver it or a separate catheter.

[0025] In some embodiments, the delivery of the targeted therapeutics may be into the blood vessels in which the electrodes were activated and / or branches thereof.

[0026] In some embodiments, the target tissue for ablation may be a tumor that is in proximity to the blood vessel and / or has infiltrated it.

[0027] In some embodiments, the target tissue for ablation may be a tumor in the pancreas and the blood vessel in which the electrode is positioned may be the celiac trunk, superior mesenteric artery, splenic artery, inferior pancreatic artery and / or any other blood vessel in the vicinity of the pancreas.

[0028] There is therefore provided, in accordance with an application of the present invention, a system for transvascular treatment of a tumor in an organ of a subj ect, the system including: (i) a first electrode assembly, including: (a) a first flexible shaft, having a first-shaft distal part, (b) a first electroporation electrode, disposed on the first-shaft distal part such that the first electroporation electrode is transluminally positionable at a first site within a first blood vessel of the organ by transluminal advancement of the first-shaft distal part, and (c) a first connector, electrically connected to the first electroporation electrode; (ii) a second electrode assembly, including: (a) a second flexible shaft, having a second-shaft distal part, (b) a second electroporation electrode, disposed on the second-shaft distal part such that the second electroporation electrode is transluminally positionable at a second site within a second blood vessel of the organ by transluminal advancement of the second-shaft distal part, and (c) a second connector, electrically connected to the second electroporation electrode; (iii) a pulse generator: (a) including a first terminal to which the first connector is connectable, and a second terminal to which the second connector is connectable, and (b) configured to electroporate cells of the tumor by, via the first terminal connected to the first connector and the second terminal connected to the second connector, driving a series of electroporation pulses transvascularly between the first electroporation electrode at the first site and the second electroporation electrode at the second site.

[0029] In an application, the first connector is disposed at a proximal part of the first electrode assembly, and the second connector is disposed at a proximal part of the second electrode assembly.

[0030] In an application, the second electroporation electrode has a surface area that is greater than that of the first electroporation electrode.

[0031] In an application, the first electroporation electrode is endovascularly expandable.

[0032] In an application: (i) the first-shaft distal part is operatively coupled to a proximal part of the first electrode assembly such that the first-shaft distal part is steerable via actuation of the proximal part of the first electrode assembly, and (ii) the second-shaft distal part is operatively coupled to a proximal part of the second electrode assembly such that the second-shaft distal part is steerable via actuation of the proximal part of the second electrode assembly.

[0033] In an application, the first electrode assembly and the second electrode assembly are components of a treatment tool that includes an extracorporeal unit to which the first electrode assembly and the second electrode assembly are coupled such that the extracorporeal unit is operatively coupled to the first-shaft distal part and the firstelectroporation electrode via the first shaft, and to the second-shaft distal part and the second electroporation electrode via the second shaft.

[0034] In an application, the first shaft is transluminally advanceable independently of the second shaft.

[0035] There is further provided, in accordance with an application of the present invention, a system for transvascular treatment of a tumor in an organ of a subj ect, the system including: (i) a first electrode assembly, including: (a) a first electroporation electrode, transluminally advanceable to a first intravascular site within the organ, and (b) a first connector, electrically connected to the first electroporation electrode; (ii) a second electrode assembly, including: (a) a second electroporation electrode, transluminally advanceable to a second intravascular site within the organ, and (b) a second connector, electrically connected to the second electroporation electrode; (iii) a pulse generator: (a) including a first terminal to which the first connector is connectable, and a second terminal to which the second connector is connectable, and (b) configured to transvascularly electroporate cells of the tumor by, via the first terminal connected to the first connector and the second terminal connected to the second connector, driving a series of electroporation pulses between the first electroporation electrode at the first site and the second electroporation electrode at the second site.

[0036] In an application: (a) the first electrode assembly includes a first flexible shaft, having a first-shaft distal part on which the first electroporation electrode is disposed such that the first electroporation electrode is transluminally positionable at the first site by transluminal advancement of the first-shaft distal part, and (b) the second electrode assembly includes a second flexible shaft, having a second-shaft distal part on which the second electroporation electrode is disposed such that the second electroporation electrode is transluminally positionable at the second site by transluminal advancement of the second-shaft distal part.

[0037] In an application, the system includes a unitary shaft having a unitary-shaft distal part on which the first and second electroporation electrodes are disposed such that the first electroporation electrode is transluminally positionable at the first site and the second electroporation electrode is transluminally positionable at the second site by transluminal advancement of the unitary-shaft distal part.

[0038] In an application, the unitary shaft is configured such that the second electroporation electrode is movable with respect to the first electroporation electrode.

[0039] In an application, the unitary shaft is configured such that the second electroporation electrode is fixed with respect to the first electroporation electrode.

[0040] There is further provided, in accordance with some implementations, a method for transvascular treatment of a tumor in an organ of a subject, the method including endovascularly advancing an electrode of an applicator into a blood vessel adjacent the tumor, clearing a margin of the tumor adjacent the blood vessel by driving the electrode to apply a series of electroporation pulses to the tumor from within the blood vessel, and / or subsequently, resecting at least some of the tumor.

[0041] For some implementations, the applicator is at a distal part of a flexible shaft, the shaft defining an axial axis along the shaft. For some implementations, a first conductive wire extends along the shaft. For some implementations, a second conductive wire extends along the shaft. For some implementations, the electrode is a first electroporation electrode. For some implementations, the applicator further includes: (i) a second electroporation electrode, and / or (ii) a non-conductive centering mechanism radially expandable into contact with a vascular wall of the blood vessel. For some implementations, the method further includes expanding the centering mechanism in a manner that: (a) supports the first and second electrodes medially from the vascular wall, and / or (b) allows blood within the blood vessel to flow past the applicator.

[0042] For some implementations, the centering mechanism is disposed axially between the first and second electrodes. For some implementations, the centering mechanism includes an expandable structure. For some implementations, the first electrode is proximal from the second electrode. For some implementations, the second electrode is slidably mounted on the shaft, and serves as an actuator of the centering mechanism. For some implementations, expanding the centering mechanism includes expanding the centering mechanism by sliding the second electrode proximally along the shaft toward the first electrode such that the expandable structure of the centering mechanism expands into contact with the vascular wall.

[0043] For some implementations, the applicator further includes a stopping mechanism, the stopping mechanism including: (i) a spring, attached to the second electrode at a first spring-end, and fixed, at a second spring-end, to the shaft, the spring biases the second electrode to rest distally; and / or (ii) a stopper, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end; configured: (a) to limit springextension, and / or (b) to slide along with the second electrode. For some implementations, sliding the second electrode proximally along the shaft includes sliding the second electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

[0044] For some implementations, the second electrode is proximal from the stopper, and sliding the second electrode proximally along the shaft is sliding the second electrode proximally along the shaft such that the spring is extended, thereby closing the gap.

[0045] For some implementations, the stopper is proximal from the second electrode, and sliding the second electrode proximally along the shaft is sliding the second electrode proximally along the shaft such that the spring is compressed, thereby opening the gap.

[0046] For some implementations, the centering mechanism includes a tube having a plurality of slots aligned with the shaft axis to define a corresponding plurality of bendable ribs. For some implementations, the centering mechanism has a delivery state in which the ribs have a low profile. For some implementations, the centering mechanism is reversibly expandable into a centering state. For some implementations, expanding the centering mechanism includes expanding the centering mechanism such that the ribs bend radially outwardly away from the shaft to contact the vascular wall.

[0047] For some implementations, the centering mechanism includes a plurality of axial ribs. For some implementations, the centering mechanism has a delivery state in which the ribs are substantially flat against the shaft. For some implementations, the centering mechanism is reversibly expandable into a centering state. For some implementations, expanding the centering mechanism includes expanding the centering mechanism such that the ribs bend radially outwardly away from the shaft to contact the vascular wall.

[0048] For some implementations, the centering mechanism is biased toward expanding, and expanding the centering mechanism includes expanding the centering mechanism by unconstraining the centering mechanism.

[0049] For some implementations, the method further includes contracting the centering mechanism.

[0050] For some implementations, the centering mechanism is biased toward contracting, and contracting the centering mechanism includes contracting the centering mechanism by constraining the centering mechanism.

[0051] For some implementations, expanding the centering mechanism includes expanding the centering mechanism by rotating the mechanism in one direction, and contracting the centering mechanism includes contracting the centering mechanism, after expanding, by rotating in an opposite direction.

[0052] For some implementations, the second wire is mechanically attached to the second electrode. For some implementations, the second wire is slidable axially within the shaft. For some implementations, the second wire is sufficiently strong in tension. For some implementations, sliding the second electrode proximally along the shaft includes sliding the second electrode proximally along the shaft by pulling the wire proximally that the expandable structure expands into contact with the vascular wall.

[0053] For some implementations, the method further including medially contracting the centering mechanism by sliding the second electrode distally along the shaft away from the first electrode.

[0054] For some implementations, sliding the second electrode includes sliding the second electrode by pushing the wire distally.

[0055] For some implementations, the applicator includes a third electroporation electrode, slidably mounted on the shaft axially between the first electrode and the second electrode. For some implementations, the expandable structure is a first expandable structure, and is disposed axially between the third electrode and the second electrode. For some implementations, the centering mechanism further includes a second expandable structure, disposed axially between the first electrode and the third electrode. For some implementations, sliding the second electrode proximally along the shaft includes sliding the second electrode proximally along the shaft toward the third and first electrodes, such that: (a) the first expandable structure expands into contact with the vascular wall, and / or (b) the third electrode slides proximally along the shaft toward the first electrode in a manner that expands the second expandable structure.

[0056] For some implementations, the centering mechanism includes a balloon. For some implementations, expanding the centering mechanism includes expanding the centering mechanism into contact with the vascular wall of the blood vessel, such that, while expanded, blood flow through the blood vessel is prevented.

[0057] For some implementations, the shaft further includes an opening in a lateral wall of the shaft, and the method further includes opening the opening to allow drug delivery to the adjacent blood vessel.

[0058] For some implementations, the centering mechanism is self-expandable, and expanding the centering mechanism includes expanding the centering mechanism via unconstraining the centering mechanism.

[0059] For some implementations, expanding the centering mechanism includes expanding the centering mechanism by rotating the mechanism in one direction.

[0060] For some implementations, the method further includes, subsequently to expanding the centering mechanism, retracting the centering mechanism by rotating in an opposite direction.

[0061] For some implementations, expanding the centering mechanism includes expanding the centering mechanism by inflating the balloon.

[0062] For some implementations, inflating the balloon includes inflating the balloon non-continuously, such that the centering mechanism becomes stable upon inflation even in an absence of maintenance of inflation pressure.

[0063] For some implementations, the method further includes, subsequently to inflating the balloon, deflating the balloon via application of a vacuum.

[0064] For some implementations, the method further includes, subsequently to inflating the balloon, deflating the balloon via absence of maintenance of inflation pressure.

[0065] For some implementations, the first electrode is proximal and the second electrode is distal. For some implementations, the centering mechanism is disposed axially between the first electrode and the second electrode. For some implementations, the method further includes, subsequently to expanding the centering mechanism, stabilizing the orientation of the applicator.

[0066] For some implementations, the method further includes, subsequently to expanding the centering mechanism, retracting and expanding the mechanism periodically during the treatment, such that, while retracted, the blood vessel is not occluded and blood is allowed to flow through the blood vessel.

[0067] For some implementations, the first electrode is proximal. For some implementations, the second electrode is distal. For some implementations, the balloon is afirst balloon, and is disposed axially proximally from the first electrode. For some implementations, the centering mechanism further includes a second balloon, disposed axially distally from the second electrode. For some implementations, the method further includes expanding the second balloon into contact with the vascular wall of the blood vessel, such that, while expanded, blood flow through the blood vessel is prevented.

[0068] For some implementations, expanding the second balloon includes expanding the second balloon independently of the expansion of the first balloon.

[0069] For some implementations, expanding the second balloon includes expanding the second balloon in dependance on the expansion of the first balloon.

[0070] For some implementations, expanding the second balloon includes expanding the second balloon simultaneously with the expansion of the first balloon.

[0071] For some implementations, expanding the second balloon includes expanding the second balloon separately from of the expansion of the first balloon.

[0072] For some implementations, subsequently to expanding the centering mechanism, clearing a margin of the tumor is clearing a margin of the tumor by driving the first electrode to apply a series of electroporation pulses between the first electrode and the second electrode while the first electrode and the second electrode are supported medially from the vascular wall by the centering mechanism.

[0073] For some implementations, the electrode is expandable, and subsequently to advancing the electrode into a blood vessel, the method further includes expanding the electrode into contact with a wall of the blood vessel.

[0074] For some implementations, the electrode is biased toward expansion, and the applicator is configured to constrain the first electrode compressed for advancement into the blood vessel, and expanding the electrode includes expanding the electrode by unconstraining the electrode.

[0075] For some implementations, the applicator includes an insulator that insulates at least part of the electrode, and unconstraining the electrode includes unconstraining the electrode by deploying the electrode out of the insulator.

[0076] For some implementations, the insulator is a sleeve, and unconstraining the electrode includes unconstraining the electrode by deploying the first electrode out of the sleeve.

[0077] For some implementations, the applicator is at a distal part of a shaft and the distal part of the shaft serves as the insulator, and unconstraining the electrode includes unconstraining the electrode by deploying the electrode out of the distal end of the shaft.

[0078] For some implementations, the electrode is biased to form a helix upon expansion, and unconstraining the electrode includes unconstraining the electrode to form a helix upon expansion.

[0079] For some implementations, the electrode is biased to form a tube upon expansion, and unconstraining the electrode includes unconstraining the electrode to form a tube upon expansion.

[0080] For some implementations, the electrode is biased to define, upon expansion, a lumen through which blood can flow, and unconstraining the electrode includes unconstraining the electrode such that blood can flow through the lumen defined by the expanded electrode.

[0081] For some implementations, the electrode is a first electrode. For some implementations, the applicator further includes a second electrode, configured such that expansion of the first electroporation electrode into contact with the wall positions the second electroporation electrode medially from the wall. For some implementations, the method further includes positioning the second electroporation electrode medially from the wall when expanding the first electrode.

[0082] For some implementations, subsequently to positioning the second electrode, and clearing a margin of the tumor includes clearing a margin of the tumor by driving the first electrode to apply a series of electroporation pulses between the first electroporation electrode and the second electroporation electrode.

[0083] For some implementations, the second electrode is non-expandable, and clearing a margin of the tumor includes clearing a margin of the tumor by driving the first electrode to apply a series of electroporation pulses between the first electroporation electrode and the non-expandable electroporation electrode.

[0084] For some implementations, the second electrode is expandable, and the method further includes expanding the second electrode.

[0085] For some implementations, the second electrode is biased toward expansion and the applicator is configured to constrain the second electrode compressed for advancement intothe blood vessel, and expanding the second electrode includes expanding the second electrode by unconstraining the second electrode.

[0086] For some implementations, the first electrode is distal from the second electrode, and unconstraining the second electrode includes unconstraining the second electrode proximally to the first electrode.

[0087] For some implementations, the applicator is at a distal part of a shaft, and the shaft has a lateral opening, disposed proximally to the first electrode, and the second electrode is configured to be constrained, while advanced, inside the shaft, and unconstraining the second electrode includes unconstraining the second electrode to emerge through the lateral opening when expanding.

[0088] For some implementations, the second electrode is biased to form a helix upon expansion, the helix encircles the shaft, and unconstraining the second electrode includes unconstraining the second electrode to form a helix upon expansion.

[0089] For some implementations, the second electrode is biased to define, upon expansion, a lumen through which blood can flow, the helix encircles the shaft, and unconstraining the second electrode includes unconstraining the second electrode such that blood can flow through the lumen defined by the expanded second electrode.

[0090] For some implementations, the method further includes intravenously administering a systemic anticancer chemotherapeutic agent prior to the endovascular advancing of the applicator.

[0091] For some implementations, the electroporation is a reversible electroporation.

[0092] For some implementations, the electroporation is an irreversible electroporation.

[0093] For some implementations, the electrode is biased toward expansion, and the method further includes constraining the second electrode in a compressed state for advancement into the blood vessel, and / or

[0094] expanding the second electrode within the blood vessel by unconstraining the second electrode.

[0095] For some implementations, clearing the margin of the tumor includes clearing the margin of the tumor by driving the electroporation pulses unidirectionally through the blood vessel wall.

[0096] There is further provided, in accordance with some implementations, a method for transvascular treatment of a tumor in an organ of a subject, the method (a) including endovascularly advancing an electrode of an applicator to an intravascular site adjacent the tumor; (b) conducting an electroporation of the tumor by driving the electrode to apply a series of electroporation pulses from the intravascular site transvascularly to the tumor; and / or (c) subsequently, resecting at least some of the tumor.

[0097] For some implementations, the method further includes intravenously administering a systemic anticancer chemotherapeutic agent prior to electroporation of the tumor.

[0098] For some implementations, the electroporation is a reversible electroporation.

[0099] For some implementations, the electroporation is an irreversible electroporation.

[0100] There is further provided, in accordance with some implementations, a method, including: (a) endovascularly advancing an electrode of an applicator to an intravascular site adjacent a tumor of a subject; (b) driving the electrode to apply a series of electroporation pulses from the intravascular site transvascularly to the tumor; (c) determining an effect that the electroporation pulses had on the tumor; and / or (d) responsively to the determining, identifying the subject as being a candidate for resection of at least some of the tumor.

[0101] For some implementations, the method further includes, responsively to the identifying, resecting at least some of the tumor.

[0102] There is further provided, in accordance with some implementations, a method, including: (a) identifying a subject as having had a series of electroporation pulses applied from an intravascular site transvascularly to a tumor of the subject; and / or (b) responsively to the identifying, resecting at least some of the tumor.

[0103] For some implementations, the method further includes, prior to the identifying, driving an endovascular electrode to apply the series of electroporation pulses from the intravascular site transvascularly to the tumor.

[0104] There is further provided, in accordance with some implementations, a method for transvascular treatment of a tumor in an organ of a subject, the method including: (a) endovascularly advancing an applicator to an intravascular site adjacent the tumor; (b) at the intravascular site, expanding a first electroporation electrode of the applicator into contact with a vascular wall; (c) at the intravascular site, positioning a second electroporation electrode of the applicator medially from the vascular wall; and / or (d) while the applicatorremains at the intravascular site, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between the first electrode and the second electrode.

[0105] For some implementations, the method further includes intravenously administering a systemic anticancer chemotherapeutic agent prior to the endovascular advancing of the applicator.

[0106] For some implementations, the second electroporation electrode has a surface area that is greater than that of the first electroporation electrode, and applying the electroporation pulses transvascularly to the tumor includes driving the electroporation pulses between (i) the first electroporation electrode, and (ii) the second electroporation electrode that has the surface area that is greater than that of the first electroporation electrode.

[0107] For some implementations, the second electroporation electrode has an axial length that is greater than that of the first electroporation electrode, and applying the electroporation pulses transvascularly to the tumor includes driving the electroporation pulses between (i) the first electroporation electrode, and (ii) the second electroporation electrode that has the axial length that is greater than that of the first electroporation electrode.

[0108] For some implementations, the method further includes intracorporeally adjusting an axial length of the first electrode.

[0109] For some implementations, applying the electroporation pulses transvascularly to the tumor includes applying the electroporation pulses radially through the vascular wall.

[0110] For some implementations, applying the electroporation pulses transvascularly to the tumor includes applying the electroporation pulses unidirectionally through the vascular wall.[OHl] For some implementations, applying the electroporation pulses transvascularly to the tumor includes applying the electroporation pulses omnidirectionally through the vascular wall.

[0112] For some implementations, the tumor is a stage 2 tumor, and endovascularly advancing the applicator to the intravascular site adjacent the tumor includes endovascularly advancing the applicator to an intravascular site adjacent the stage 2 tumor.

[0113] For some implementations, the tumor is a stage 3 tumor, and endovascularly advancing the applicator to the intravascular site adjacent the tumor includes endovascularly advancing the applicator to an intravascular site adjacent the stage 3 tumor.

[0114] For some implementations, the tumor is a pancreatic tumor, and endovascularly advancing the applicator to the intravascular site adjacent the tumor includes endovascularly advancing the applicator to an intravascular site adjacent the pancreatic tumor.

[0115] For some implementations, the tumor is a locally advanced tumor, and endovascularly advancing the applicator to the intravascular site adjacent the tumor includes endovascularly advancing the applicator to an intravascular site adjacent the locally advanced tumor.

[0116] For some implementations, the method further includes determining an effect of the electroporation pulses on the tumor.

[0117] For some implementations, the method further includes responsively to the determining, resecting at least some of the tumor.

[0118] For some implementations, the method further includes responsively to the determining, identifying the subject as being a candidate for resection of at least some of the tumor.

[0119] For some implementations, the method further includes responsively to the identifying, resecting at least some of the tumor.

[0120] There is further provided, in accordance with some implementations, a system for treatment of a tumor adjacent to a blood vessel of a subject, the system including a tool, and / or a pulse generator.

[0121] For some implementations, the tool includes a flexible shaft and / or at a proximal part of the shaft, a connector assembly. For some implementations, an applicator is at a distal part of the shaft, and is advanceable into the blood vessel. For some implementations, the applicator includes an expandable first electroporation electrode, expandable into contact with a wall of the blood vessel; and / or a second electroporation electrode, configured such that expansion of the first electroporation electrode into contact with the wall biases the second electroporation electrode medially away from the wall. For some implementations, the connector assembly includes (a) a first connector, electrically connected to the first electroporation electrode; and / or (b) a second connector, electrically connected to the second electroporation electrode. For some implementations, the pulse generator: (i) includes a first terminal to which the first connector is connectable, and (ii) a second terminal to which the second connector is connectable. For some implementations, the pulse generator is configured to electroporate cells of the tumor by, via the first terminal connected to the firstconnector and the second terminal connected to the second connector, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between (i) the first electroporation electrode in contact with the wall, and (ii) the second electroporation electrode disposed medially from the wall.

[0122] For some implementations, the second electroporation electrode has a surface area which is greater than that of the first electroporation electrode.

[0123] For some implementations, the second electroporation electrode has an axial length which is greater than that of the first electroporation electrode.

[0124] For some implementations, the first electroporation electrode is proximal from the second electroporation electrode.

[0125] For some implementations, the first electroporation electrode is distal from the second electroporation electrode.

[0126] For some implementations, the second electroporation electrode is advanceable through the first electroporation electrode.

[0127] For some implementations, the first electroporation electrode is advanceable through the second electroporation electrode.

[0128] For some implementations, the applicator is operable to intracorporeally adjust an effective axial length of the first electroporation electrode.

[0129] For some implementations, the applicator is configured such that the electroporation pulses are applied radially through the vascular wall.

[0130] For some implementations, the applicator is configured such that the electroporation pulses are applied unidirectionally through the vascular wall.

[0131] For some implementations, the applicator is configured such that the electroporation pulses are applied omnidirectionally through the vascular wall.

[0132] For some implementations, the first electrode is biased toward expansion, and the applicator is configured to:

[0133] constrain the first electrode compressed for advancement into the blood vessel, and / or

[0134] expand the first electrode within the blood vessel by unconstraining the first electrode.

[0135] For some implementations, the applicator includes an insulator that insulates at least part of the first electrode, and the applicator is configured to unconstrain the first electrode by deploying the first electrode out of the insulator.

[0136] For some implementations, the insulator is a sleeve.

[0137] For some implementations, the distal part of the shaft serves as the insulator.

[0138] For some implementations, the first electrode is biased to form a helix upon expansion.

[0139] For some implementations, the first electrode is biased to form a tube upon expansion.

[0140] For some implementations, the first electrode is biased to define, upon expansion, a lumen through which blood can flow.

[0141] For some implementations, the second electrode is non-expandable.

[0142] For some implementations, the second electrode is biased toward expansion, and the applicator is configured to: (i) constrain the second electrode compressed for advancement into the blood vessel, and / or (ii) expand the second electrode within the blood vessel by unconstraining the second electrode.

[0143] For some implementations, the first electrode is distal from the second electrode.

[0144] For some implementations, the shaft has a lateral opening, disposed proximally to the first electrode, and the second electrode is configured to: (i) be constrained, while advanced, inside the shaft, and / or (ii) emerge through the lateral opening when expanding.

[0145] For some implementations, the second electrode is biased to form a helix upon expansion, the helix encircles the shaft.

[0146] For some implementations, the second electrode is biased to define, upon expansion, a lumen through which blood can flow.

[0147] There is further provided, in accordance with some implementations, a system for treatment of a tumor adjacent to a blood vessel of a subject, the system including a tool, and / or a pulse generator. For some implementations, the tool includes (i) a flexible shaft, defining an axial axis along the shaft, (ii) a first conductive wire extending along the shaft, (iii) a second conductive wire extending along the shaft, and / or (iv) at a distal part of the shaft, an applicator, advanceable into the blood vessel, and including: (a) a firstelectroporation electrode, (b) a second electroporation electrode, and / or (c) a non-conductive centering mechanism radially expandable into contact with a vascular wall of the blood vessel in a manner that: (I) supports the first and second electrodes medially from the vascular wall, and / or (II) allows blood within the blood vessel to flow past the applicator. For some implementations, at a proximal part of the shaft there is a connector assembly that includes (i) a first connector, electrically connected to the first electrode via the first wire; and / or (ii) a second connector, electrically connected to the second electrode via the second wire. For some implementations, the pulse generator: (i) includes a first terminal to which the first connector is connectable, and a second terminal to which the second connector is connectable; and / or (ii) is configured to electroporate cells of the tumor by, via the first terminal connected to the first connector and the second terminal connected to the second connector, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between the first electrode and the second electrode while the first electrode and the second electrode are supported medially from the vascular wall by the centering mechanism.

[0148] For some implementations, the centering mechanism: (i) includes a tube having a plurality of slots aligned with the shaft axis to define a corresponding plurality of bendable ribs, (ii) has a delivery state in which the ribs have a low profile; and / or (iii) is reversibly expandable into a centering state in which the ribs bend radially outwardly away from the shaft to contact the vascular wall.

[0149] For some implementations, the centering mechanism: (i) includes a plurality of axial ribs, (ii) has a delivery state in which the ribs are substantially flat against the shaft, and / or (iii) is reversibly expandable into a centering state in which the ribs bend radially outwardly away from the shaft to contact the vascular wall.

[0150] For some implementations, the centering mechanism is biased toward expanding.

[0151] For some implementations, the centering mechanism is biased toward contracting.

[0152] For some implementations, the centering mechanism expands by rotating the mechanism in one direction, and retracts, after expanding, by rotating in an opposite direction.

[0153] For some implementations: (i) the centering mechanism is disposed axially between the first and second electrodes, (ii) the first electrode is proximal from the second electrode, (iii) the second electrode is slidably mounted on the shaft, and serves as an actuator of thecentering mechanism such that sliding the second electrode proximally along the shaft toward the first electrode expands an expandable structure of the centering mechanism into contact with the vascular wall.

[0154] For some implementations, the second wire is: (i) mechanically attached to the second electrode, (ii) slidable axially within the shaft, and / or (iii) is sufficiently strong in tension that the expandable structure is expandable by the second electrode being slid proximally along the shaft toward the first electrode via pulling the wire proximally.

[0155] For some implementations, the tool is configured such that the centering mechanism is medially contractible by the second electrode being slid distally along the shaft away from the first electrode via pushing the wire distally.

[0156] For some implementations, the applicator further includes a stopping mechanism, the stopping mechanism including: (i) a spring, attached to the second electrode at a first spring-end, and fixed, at a second spring-end, to the shaft, the spring biases the second electrode to rest distally; and / or (ii) a stopper, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end, configured: (a) to limit spring extension, and / or (b) to slide along with the second electrode. For some implementations, the stopping mechanism is configured to stop the sliding of the second electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

[0157] For some implementations, the second electrode is proximal from the stopper and the spring is extended, closing the gap.

[0158] For some implementations, the stopper is proximal from the second electrode and the spring is compressed, opening the gap.

[0159] For some implementations, the spring and the second electrode are formed from a single material such that the spring serves as a continuation of the second electrode in applying electroporation pulses to the tumor.

[0160] For some implementations, the stopper and the second electrode are formed from a single material such that the stopper serves as a continuation of the second electrode in applying electroporation pulses to the tumor.

[0161] For some implementations, the entire stopping mechanism is formed from a single material such that the entire stopping mechanism serves as the second electrode in applying electroporation pulses to the tumor.

[0162] For some implementations, the system further includes, at shaft proximal end, an extracorporeal unit, operatively coupled to the second electrode mechanism; and the extracorporeal unit is configured to slide the second electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

[0163]

[0164] For some implementations, the extracorporeal unit further includes a connector, electrically connected to the second electrode. For some implementations, the system further includes a pulse generator, including a terminal to which the connector is connectable, the pulse generator is configured to apply, via the connector connected to the second electrode, electroporation pulses transvascularly to the tumor.

[0165] For some implementations, the applicator includes a third electroporation electrode, slidably mounted on the shaft axially between the first electrode and the second electrode. For some implementations, the expandable structure is a first expandable structure, and is disposed axially between the third electrode and the second electrode. For some implementations, the centering mechanism further includes a second expandable structure, disposed axially between the first electrode and the third electrode. For some implementations, sliding the second electrode proximally along the shaft toward the third and first electrodes: (i) expands the first expandable structure into contact with the vascular wall, and / or (ii) slides the third electrode proximally along the shaft toward the first electrode in a manner that expands the second expandable structure.

[0166] For some implementations, the centering mechanism includes a balloon configured to: (i) expand into contact with the vascular wall of the blood vessel, and / or (ii) while expanded, to prevent blood flow through the blood vessel.

[0167] For some implementations, the shaft further includes an opening in a lateral wall of the shaft, the opening is configured to allow drug delivery to the adjacent blood vessel.

[0168] For some implementations, the centering mechanism is self-expandable.

[0169] For some implementations, the centering mechanism expands by rotating the mechanism in one direction, and retracts, after expanding, by rotating in an opposite direction.

[0170] For some implementations, the centering mechanism expands via inflation of the balloon.

[0171] For some implementations, the centering mechanism is configured to become stable upon inflation even in an absence of maintenance of inflation pressure.

[0172] For some implementations, the centering mechanism is configured to be deflated via application of a vacuum.

[0173] For some implementations, the centering mechanism is configured to deflate in an absence of maintenance of inflation pressure.

[0174] For some implementations, the first electrode is proximal and the second electrode is distal, and the centering mechanism is disposed axially between the first electrode and the second electrode.

[0175] For some implementations, the centering mechanism expands and retracts periodically during the treatment, such that, while retracted, the blood vessel is not occluded and blood is allowed to flow through the blood vessel.

[0176] For some implementations, the first electrode is proximal. For some implementations, the second electrode is distal. That is, the first electrode can be proximal from the second electrode. For some implementations, the balloon is a first balloon, and is disposed axially proximally from the first electrode. For some implementations, the centering mechanism further includes a second balloon, disposed axially distally from the second electrode. For some implementations, the second balloon is configured to: (i) expand into contact with the vascular wall of the blood vessel, and / or (ii) while expanded, to prevent blood flow through the blood vessel.

[0177] For some implementations, the second balloon is expandable independently of the expansion of the first balloon.

[0178] For some implementations, the second balloon expansion is dependent on the expansion of the first balloon.

[0179] For some implementations, the second balloon expands simultaneously with the expansion of the first balloon.

[0180] For some implementations, the second balloon expands separately from the expansion of the first balloon.

[0181] There is further provided, in accordance with some implementations, a system for treatment of a tumor adjacent to a blood vessel of a subject, the system including a tool that includes: (i) a flexible shaft, and / or (ii) at a distal part of the shaft, an applicator. For some implementations, the applicator is advanceable into the blood vessel, and includes: (i) an expandable first electroporation electrode, expandable into contact with a wall of the blood vessel; and / or (ii) a second electroporation electrode, configured such that expansion of the first electroporation electrode into contact with the wall biases the second electroporation electrode medially away from wall. For some implementations, the system is configured to electroporate cells of the tumor by applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between (i) the first electroporation electrode in contact with the wall, and (ii) the second electroporation electrode disposed medially from the wall.

[0182]

[0183] There is further provided, in accordance with some implementations, a system for treatment of a tumor adjacent to a blood vessel of a subject, the system including a tool, an extracorporeal unit, and / or a pulse generator.

[0184] For some implementations, the tool includes a flexible shaft, and / or at the shaft's distal end, an electrode mechanism, including: (a) an electroporation electrode, slidable along the shaft, (b) a spring, attached to the electrode at a first spring-end, and fixed, at a second spring-end, to the shaft, the spring biases the electrode to rest distally; and / or (c) a stopper, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end; configured: (i) to limit spring extension, and / or (ii) to slide along with the electrode. For some implementations, at the shaft's proximal end, the extracorporeal unit is operatively coupled to the electrode mechanism, the extracorporeal unit including a connector, electrically connected to the electroporation electrode. For some implementations, the pulse generator includes a terminal to which the connector is connectable, the pulse generator is configured to apply, via the connector connected to the electrode, electroporation pulses transvascularly to the tumor. For some implementations, the extracorporeal unit is configured to slide the electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

[0185] For some implementations, the electrode is proximal from the stopper and the spring is extended, closing the gap.

[0186] For some implementations, the stopper is proximal from the electrode and the spring is compressed, opening the gap.

[0187] For some implementations, the tool further includes a centering mechanism proximally from the electrode mechanism along the shaft, the centering mechanism is configured to bias the electrode medially away from a wall of the blood vessel, and the electrode sliding actuates the centering mechanism.

[0188] For some implementations: (i) the system further includes a second electroporation electrode proximally from the centering mechanism along the shaft, (ii) the connector is a first connector, (iii) the extracorporeal unit is operatively coupled to the second electrode and including a second connector that is connectable to the terminal and electrically connected to the second electroporation electrode; and / or (iv) the pulse generator is configured to apply, via the second connector connected to the second electrode, electroporation pulses transvascularly to the tumor.

[0189] For some implementations, the spring and the electrode are formed from a single material such that the spring serves as a continuation of the electrode in applying electroporation pulses to the tumor.

[0190] For some implementations, the stopper and the electrode are formed from a single material such that the stopper serves as a continuation of the electrode in applying electroporation pulses to the tumor.

[0191] For some implementations, the entire electrode mechanism is formed from a single material such that the entire electrode mechanism serves as the electrode in applying electroporation pulses to the tumor.

[0192] The present invention will be more fully understood from the following detailed description of applications thereof, taken together with the drawings, in which:BRIEF DESCRIPTION OF THE DRAWINGS

[0193] Fig. 1 A is a schematic illustration of a tool 101 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0194] Fig. IB is a schematic illustration of a system comprised of tool 101 and a tool 102 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0195] Fig. 2 is a schematic illustration of a tool 103 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0196] Fig. 3 A is a schematic illustration of a tool 104 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0197] Fig. 3B is a schematic illustration of a tool 105 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0198] Fig. 4 is a schematic illustration of a treatment tool 200 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0199] Fig. 5 is a schematic illustration showing a system that includes a treatment tool, in accordance with some implementations;

[0200] Fig. 6 is a schematic illustration showing a system that includes a treatment tool, in accordance with some implementations; and

[0201] Fig. 7 is a flow chart showing at least some steps of a method for transvascular treatment of a tumor of a subject, in accordance with some implementations.

[0202] Fig. 8A is a schematic illustration of a tool 600 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0203] Fig. 8B is a schematic illustration of a tool 600 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0204] Fig. 8C is a schematic illustration of part of a tool 600 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0205] Fig. 8D is a schematic illustration of a tool 650 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0206] Figs. 9A-B are schematic illustrations of a stopping mechanism 681 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0207] Fig. 9C-D are schematic illustrations of a combination configuration 680a for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0208] Fig. 9E-F are schematic illustrations of a combination configuration 680b for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0209] Fig. 9G is a schematic illustration of a combination configuration 691 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0210] Fig. 10A is a schematic illustrations of a tool 700 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0211] Fig. 10B is a schematic illustrations of a tool 750 for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0212] Fig. 11 A is a schematic illustration of a tool 900a for endovascular tissue ablation, in accordance with some embodiments of this invention;

[0213] Fig. 1 IB is a schematic illustration of a tool 900b for endovascular tissue ablation, in accordance with some embodiments of this invention; and

[0214] Fig. 11C is a schematic illustration of a tool 1000 for endovascular tissue ablation, in accordance with some embodiments of this invention.DETAILED DESCRIPTION OF EMBODIMENTS

[0215] The described systems, apparatuses, devices, methods, etc. should not be construed as limiting in any way. Instead, the present disclosure is directed toward all novel and nonobvious features and aspects of the various disclosed implementations and applications, alone and in various combinations and sub-combinations with one another. The disclosed systems, apparatuses, devices, methods, etc. are not limited to any specific aspect, feature, or combination thereof, nor do the disclosed systems, apparatuses, devices, methods, etc. require that any one or more specific advantages be present or problems be solved.

[0216] Reference is made to Figs. 1 A-B, 2, 3A-B, 4, 5, 6, 7, 8A-D, 9A-G 10A-D, and 11 A-C, which are schematic illustrations of various apparatuses and systems for endovascular tissue ablation in accordance with some embodiments of the present invention.

[0217] Figs. 1A-B show a target tissue 4 to be ablated, which is part of a body organ 3. In some embodiments, the target tissue 4 is a tumor. In some embodiments, the body organ 3 is an organ with nearby blood vessels which are endovascularly accessible, for example, the pancreas, the brain, the kidneys, the liver, the lungs.

[0218] Figs. 1 A-B further show a blood vessel 1 and a blood vessel 2, which may supply, drain and / or surround body organ 3 and / or target tissue 4. For example, in implementations in which the body organ is the pancreas, the blood vessels may be the celiac trunk, superiormesenteric artery (MSA), splenic artery, inferior pancreatic artery and / or any other blood vessel in the vicinity of the pancreas.

[0219] An endovascular ablation system may include one or more electrodes attached to one or more catheters, wires and / or shafts designed to be inserted into one or more blood vessels. In some embodiments, the system may include a single electrode and a grounding pad. In some embodiments the system may include more than one electrode on the same catheter, wire or shaft. In some embodiments the system may include one or more electrodes on more than one catheter, wire and / or shaft.

[0220] In some embodiments, the system may include additional guidewires, catheters and / or sheaths for the delivery of the electrodes. For example, a catheter may be navigated into position over a guidewire, and the guidewire may then be removed and replaced with the electrode device which may be positioned and exposed by pulling back the catheter.

[0221] In some embodiments, the system may include a sheath for initial access into the blood vessel, where the blood vessel may be a vein or artery. In some embodiments, the system may additionally or alternatively include a catheter that may be navigated to the desired location. In some embodiments, the system may additionally or alternatively include a guidewire over which the electrodes may be delivered.

[0222] In some embodiments the endovascular ablation system may include a pulse generator. Typically, for such embodiments, the pulse generator is configured to apply high voltage pulses (e.g., unipolar pulses or bipolar pulses) required for electroporation. In some such implementations, each pulse duration is no more than 1 second long, for example no more than 1 millisecond long, for example less than 1 millisecond. For example, the pulse duration may be 50-150 microseconds (e.g., for unipolar pulses) or 0.5-10 microseconds (e.g., for bipolar pulses). Voltages should be sufficient to induce either reversible or irreversible electroporation, for example at least 500V, for example at least 2kV. In some embodiments, the polarity of the voltage may alternate between positive and negative polarities, or alternatively the voltage may also be unipolar in nature. In some embodiments high frequency electroporation may be achieved using bursts of bipolar electric pulses that are under 10 microsecond in duration, for example between 0.5 and 2 microseconds. The use of electroporation may be especially advantageous for endovascular ablation as it typically may be less damaging to the blood vessel itself.

[0223] In some embodiments, the power generator may be used to apply RF energy required for RF ablation, using alternating currents of between 300-600kHz.

[0224] In some embodiments, one or more of the electrodes may be expandable. Having an expandable electrode may be advantageous in order to ensure ablation in the tissue surrounding the blood vessel, both in terms of ablating the entire circumference and in terms of reducing the distance between the electrode and target tissue. In some such implementations, the electrodes may be self-expandable, i.e., the electrodes may automatically expand once unsheathed.

[0225] In some embodiments, one or more of the expandable electrodes may be detachable from a delivery tool of the system. Having an expandable and detachable electrode may be advantageous as it may allow for maintenance of the patency of the blood vessel after the ablation. For example, in some implementations, there may be damage to (e.g., occlusion of) the blood vessel as a result of the ablation, and the detached electrode may maintain the blood vessel open. In some such implementations, the detached electrode can act as a stent within the blood vessel post-ablation.

[0226] An exemplary endovascular ablation system that comprises a tool 101 is shown in Fig. 1A. Tool 101 comprises an expandable electrode 5, a detachment mechanism 6 and a delivery shaft 7. A distal part of tool 101 is adapted to be advanced into a blood vessel, e.g., blood vessel 1.

[0227] In some embodiments, expandable electrode 5 may be in the form of a stent, mesh or coil. In some embodiments, the expanded diameter of electrode 5 is oversized in comparison with the target blood vessel diameter. For example, it may have an expanded diameter of above 5mm. In some embodiments the exposed length of electrode 5 may be more than 10mm but less than 100mm, for example less than 50mm. In some embodiments the electrode may be constructed of a biocompatible conductive material, or combination of materials, such as, nitinol, stainless steel, Platinum, Iridium, Gold, Tungsten, etc.

[0228] In some embodiments, detachment mechanism 6 may be a mechanical mechanism which enables release of the expandable electrode 5 from the shaft 7.

[0229] In some embodiments, shaft 7 includes means to deliver electric currents to electrode 5. For example, an insulated wire, braid or coil that is connected to electrode 5 on one end and to a terminal allowing connection to a power generator (not shown here).

[0230] In some embodiments, tool 101 may also include an external grounding pad and the ablation energy may be passed between electrode 5 and the grounding pad.

[0231] Reference is now made to Fig. IB, which is a schematic illustration of a system for endovascular tissue ablation in accordance with some embodiments of the present invention.

[0232] The system is comprised of 2 electrodes which are inserted endovascularly. In some embodiments, the first electrode is positioned in a first blood vessel 1 in close proximity, adjacent to or in direct contact with the target tissue 4 and the second electrode may be positioned in a second blood vessel 2 in close proximity, adjacent to or in direct contact with the target tissue 4 at an opposing side. In some embodiments, the second electrode may be at a larger distance from the target tissue than the first electrode. In some embodiments, the second electrode may have a larger surface area than the first electrode.

[0233] Having a larger surface area on one electrode may be advantageous as it may allow to concentrate the ablation energy to specific regions. For example, having the smaller electrode near the target tissue may cause higher intensity electric fields surrounding it in comparison with the larger electrode.

[0234] For example, as shown in Fig. IB, the system may be comprised of tool 101 described above, and tool 102 which is similar to tool 101 but with electrode 8 instead of electrode 5. Electrode 8 differs from electrode 5 in that it may have a larger surface area than electrode 5. For example, it may be of a similar structure but longer. Alternatively or additionally, it may be denser, for example, a coil with a tighter pitch or a stent or mesh with additional struts or intersections. In some embodiments the surface area of electrode 8 is at least 1.5 larger than that of electrode 5, for example at least 3 times larger than that of electrode 5. The ablation energy may be delivered between the electrode of tool 101 and the electrode of tool 102.

[0235] Reference is now made to Fig. 2, which is a schematic illustration of tool 103 for endovascular tissue ablation in accordance with some embodiments of the present invention.

[0236] Tool 103 include a shaft 9, a first electrode 12, a second electrode 10 and an insulation 11 between the electrodes.

[0237] In some embodiments the electrodes may be constructed of a biocompatible conductive material, or combination of materials, such as nitinol, stainless steel, Platinum, Iridium, Gold, Tungsten, etc. In some embodiments, the surface area of the second electrodeis larger than that of the second electrode. In some embodiments there are more than 2 electrodes mounted on the shaft.

[0238] In some embodiments, the ablation energy is delivered between the electrodes mounted on the shaft.

[0239] In some embodiments the shaft is hollow and allows passage of guidewire or injection of liquids.

[0240] Reference is now made to Fig. 3A-B, which are schematic illustrations of tool 104 and 105 for endovascular tissue ablation in accordance with some embodiments of the present invention.

[0241] Tool 104 includes a shaft 16, a first tine electrode 14, a second tine electrode 15 with their respective proximal segments 14p and 15p.

[0242] In some embodiments the tine electrodes may be constructed of a biocompatible conductive material, or combination of materials, such as nitinol, stainless steel, Platinum, Iridium, Gold, Tungsten, etc. In some embodiments, the exposed surface area of the second electrode is larger than that of the first electrode. In some embodiments there are more than 2 tine electrodes mounted on the shaft. In some embodiments the tool includes only one tine electrode.

[0243] In some embodiments, the proximal segments of the tine electrode (14p and 15p) may be electrically insulated. In some embodiments a distal segment of the electrodes is electrically insulated.

[0244] In some embodiments, each tine electrode may be selectively activated, and the ablation energy may be delivered between them. In some embodiments, the ablation energy may be delivered between one or more of the tine electrodes and a separate electrode, for example an external grounding pad or a separate endovascularly positioned electrode.

[0245] Tool 105 is similar to tool 104 and includes a balloon 17 that provides additional electrical insulation surrounding the electrodes. The use of the balloon may be beneficial in focusing the electric fields on the target areas and / or improving the contact between the electrode and blood vessel.

[0246] In some embodiments there may be one electrode. In some embodiments, the tool may be rotated in order to selectively choose the ablation area.

[0247] In some embodiments, any of the above-mentioned systems may be combined with the systemic or targeted delivery of therapeutics. For example, the delivery of chemotherapy before, after and / or during the ablation. Targeted delivery may be advantageous in order to reduce the overall toxicity and increase the potential damage to the target tissue.

[0248] In some embodiments, the delivery of the targeted therapeutics may be into the blood vessels in which the electrodes were activated, branches thereof and / or a more proximal segment of it. Since the target tissue has been endovascularly accessed using the endovascular ablation systems described above, the targeted delivery of therapeutics is made simpler. In addition, the target tissue may be more sensitive during and after the ablation procedure, increasing the effectiveness of the drugs. For example, certain areas of the target tissue may be affected by reversible electroporation which enhances their sensitivity.

[0249] In some embodiments, large volumes of reversible electroporated tissue may be desirable in order to effectively treat the target organ with the therapeutics.

[0250] A method to endovascularly treat a tumor is described in accordance with some embodiments of the present invention.

[0251] A first electrode may be endovascularly introduced and positioned in proximity to a target tumor. In some embodiments a second electrode may be delivered into the same or a second blood vessel. Alternatively, or additionally, a grounding pad may be used. Alternatively, or additionally, additional electrodes may be used and introduced into the same and / or additional blood vessels.

[0252] In some embodiments the second electrode, and / or any of the additional electrodes may have a larger surface area than the first electrode.

[0253] In some embodiments the distance between the tumor and the first electrode is smaller than the distance between the tumor and the second electrode.

[0254] In some embodiments, multiple electrodes may be inserted over the same shaft.

[0255] In some embodiments one or more of the electrodes may be expandable. In some embodiments, one or more of the electrodes may be detachable.

[0256] After positioning the one or more electrodes endovascularly, ablation energy may be delivered. In some embodiments, RF ablation may be used. In some embodiments electroporation may be used.

[0257] In some embodiments, the operator may detach one or more of the electrodes after completing the ablation. In some embodiments, the operator may reconnect with the detached electrode to repeat the ablation or remove it.

[0258] In some embodiments, systemic and / or targeted delivery of therapeutics may be administered before, after and / or during the ablation. For example, the delivery of chemotherapy.

[0259] In some embodiments, the ablation may be repeated in one or more blood vessels. In some embodiments, the ablation may be repeated in one or more segments of the same blood vessel.

[0260] A method to endovascularly treat a tumor is described in accordance with some embodiments of the present invention. The method may include a first step of systemic administration of therapeutics, for example intravenous administration of chemotherapy. A second step of the method may include performing endovascular electroporation to induce either reversible electroporation, irreversible electroporation, or combination thereof. A third step of the method may include a local administration of therapeutics, for example a local injection of chemotherapy into the area of the tumor.

[0261] In some embodiments, the endovascular electroporation is followed by surgical resection of the treated tissue. In some embodiments, the surgical resection is performed within a time window of 2-10 weeks following the endovascular electroporation.

[0262] In some embodiments, the method may be performed without the systemic administration of therapeutics. Additionally, or alternatively, systemic administration of therapeutics may be performed during and / or after the ablation procedure.

[0263] In some embodiments, the local administration of therapeutics may be performed before, during and / or after the ablation procedure.

[0264] In some embodiments, the endovascular ablation may be performed in an artery supplying the tumor and the local administration of therapeutics may be by means of the endovascular ablation system or catheters used to position it.

[0265] In some embodiments, the target tissue may be the entire affected organ, in order to reduce the chance of metastasis.

[0266] Reference is made to Fig. 4, which is a schematic illustration showing a treatment tool 200, in accordance with some implementations. In some implementations, and asshown, tool 200 comprises a pair of electrode assemblies 201, 202 that are advanced transluminally (e.g., transvascularly) to a site of an organ 3, such as a tumor 4. Typically for such implementations, electrode assemblies 201, 202 each comprise an electroporation electrode 205. Fig. 4 shows electroporation electrodes 205 positioned to electroporate cells of tumor 4 by transvascularly driving electroporation pulses between the electrodes.

[0267] In some implementations, electrodes 205 are similar to electrode 5 of tool 101 described hereinabove with reference to Fig. 1 A, mutatis mutandis. Alternatively, one of the electrodes can have a greater surface area than the other electrode, e.g., similarly to respective electrodes 5, 8 of tool 101 and tool 102 described hereinabove with reference to Fig. IB. In some implementations, electrodes 205 are endovascularly expandable and / or detachable from shaft 7 (e.g., via detachment mechanism 6, as shown), similarly to electrode 5 of tool 101 described hereinabove.

[0268] Fig. 4 shows each electrode 205 having been advanced through a respective blood vessel 1, 2, e.g., such that the electrodes are each on opposite sides of organ 3. This is for illustrative purposes only, and electrodes may be intravascularly advanced through respective blood vessels 1, 2 within organ 3, e.g., on opposite sides of tumor 4.

[0269] In some implementations, and as shown, each electrode 205 is transluminally advanced by advancing a flexible shaft 207 to which electrode 205 is attached, e.g., at a distal part 209 of the shaft. In some such implementations, each shaft 207 is transluminally advanced (e.g., independently of the other shaft) through respective blood vessels 1, 2, such that driving a series of electroporation pulses transvascularly between electrodes 205 electroporates cells of tumor 4.

[0270] In some implementations, distal parts 209 of shafts 207 can both be advanced within the same blood vessel (not shown). In some such implementations, electrodes 205 are disposed on a unitary shaft, such as shaft 16 of tool 104 shown above in Fig. 3 A, such that advancing the unitary shaft positions each electrode at a respective intravascular site within organ 3. For example, each electrode 205 may be moveable independently of each other. Alternatively, electrodes 205 may be fixed with respect to each other.

[0271] In some implementations, and as shown in Fig. 4, tool 200 comprises a pulse generator 251 (e.g., housed within an extracorporeal unit 250). Typically for such implementations, pulse generator 251 comprises a pair of terminals 254 that are each electrically connected to electrode assemblies 201, 202 by a respective connector 252, e.g.,at each electrode assembly's proximal part 256. In this way, pulse generator 251 extracorporeally supplies current to drive a series of electroporation pulses between electrodes 205. In some such implementations, distal part 209 of each shaft 207 is steerable by actuating each electrode assembly's proximal part 256, e.g., by operating unit 250, thereby extracorporeal steering electrodes 205 into position.

[0272] In some implementations, the system includes a tool, that includes a flexible shaft. The shaft includes, at a distal part of the shaft, an applicator, advanceable into the blood vessel. The applicator includes an expandable first electroporation electrode, expandable into contact with a wall of the blood vessel; and a second electroporation electrode, configured such that expansion of the first electroporation electrode into contact with the wall positions the second electroporation electrode medially from the wall. The shaft further includes, at a proximal part of the shaft, a connector assembly. The connector assembly includes a first connector, electrically connected to the first electroporation electrode; and a second connector, electrically connected to the second electroporation electrode.

[0273] The system further includes a pulse generator, including a first terminal to which the first connector is connectable, and a second terminal to which the second connector is connectable. The system is configured to electroporate cells of the tumor by, via the first terminal connected to the first connector and the second terminal connected to the second connector, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between (i) the first electroporation electrode in contact with the wall, and (ii) the second electroporation electrode disposed medially from the wall.

[0274] For example, and as shown in Fig. 5, the system may include a treatment tool 300. The system may also include a pulse generator 350. Tool 300 includes a pair of electrode assemblies 301, 302 transluminally (e.g., transvascularly) advanced through a blood vessel such as blood vessel 307. Typically for such implementations, electrode assemblies 301, 302 each comprise an electroporation electrode 303 and 304, respectively. Fig. 5 shows electroporation electrodes 303 and 304 positioned to electroporate cells of the tissue surrounding blood vessel 307 by transvascularly driving electroporation pulses 390 between the electrodes.

[0275] Electrode 303 is expandable, such that it may be delivered in a collapsed state to the target site and expanded at the target site. The electrode may either be self-expandable, i.e. delivered inside or through an additional catheter or sheath (not shown in the figure) andunsheathed once positioned at the desired location, or expanded by the user using an expansion mechanism, such as a variety of pull-wires or an inflatable balloon. Electrode 303 is connected to electrode delivery shaft 306 through which the electric wiring is passed to the proximal end of the device (not shown).

[0276] In some embodiments only part of the expandable portion is electrically exposed in order to focus the ablation energy only to a specific segment of the electrode, for example, only to length marked as L3 which may be shorter than 30mm, such as shorter than 10mm in length. In some embodiments the exposed section reaches the distal end of electrode 303.

[0277] While it is shown by example that electrode 303 is expanded to a diameter smaller than the diameter of the blood vessel 307, it may be beneficial to have it expand to the diameter of the blood vessel such that there is good electrical contact between the two, or even apply radial forces against the blood vessel such that the blood vessel may be stretched towards the target tissue. In some embodiments, the radial force may be achieved by oversizing the expandable electrode in comparison with the blood vessel diameter, such as that it may have in its relaxed state (no radial constrains) a diameter greater than 10%, and for example more than 30%, than the diameter of the blood vessel.

[0278] While it is shown by example that electrode 303 may have or be stent shape, the first electrode may have a helical shape.

[0279] Electrode assembly 301 may be hollow to allow passage of electrode assembly 302 through it. Electrode assembly 302 itself may also be hollow to allow passage of additional tool or injection of therapeutic materials.

[0280] Electrode assembly 302 is comprised of electroporation electrode 304 that is connected to electrode delivery shaft 306 through which the electric wiring is passed to the proximal end of the device (not shown). Electrode 304 is shown in this example to be nonexpandable and cover length longer than the exposed segment of electrode 303 (L3). For example, the length of electrode 304 may be 50% greater than L3, such as at least twice as long. The overall surface area of electrode 304 may also be greater than that of exposed electrode 303, for example more than 50% greater. This may be beneficial in cases where the operator may want to have ablation energy penetrate deeper towards the surrounding of electrode 303.

[0281] Having electrode 304 be non-expandable and positioned through and distal to an expandable element such as electrode 303 may allow avoiding unwanted damage to tissuesurrounding electrode 304 in case focal treatment surrounding electrode 303 is desired, as it is positioned at the center of the blood vessel, further away from the surrounding tissue. This configuration may also be more optimal in term of cooling electrode 304 due to the larger contact with blood flowing surrounding it (in comparison with the case where it where in complete contact with the blood vessel).

[0282] Reference is made to Fig. 6, which is a schematic illustration showing a treatment tool 400, in accordance with some implementations. In some implementations, and as shown, tool 400 comprises a pair of electrodes 403, 404 that are advanced transluminally (e.g., transvascularly) a blood vessel such as blood vessel 407.

[0283] Electrode 401 is connected to electrode delivery shaft 406 through which the electric wiring is passed to the proximal end of the device (not shown). Electrode 403 is shown to be connected to electrode delivery shaft 406’ through which the electric wiring is passed to the proximal end of the device (not shown).

[0284] Electrode delivery shaft 406’ may be part of electrode delivery shaft 406 or a separate shaft that is passed through it. The electrode delivery shafts may be movable in relation to one another or fixed.

[0285] Fig. 6 shows electrode 403 to be expandable, such that it may be delivered in a collapsed state to the target site and expanded at the target site. The electrode may either be self-expandable, i.e. delivered inside or through an additional catheter or sheath (not shown in the figure) and unsheathed once positioned at the desired location, or expanded by the user using an expansion mechanism, such as a variety of pull-wires or an inflatable balloon.

[0286] Treatment tool 400 may include an internal lumen for the delivery of tools or therapeutic agents. Electrode 404 is shown in this example to be non-expandable and cover length longer than the exposed segment of electrode 403. The overall surface area of electrode 404 may also be greater than that of exposed electrode 403, for example more than 50% greater. This may be beneficial in cases where the operator may want to have ablation energy penetrate deeper towards the surrounding of electrode 403.

[0287] While in this example electrode 404 is shown to be non-expandable, it may be expandable as well. While it is shown by example that electrode 403 is expanded to a diameter smaller than the diameter of the blood vessel 407, it may be beneficial to have it expand to the diameter of the blood vessel such that there is good electrical contact between the two, or alternatively even apply radial forces against the blood vessel such that the bloodvessel may be stretched towards the target tissue. In some embodiments, the radial force may be achieved by oversizing the expandable electrode in comparison with the blood vessel diameter, such as that may have in its relaces state (no radial constrains) a diameter greater than 10%, and for example more than 30%, than the diameter of the blood vessel.

[0288] With reference again made to Figs. 5-6, the following description of the system shown therein may be considered to be an alternative description of the same systems in accordance with some implementations, or may be considered to be a description of alternative implementations of the systems:

[0289] Fig. 5 is a schematic illustration showing a system that includes a treatment tool 300, in accordance with some implementations. The system may also include a pulse generator 350. In some implementations, and as shown, tool 300 comprises a flexible shaft 320 and, at a distal part of the shaft, an applicator 305 that is advanceable into a blood vessel 307. Fig. 5 shows applicator 305 having been advanced to an intravascular site within blood vessel 307 adjacent to a tumor 370.

[0290] Applicator 305 may comprise a first electroporation electrode 303, which may be a component of a first electrode assembly 301. Electrode assembly 301 may further comprise a shaft (not shown) on which electrode 303 is mounted, and via which electrode 303 is manipulable. Applicator 305 may alternatively or additionally comprise a second electroporation electrode 304, which may be a component of a second electrode assembly 302. Electrode assembly 302 may further comprise a shaft 306 on which electrode 304 is mounted, and via which electrode 304 is manipulable.

[0291] Electrode assemblies 301 and 302 may be axially movable with respect to each other - e.g. by sliding shaft 306 with respect to electrode assembly 301. For example, shaft 306 may extend through electrode 303 (and / or the shaft on which electrode 303 is mounted). In the example shown, this is facilitated by electrode 303 being hollow (e.g. tubular).

[0292] Electrode 303 may be expandable, such that it can be delivered in a collapsed state to the blood vessel where it is expanded at the intravascular site. In some implementations, electrode 303 is self-expanding - e.g. is delivered constrained within shaft 320, and unsheathed once positioned at the intravascular site where it expands responsively to being unsheathed. In some implementations, electrode 303 is actively expanded using an expansion mechanism, such as pull-wires or a balloon. Electroporation electrode 303 isconfigured (e.g. dimensioned) such that its expansion places it into contact with a vascular wall 308 (i.e. an inner surface) of blood vessel 307.

[0293] In some implementations, applicator 305 is configured to be driven to apply electroporation energy (e.g. pulses) 390 through vascular wall 308 while electrode 303 is in contact with the vascular wall (e.g. has been expanded into contact with the vascular wall). In some such implementations, applicator 305 is configured to be driven to apply electroporation energy (e.g. pulses) 390 through vascular wall 308 while electrode 304 is positioned medially from the vascular wall and / or is not in contact with the vascular wall. That is, applicator 305 may have a working state in which electrode 303 is expanded into contact with vascular wall 308, and electrode 304 is positioned medially from the vascular wall.

[0294] In some implementations, applicator 305 is configured such that expansion of electrode 303 into contact with the vascular wall positions electrode 304 medially from the vascular wall. This may be mediated by the relative positions and / or dimensions of electrodes 303 and 304, and / or stiffness of shaft 306.

[0295] In some implementations, electrode 304 has a greater surface area (e.g. effective surface area) than electrode 303. In some implementations, electrode 304 has a greater axial length than electrode 303. Such configurations may advantageously shape the field of the electroporation pulses 390 to have (i) greater charge / energy density in the vicinity of electrode 303, which is positioned adjacent to the vessel wall 308, opposite which tumor 370 is located, thereby focusing the electroporation effect on the tumor, and (ii) lesser charge / energy density in the vicinity of electrode 304, which is positioned within the bloodstream, thereby weakening the electroporation effect on the blood and / or other tissues remote from the tumor.

[0296] In some implementations, the electroporation charge / energy is radial / circumferential, unidirectional, multidirectional and / or omnidirectional.

[0297] In some implementations, a first connector 360 is electrically connected to the first electroporation electrode 303, and a second connector 362 is electrically connected to the second electroporation electrode 304.

[0298] In some implementations, a pulse generator 350 comprises a first terminal 352 to which the first connector 360 is connectable, and a second terminal 354 to which the second connector 362 is connectable. The pulse generator 350 is configured to electroporate cells ofthe tumor by, via the first terminal 352 connected to the first connector 360 and the second terminal 354 connected to the second connector 362, applying electroporation pulses 390 transvascularly to the tumor by driving the electroporation pulses between (i) the first electroporation electrode 303 in contact with the vascular wall 308, and (ii) the second electroporation electrode 304 disposed medially from the vascular wall 308.

[0299] As noted hereinabove, tool 300 may be configured and / or used to electroporate a tumor that is proximate and / or associated with (e.g. connected to) a blood vessel. Electroporation of such a tumor may be performed prior to resecting the tumor. For example, tool 300 may be configured and / or used to increase the possibility and / or likelihood of success of resection of such a tumor - e.g. disassociating (e.g. disconnecting) the tumor, or at least live cells thereof, from the blood vessel. This may be described as creating a margin 372 between the blood vessel and the tumor. In some cases, this may convert a tumor from being inoperable to operable.

[0300] In some implementations, only part of the expandable portion is electrically exposed, in order to focus the energy of electroporation pulses 390 only to a specific segment of the electrode - i.e. changing the effective length of the electrode. That is, electrode 303 may have adjustable axial length.

[0301] For example, as shown in Fig. 5, a length L3 of electroporation electrode 303 is exposed, although the electrode may in fact be longer (e.g. continuing into sheath 320). Length L3 may, for example, be shorter than 30 mm, such as shorter than 10mm in length. In some implementations the exposed section reaches the distal end of electrode 303.

[0302] Fig. 6 is a schematic illustration showing a system that includes a treatment tool 400, in accordance with some implementations. In some implementations, this system (e.g. tool 400 thereof) may be as described for the system of Fig. 5 (e.g. tool 300 thereof), mutatis mutandis, except where noted. In particular, the arrangement of the electrodes of an applicator 405 of tool 400 is different to that of applicator 305 of tool 300 - e.g. their axial positions are switched. That is, electrode 403 is the expandable and / or smaller electrode of tool 400 (e.g. corresponding to electrode 303 of tool 300, mutatis mutandis), and is distal to electrode 404, which is the medially-positioned and / or larger electrode of tool 400 (e.g. corresponding to electrode 304 of tool 300, mutatis mutandis). For example, and as shown, whereas electrode assembly 301 of tool 300 is slidable over shaft 306 of electrode assembly 302, electrode assembly 401 (of which electrode 403 is a component) is slidable within ashaft 406 of electrode assembly 402 (of which electrode 404 is a component). In the example shown, this is facilitated by electrode 404 and shaft 406 being hollow (e.g. tubular).

[0303] There is therefore provided, in accordance with some implementations, a method for transvascular treatment of a tumor in an organ of a subject, the method comprising (i) endovascularly advancing an applicator (e.g. applicator 305 or 405) to an intravascular site adjacent the tumor; (ii) at the intravascular site, expanding a first electrode of the applicator (e.g. electrode 303 or 403) into contact with a vascular wall; (iii) at the intravascular site, positioning a second electrode of the applicator (e.g. electrode 304 or 404) medially from the vascular wall; and / or (iv) while the applicator remains at the intravascular site, applying electroporation pulses (e.g. pulses 390) transvascularly to the tumor by driving the electroporation pulses between the first electrode and the second electrode.

[0304] Fig. 7 is a flow chart showing at least some steps of a method 500 for transvascular treatment of a tumor of a subject, in accordance with some implementations. Method 500 comprises a margin clearance step 520 in which electrodes are endovascularly advanced to an intravascular site adjacent to a tumor, and driving the electrodes to apply a series of electroporation pulses from intravascular site transvascularly to the tumor. For example, this step may create and / or enlarge a margin between the tumor and the blood vessel in which the electrodes are disposed - e.g. as described hereinabove. Subsequently, in a determination step 530, the effect that the electroporation pulses had on the tumor is determined - e.g. using imaging techniques. For example, the presence and / or extent (e.g. width) of a margin between the tumor and the blood vessel may be determined - e.g. to determine whether step 520 was successful. Responsively to this determination, the subject may be identified as being a candidate for resection of the tumor (or at least some of the tumor). For example, the subject may be referred for resection surgery. If the subject was identified as a candidate for resection, then a resection step 540 may take place, where at least some of the tumor is resected.

[0305] If in determination step 530 it was determined a margin was not cleared (or that it is insufficient) then margin clearance 520 may be repeated. Steps 520 and 530 may continue iteratively until the subject becomes a candidate for resection step 540.

[0306] In some implementations, resection step 540 is performed immediately subsequently to determination step 530 - e.g. by the same physician and / or in the samemedical facility. Alternatively, resection step 540 may be performed at a later date, by a different physician, and / or at a different medical facility.

[0307] In some implementations, prior to margin clearance step 520 a chemotherapy step 510 is performed - e.g. intravenous administration of a systemic anticancer chemotherapeutic agent. In some implementations, chemotherapy step 510 is performed immediately prior to margin clearance step 520 - e.g. by the same physician and / or in the same medical facility. Alternatively, chemotherapy step 510 may be performed at a later date, by a different physician, and / or at a different medical facility.

[0308] In some implementations the electroporation of step margin clearance 520 is a reversible electroporation.

[0309] In some implementations the electroporation of step margin clearance 520 is an irreversible electroporation.

[0310] In some implementations, the tool and techniques described with reference to Figs.5-7 may be particularly advantageous when used on a stage 2 tumor, a stage 3 tumor, a pancreatic tumor and / or a locally advanced tumor. For example, these techniques may convert an inoperable tumor (e.g. one that cannot be resected due to proximity and / or association with a blood vessel) into an operable tumor.

[0311] Reference is now made to Fig. 8A-D, which are schematic illustrations of tools 600 and 650 for endovascular tissue ablation in accordance with some embodiments of the present invention.

[0312] Fig. 8A is schematic illustration of an applicator 609 of tool 600. Applicator 609 includes a pair of electrode assemblies 601 and 602, and is configured to be advanced transluminally (e.g., transvascularly) into a blood vessel. Typically for such implementations, each of electrode assemblies 601 and 602 comprises a respective electroporation electrode 603 and 604.

[0313] Tool 600 further includes a flexible shaft 606, and applicator 609 is disposed at a distal part of the shaft. A first conductive wire (not visible) extends along the shaft through a lumen 620, and a second conductive wire 618 extends along the shaft through a lumen 622. Tool 600 may further comprise a dilator 630 that serves as a distal tip. Shaft 606 defines an axial axis along the shaft.

[0314] Tool 600 comprises a centering mechanism 605. Centering mechanism 605 comprises an expandable structure 607. In some implementations, and as shown, expandable structure comprises or defines a plurality of axial ribs 608. Fig. 8 A shows the ribs having low profile such that they are substantially flat against shaft 606, for advancement through the vasculature. This may be considered a delivery state of tool 600. The centering mechanism is reversibly expandable into a centering state (Fig. 8B) in which the ribs bend radially outwardly away from the shaft to contact the vascular wall. The centering mechanism is re-contractable.

[0315] In some implementations, and as shown, centering mechanism 605 is disposed axially between electrode 603 and electrode 604. Electrode 604 is slidably mounted on shaft 606, and serves as an actuator of the centering mechanism such that sliding electrode 604 proximally along the shaft toward electrode 603 (e.g. as indicated by the bold arrow in Fig.8B) expands expandable structure 607 into contact with the vascular wall.

[0316] Wire 618 is mechanically attached to electrode 604, and is slidable axially within shaft 606, such that expandable structure 607 is expandable by electrode 604 being slid proximally along the shaft toward electrode 603 via pulling of the wire proximally - e.g. from an extracorporeal portion or handle of tool 600. Wire 618 may therefore be sufficiently strong in tension to achieve this functionality. Thus, wire 618 may have two functions: (1) electrical conduction for electrode 604, and (2) mechanical sliding of electrode 604.

[0317] Furthermore, centering mechanism 605 may be medially contractible (e.g. returnable to its delivery state) by electrode 604 being slid distally along shaft 606 away from electrode 603 via pushing wire 618 distally.

[0318] In some implementations, electrode 604 may be considered to be a mechanical actuator of expandable structure 607.

[0319] Fig. 8B is schematic illustration of tool 600 when centering mechanism 605 is expanded, in accordance with some implementations. Electrode 604 is pulled back such that ribs 608 are bent radially outwardly away from shaft 606 such that they are able to contact the vascular wall. Electrode 604 is pushable by wire 618 such that it slides distally from electrode 603, contracting expandable structure 607 to have ribs 608 go back to low profile being substantially flat against the shaft.

[0320] In some implementations, and as shown, wire 618 is routed such that it exits its lumen 622 through a port 614, to where it is affixed to electrode 604.

[0321] Fig. 8D is schematic illustration of a tool 650 where the tool includes a third electroporation electrode, electrode 610, slidably mounted on the shaft axially between electrodes 603 and 604. Tool 650 may be as described for tool 600 except where noted. Expandable structure 607 is a first expandable structure, and is disposed axially between electrodes 610 and 604. Centering mechanism 605 further comprises a second expandable structure 607a with ribs 608a, that perform similarly to expandable structure 607, disposed axially between the electrodes 603 and 610, such that sliding electrode 604 proximally along shaft 606 toward the electrodes 610 and 603: (i) expands expandable structure 607 into contact with the vascular wall, and (ii) slides electrode 610 proximally along the shaft toward electrode 603 in a manner that also expands expandable structure 607a.

[0322] Reference is made to Figs. 9A-B, which are schematic illustrations showing an electrode mechanism 681, in accordance with some embodiments of the present invention.

[0323] Electrode mechanism 681 includes an electrode 682. Electrode mechanism 681 further includes a spring 684, attached to electrode 682 at a first spring-end, and fixed, at a second spring-end, to a fixed point with an anchor 686. The spring biases the electrode to rest distally. Electrode mechanism 681 further includes a stopper 688, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end. The stopper is configured: (i) to limit spring extension, and (ii) to slide along with the second electrode.

[0324] Spring 684, anchor 686 and stopper 688 collectively can be referred to as a stopping mechanism.

[0325] Reference is made to Figs. 9C-F, which are schematic illustrations of a combination configuration 680a and 680b for endovascular tissue ablation, in accordance with some embodiments of the present invention.

[0326] In some implementations, electrode mechanism 681 is combined with an expandable structure, such as an expandable structure 690. Electrode mechanism 681 and expandable structure 690 define a combination configuration.

[0327] In some implementations, the combination configuration is part of a tool for endovascular tissue ablation, such as tool 600 (e.g. Figs. 8A-B). In such implementations, electrode mechanism 681 replaces electrode 404 and expandable structure 690 replaces expandable structure 607, in tool 400. Anchor 686 fixes second spring-end of spring 684 to a shaft696. First spring-end of spring 684 is slidable, with electrode 682 and stopper 688,along shaft 696. The electrode mechanism is configured to stop the sliding of electrode 404 proximally along shaft 696 at a maximal displacement defined by a gap between stopper 688 and the second spring-end of spring 684.

[0328] In some implementations, the combination configuration, as in combination configuration 680a, is such that electrode mechanism 681 is connected to expandable structure 690 via electrode 682. At rest, when electrode 682 rests distally, the spring is compressed and expandable structure 690 is contracted. When electrode 682 is slid along shaft 696, spring 684 is extended and expandable structure 690 is thereby expanded until stopper 688 closes the gap.

[0329] In some implementations, the combination configuration, as in combination configuration 680b, is such that electrode mechanism 681 is connected to expandable structure 690 via stopper 688. At rest, when electrode 682 rests distally, spring 684 is extended to the maximal displacement allowed by the stopper, and expandable structure 690 is contracted. When electrode 682 is slid along shaft 696, spring 684 is compressed, thereby opening the gap between spring 684 and stopper 688, and expandable structure 690 is thereby expanded.

[0330] Reference is made to Fig. 9G, which is a schematic illustration of a combination configuration 691 for endovascular tissue ablation, in accordance with some embodiments of the present invention.

[0331] In some implementations, a combination configuration, such as combination configuration 691 includes electrodes 693 and 694, and electrode mechanism 681. Combination configuration 691 further includes expandable structures 690a and 690b, wherein the electrode mechanism connects expandable structures 690a and 690b. The expandable structures and the electrode mechanism connect electrodes 693 and 694. This combination configuration can replace the electrodes and expandable structures of tool 650, described hereinabove and shown in Fig. 8D, wherein electrode 693 and 694 replace electrodes 603 and 604 respectively, expandable structures 690a and 690b replace expandable structures 607 and 607a respectively, and electrode mechanism 681 replaces electrode 610. Sliding electrode 682 proximally along a shaft 698 expands expandable structures 690a, and sliding electrode 694 proximally along shaft 698 expands expandable structures 690b.

[0332] In some implementations, electrode mechanism 681 in combination configuration 691 is a first electrode mechanism, and electrode 694 is replaced by a second electrode mechanism.

[0333] In some implementations, the spring and the electrode of the electrode mechanism are formed from a single material such that the spring serves as a continuation of the electrode in applying electroporation pulses to the tumor. In some implementations, the stopper and the electrode of the electrode mechanism are formed from a single material such that the stopper serves as a continuation of the electrode in applying electroporation pulses to the tumor. In some implementations, the entire electrode mechanism is formed from a single material such that the entire electrode mechanism serves as the electrode in applying electroporation pulses to the tumor.

[0334] Reference is now made to Figs. 10A-B, which are schematic illustrations of tools 700 and 750 for endovascular tissue ablation in accordance with some embodiments of the present invention.

[0335] Fig. 10A is a schematic illustration of an applicator 710 of a tool 700. Applicator 710 includes a pair of electrode assemblies 701 and 702 and is configured to be advanced transluminally (e.g., transvascularly) into a blood vessel. Typically for such implementations, each of electrode assemblies 701 and 702 comprises a respective electroporation electrode 703 and 704.

[0336] Tool 700 further includes a flexible shaft 706, and applicator 710 is disposed at a distal part of the shaft. A first conductive wire and a second conductive wire (not visible) extend along the shaft. Shaft 706 defines an axial axis along the shaft.

[0337] Tool 700 further comprises a centering mechanism 705. Centering mechanism 705 comprises a balloon 707. Balloon 707 may be configured to: (i) expand into contact with a vascular wall 709 of a blood vessel 708, and (ii) while expanded, to prevent blood flow through the blood vessel.

[0338] Centering mechanism 705 may be reversibly expandable into a centering state. Centering mechanism 705 may further be reversibly contractable out of the centering state. When the centering mechanism is contracted, blood may flow through the blood vessel.

[0339] In some implementations, centering mechanism 705 is self-expandable. In some implementations, centering mechanism 705 expands by rotating the centering mechanism in one direction, and retracts, after expanding, by rotating in an opposite direction.

[0340] In some implementations, centering mechanism 705 expands via inflation of balloon 707. In some implementations, the centering mechanism is configured to become stable upon inflation even in an absence of maintenance of inflation pressure. In some implementations, the centering mechanism is configured to be deflated via application of a vacuum. In some implementations, the centering mechanism is configured to deflate in an absence of maintenance of inflation pressure.

[0341] In some implementations, electrode 703 is proximal and electrode 704 is distal, and centering mechanism 705 is disposed axially between electrode 703 and electrode 704.

[0342] In some implementations, and as shown in Fig. 10B, electrode 703 is proximal, electrode 704 is distal. In such implementations, balloon 707 may be a first balloon, disposed axially proximally from electrode 703. Centering mechanism 705 may further comprise a second balloon, balloon 739, disposed axially distally from electrode 704. Second balloon 739 may be configured to: (i) expand into contact with vascular wall 709 of blood vessel 708, and (ii) while expanded, to prevent blood flow through the blood vessel.

[0343] In some implementations, second balloon 739 is expandable independently of the expansion of the first balloon. In some implementations, second balloon 739 expansion is dependent on the expansion of balloon 707. In some implementations, second balloon 739 expands simultaneously with the expansion of balloon 707. In some implementations, second balloon 739 expands separately of the expansion of first balloon 707.

[0344] In some implementations, centering mechanism 705 expands and retracts periodically during the treatment, such that, while retracted, the blood vessel is not occluded and blood is allowed to flow through the blood vessel.

[0345] In some implementations, shaft 706 further includes an opening 716 in a lateral wall of the shaft. Opening 716 is configured to allow drug delivery to the adjacent blood vessel.

[0346] Reference is now made to Fig. 11 A-C, which are schematic illustrations of various tools for endovascular tissue ablation in accordance with some embodiments of the present invention.

[0347] Fig. 11A is schematic illustration of an applicator 905a of a tool 900a. Applicator 905a includes a pair of electrode assemblies 901 and 902, and is configured to be advanced transluminally (e.g., transvascularly) into a blood vessel. Typically for such implementations, each of electrode assemblies 901 and 902 comprises a respective electroporation electrode 903 and 904.

[0348] Tool 900a further includes a flexible shaft 906a, A first conductive wire and a second conductive wire (not visible) extend along the shaft. Shaft 906a defines an axial axis along the shaft.

[0349] In some implementations, electrode 903 is biased toward expansion, and applicator 905a is configured to: (i) constrain electrode 903 compressed for advancement into the blood vessel, and (ii) expand electrode 903 within the blood vessel by unconstraining electrode 903.

[0350] In some implementations, applicator 905a comprises an insulator that insulates at least part of electrode 903. Applicator 905a may be configured to unconstrain electrode 903 by deploying electrode 903 out of the insulator. In some implementations, the insulator is a sleeve 911 (Fig. 11 A). In some implementations, the insulator is a distal part of the shaft that serves as the insulator. For example, and as shown in Fig. 11B, tool 900b includes an insulator 912 that is a distal part of a shaft 906b that serves as the insulator.

[0351] In some implementations, electrode 903 is biased to form a helix upon expansion. In some implementations, electrode 903 is biased to form a tube upon expansion (not shown). In some implementations, electrode 903 is biased to form define, upon expansion, a lumen through which blood can flow.

[0352] In some implementations, electrode 904 is non-expandable.

[0353] In some implementations, and as shown in Fig. 11C, tool 1000 includes shaft 1006, electrode assembly 901, electrode 903 and insulator 912. Tool 1000 further includes an applicator 1005 that includes an electrode 1004. That is, the main difference between tool 900b and tool 1000 is with the second electrode. Electrode 1004 is biased toward expansion, and applicator 1005 is configured to: (i) constrain electrode 1004 compressed for advancement into the blood vessel, and (ii) expand electrode 1004 within the blood vessel by unconstraining electrode 1004.

[0354] In some implementations, shaft 1006 has a lateral opening 1014, disposed proximally to electrode 903, and electrode 1004 is configured to be constrained, while advanced, inside the shaft, and emerge through lateral opening 1014 when expanding.

[0355] In some implementations, electrode 1004 is biased to form a helix upon expansion. The helix may encircle the shaft. In some implementations, electrode 1004 is biased to define, upon expansion, a lumen through which blood can flow.

[0356] The various systems, devices, apparatuses, etc. in this disclosure can be sterilized (e.g., with heat, radiation, ethylene oxide, hydrogen peroxide, etc.) to ensure they are safe for use with patients, and the methods herein can comprise such sterilization of the associated system, device, apparatus, etc. Furthermore, the scope of the present disclosure includes, for some implementations, sterilizing one or more of any of the various systems, devices, apparatuses, etc. in this disclosure.

[0357] Any of the techniques, methods, operations, steps, etc. described or suggested herein can be performed on a living animal (e.g., human, other mammal, etc.) or on a non-living simulation, such as a cadaver, a cadaver heart, an anthropomorphic ghost, and / or a simulator device (which may include computerized and / or physical representations of body parts, tissue, etc.).

[0358] Various implementations of systems, devices, methods, etc. are disclosed herein, and any combination of their features, components, and options can be made unless specifically excluded.

[0359] Although the operations of some of the disclosed methods are described in a particular, sequential order for convenient presentation, it should be understood that this manner of description encompasses rearrangement, unless a particular ordering is required by specific language set forth below. For example, operations described sequentially can in some cases be rearranged or performed concurrently. Moreover, for the sake of simplicity, the attached figures may not show the various ways in which the disclosed systems, apparatuses, devices, methods, etc. can be used in conjunction with other systems, apparatuses, devices, methods, etc.

[0360] It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of embodiments of the present invention includes both combinations and sub combinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.Example implementations (Some example implementations of the ideas described and / or claimed herein.)

[0361] In some implementations, the system containing two or more electrodes for electroporation varying in length and surface area with a non-occlusive centering mechanism in between. This centering mechanism allows blood flow through vital arteries that provides a cooling to the treatment site and oxygen to the relevant organs.

[0362] The centering mechanism is nonconductive. The centering mechanism can be self-deployable or actuated by a pull / push wire or by rotation. The push / pull action can be done by pushing and pulling one side of the centering mechanism or by pushing and pulling one or both surrounding electrodes.

[0363] Both electrodes are mounted on a multi-lumen catheter with two or more lumens. Each lumen guides a conducting wire to each electrode. The conducting wire to the static electrode is mounted at the distal and the proximal part of the catheter thus eliminating the bending of the catheter while pushing or pulling the other wire / s.

[0364] The push pull wire can be the same wire that carries the power to the electrode. Electrical power wire is guided in one of the lumens and can be used for pull push of the relevant electrode or electrodes.

[0365] The device can have an array of electrodes with a centering device between each two.

[0366] In some implementations, the system containing two or more electrodes for electroporation varying in length and surface area with a centering mechanism in between them or around them.

[0367] The system may have an opening in the shaft for drug delivery into the treatment area.

[0368] The centering mechanism can be self-deployable or activated by a push / pull mechanism or a balloon.

[0369] The centering mechanism can be retracted and deployed multiple times during the treatment to allow blood flow in the blood vessel. The frequency of the deployment and the retraction can be synchronized or dependent on the heart rate (e.g. every beat, every other beat, etc.) or the frequency of activations.

[0370] In some implementations, the system containing two or more electrodes for electroporation varying in length and diameter with one of the electrodes is deployable and non-occlusive and can vary in length of deployment. This configuration allows blood flow through the treatment area, thus creating a cooling effect and will allow oxygen supply to relevant organs.

[0371] A proximal part of the distal electrode can be insulated by a sleeve or coating on the electrode or by the tip of a shaft. This insulation will prevent arching through the blood and will allow higher energy delivery during every pulse.

[0372] The deployment of the distal electrode centers both electrodes.

[0373] In some implementations, both electrodes can be deployable and self-centered.

[0374] Further Example Implementations (some non-limiting examples of the concepts herein are recited below):

[0375] Example 1. A method for transvascular treatment of a tumor in an organ of a subject, the method comprising: (i) endovascularly advancing an electrode of an applicator into a blood vessel adjacent the tumor; (ii) clearing a margin of the tumor adjacent the blood vessel by driving the electrode to apply a series of electroporation pulses to the tumor from within the blood vessel; and / or (iii) subsequently, resecting at least some of the tumor.

[0376] Example 2. The method according to example 1, wherein: (i) the applicator is at a distal part of a flexible shaft, the shaft defining an axial axis along the shaft, (ii) a first conductive wire extends along the shaft, (iii) a second conductive wire extends along the shaft, (iv) the electrode is a first electroporation electrode, (v) the applicator further comprises: (a) a second electroporation electrode, and / or (b) a non-conductive centering mechanism radially expandable into contact with a vascular wall of the blood vessel; and / or (vi) the method further comprises expanding the centering mechanism in a manner that: (A) supports the first and second electrodes medially from the vascular wall, and / or (B) allows blood within the blood vessel to flow past the applicator.

[0377] Example s. The method according to example 2, wherein: (i) the centering mechanism is disposed axially between the first and second electrodes, (ii) the centering mechanism comprises an expandable structure, (iii) the first electrode is proximal from the second electrode, (iv) the second electrode is slidably mounted on the shaft, and serves as an actuator of the centering mechanism; and / or (v) expanding the centering mechanism comprises expanding the centering mechanism by sliding the second electrode proximallyalong the shaft toward the first electrode such that the expandable structure of the centering mechanism expands into contact with the vascular wall.

[0378] Example 4. The method according to example 3, wherein the applicator further comprises a stopping mechanism, the stopping mechanism comprising: (i) a spring, attached to the second electrode at a first spring-end, and fixed, at a second spring-end, to the shaft, the spring biases the second electrode to rest distally; and / or (ii) a stopper, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end; configured: (a) to limit spring extension, and / or (b) to slide along with the second electrode, and wherein sliding the second electrode proximally along the shaft comprises sliding the second electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

[0379] Example 5. The method according to example 4, wherein the second electrode is proximal from the stopper, and wherein sliding the second electrode proximally along the shaft is sliding the second electrode proximally along the shaft such that the spring is extended, thereby closing the gap.

[0380] Example 6. The method according to example 4, wherein the stopper is proximal from the second electrode, and wherein sliding the second electrode proximally along the shaft is sliding the second electrode proximally along the shaft such that the spring is compressed, thereby opening the gap.

[0381] Example 7. The method according to example 2, wherein the centering mechanism: (i) comprises a tube having a plurality of slots aligned with the shaft axis to define a corresponding plurality of bendable ribs, (ii) has a delivery state in which the ribs have a low profile, and / or (iii) is reversibly expandable into a centering state, wherein expanding the centering mechanism comprises expanding the centering mechanism such that the ribs bend radially outwardly away from the shaft to contact the vascular wall.

[0382] Example 8. The method according to example 2, wherein the centering mechanism (i) comprises a plurality of axial ribs, (ii) has a delivery state in which the ribs are substantially flat against the shaft, and / or (iii) is reversibly expandable into a centering state, and wherein expanding the centering mechanism comprises expanding the centering mechanism such that the ribs bend radially outwardly away from the shaft to contact the vascular wall.

[0383] Example 9. The method according to example 2, wherein the centering mechanism is biased toward expanding, and wherein expanding the centering mechanism comprises expanding the centering mechanism by unconstraining the centering mechanism.

[0384] Example 10. The method according to example 2, wherein the method further comprises contracting the centering mechanism.

[0385] Example 11. The method according to example 10, wherein the centering mechanism is biased toward contracting, and wherein contracting the centering mechanism comprises contracting the centering mechanism by constraining the centering mechanism.

[0386] Example 12. The method according to example 10, wherein expanding the centering mechanism comprises expanding the centering mechanism by rotating the mechanism in one direction, and wherein contracting the centering mechanism comprises contracting the centering mechanism, after expanding, by rotating in an opposite direction.

[0387] Example 13. The method according to example 3, wherein the second wire is: (i) mechanically attached to the second electrode, (ii) slidable axially within the shaft, and / or (iii) is sufficiently strong in tension, and wherein sliding the second electrode proximally along the shaft comprises sliding the second electrode proximally along the shaft by pulling the wire proximally that the expandable structure expands into contact with the vascular wall.

[0388] Example 14. The method according to example 13, wherein the method further comprising medially contracting the centering mechanism by sliding the second electrode distally along the shaft away from the first electrode.

[0389] Example 15. The method according to example 14, wherein sliding the second electrode comprises sliding the second electrode by pushing the wire distally.

[0390] Example 16. The method according to example 3, wherein: (i) the applicator comprises a third electroporation electrode, slidably mounted on the shaft axially between the first electrode and the second electrode, (ii) the expandable structure is a first expandable structure, and is disposed axially between the third electrode and the second electrode, (iii) the centering mechanism further comprises a second expandable structure, disposed axially between the first electrode and the third electrode, and wherein sliding the second electrode proximally along the shaft comprises sliding the second electrode proximally along the shaft toward the third and first electrodes, such that: (a) the first expandable structure expands intocontact with the vascular wall, and / or (b) the third electrode slides proximally along the shaft toward the first electrode in a manner that expands the second expandable structure.

[0391] Example 17. The method according to example 2, wherein the centering mechanism comprises a balloon, and wherein expanding the centering mechanism comprises expanding the centering mechanism into contact with the vascular wall of the blood vessel, such that, while expanded, blood flow through the blood vessel is prevented.

[0392] Example 18. The method according to example 17, wherein the shaft further comprises an opening in a lateral wall of the shaft, and wherein the method further comprises opening the opening to allow drug delivery to the adjacent blood vessel.

[0393] Example 19. The method according to example 17, wherein the centering mechanism is self-expandable, and wherein expanding the centering mechanism comprises expanding the centering mechanism via unconstraining the centering mechanism.

[0394] Example 20. The method according to example 17, wherein expanding the centering mechanism comprises expanding the centering mechanism by rotating the mechanism in one direction.

[0395] Example 21. The method according to example 20, wherein the method further comprises, subsequently to expanding the centering mechanism, retracting the centering mechanism by rotating in an opposite direction.

[0396] Example 22. The method according to example 17, wherein expanding the centering mechanism comprises expanding the centering mechanism by inflating the balloon.

[0397] Example 23. The method according to example 22, wherein inflating the balloon comprises inflating the balloon non-continuously, such that the centering mechanism becomes stable upon inflation even in an absence of maintenance of inflation pressure.

[0398] Example 24. The method according to example 22, wherein the method further comprises, subsequently to inflating the balloon, deflating the balloon via application of a vacuum.

[0399] Example 25. The method according to example 22, wherein the method further comprises, subsequently to inflating the balloon, deflating the balloon via absence of maintenance of inflation pressure.

[0400] Example 26. The method according to example 17, wherein: (i) the first electrode is proximal and the second electrode is distal, and / or (ii) the centering mechanism is disposed axially between the first electrode and the second electrode, and wherein the method further comprises, subsequently to expanding the centering mechanism, stabilizing the orientation of the applicator.

[0401] Example 27. The method according to example 17, wherein the method further comprises, subsequently to expanding the centering mechanism, retracting and expanding the mechanism periodically during the treatment, such that, while retracted, the blood vessel is not occluded and blood is allowed to flow through the blood vessel.

[0402] Example 28. The method according to example 17, wherein: (i) the first electrode is proximal, (ii) the second electrode is distal, (iii) the balloon is a first balloon, and is disposed axially proximally from the first electrode, (iv) the centering mechanism further comprises a second balloon, disposed axially distally from the second electrode, and / or (v) the method further comprises expanding the second balloon into contact with the vascular wall of the blood vessel, such that, while expanded, blood flow through the blood vessel is prevented.

[0403] Example 29. The method according to example 28, wherein expanding the second balloon comprises expanding the second balloon independently of the expansion of the first balloon.

[0404] Example 30. The method according to example 28, wherein expanding the second balloon comprises expanding the second balloon in dependance on the expansion of the first balloon.

[0405] Example 31. The method according to example 28, wherein expanding the second balloon comprises expanding the second balloon simultaneously with the expansion of the first balloon.

[0406] Example 32. The method according to example 28, wherein expanding the second balloon comprises expanding the second balloon separately from of the expansion of the first balloon.

[0407] Example 33. The method according to example 2, wherein, subsequently to expanding the centering mechanism, clearing a margin of the tumor is clearing a margin of the tumor by driving the first electrode to apply a series of electroporation pulses betweenthe first electrode and the second electrode while the first electrode and the second electrode are supported medially from the vascular wall by the centering mechanism.

[0408] Example 34. The method according to any one of examples 1-33, wherein the electrode is expandable, and subsequently to advancing the electrode into a blood vessel, the method further comprises expanding the electrode into contact with a wall of the blood vessel.

[0409] Example 35. The method according to example 34, wherein the electrode is biased toward expansion, and the applicator is configured to constrain the first electrode compressed for advancement into the blood vessel, and wherein expanding the electrode comprises expanding the electrode by unconstraining the electrode.

[0410] Example 36. The method according to example 35, wherein the applicator comprises an insulator that insulates at least part of the electrode, and wherein unconstraining the electrode comprises unconstraining the electrode by deploying the electrode out of the insulator.

[0411] Example 37. The method according to example 36, wherein the insulator is a sleeve, and wherein unconstraining the electrode comprises unconstraining the electrode by deploying the first electrode out of the sleeve.

[0412] Example 38. The method according to example 36, wherein the applicator is at a distal part of a shaft and the distal part of the shaft serves as the insulator, and unconstraining the electrode comprises unconstraining the electrode by deploying the electrode out of the distal end of the shaft.

[0413] Example 39. The method according to example 35, wherein the electrode is biased to form a helix upon expansion, and unconstraining the electrode comprises unconstraining the electrode to form a helix upon expansion.

[0414] Example 40. The method according to example 35, wherein the electrode is biased to form a tube upon expansion, and unconstraining the electrode comprises unconstraining the electrode to form a tube upon expansion.

[0415] Example 41. The method according to example 35, wherein the electrode is biased to define, upon expansion, a lumen through which blood can flow, and unconstraining the electrode comprises unconstraining the electrode such that blood can flow through the lumen defined by the expanded electrode.

[0416] Example 42. The method according to example 34, wherein: (i) the electrode is a first electrode, (ii) the applicator further comprises a second electrode, configured such that expansion of the first electroporation electrode into contact with the wall positions the second electroporation electrode medially from the wall, and / or (iii) the method further comprises positioning the second electroporation electrode medially from the wall when expanding the first electrode.

[0417] Example 43. The method according to example 42, wherein subsequently to positioning the second electrode, and wherein clearing a margin of the tumor comprises clearing a margin of the tumor by driving the first electrode to apply a series of electroporation pulses between the first electroporation electrode and the second electroporation electrode.

[0418] Example 44. The method according to example 43, wherein the second electrode is non-expandable, and wherein clearing a margin of the tumor comprises clearing a margin of the tumor by driving the first electrode to apply a series of electroporation pulses between the first electroporation electrode and the non-expandable electroporation electrode.

[0419] Example 45. The method according to example 43, wherein the second electrode is expandable, and the method further comprises expanding the second electrode.

[0420] Example 46. The method according to example 45, wherein the second electrode is biased toward expansion and the applicator is configured to constrain the second electrode compressed for advancement into the blood vessel, and wherein expanding the second electrode comprises expanding the second electrode by unconstraining the second electrode.

[0421] Example 47. The method according to example 46, wherein the first electrode is distal from the second electrode, and wherein unconstraining the second electrode comprises unconstraining the second electrode proximally to the first electrode.

[0422] Example 48. The method according to example 47, wherein the applicator is at a distal part of a shaft, and the shaft has a lateral opening, disposed proximally to the first electrode, and the second electrode is configured to be constrained, while advanced, inside the shaft, and wherein unconstraining the second electrode comprises unconstraining the second electrode to emerge through the lateral opening when expanding.

[0423] Example 49. The method according to example 47, wherein the second electrode is biased to form a helix upon expansion, the helix encircles the shaft, and whereinunconstraining the second electrode comprises unconstraining the second electrode to form a helix upon expansion.

[0424] Example 50. The method according to example 49, wherein the second electrode is biased to define, upon expansion, a lumen through which blood can flow, the helix encircles the shaft, and wherein unconstraining the second electrode comprises unconstraining the second electrode such that blood can flow through the lumen defined by the expanded second electrode.

[0425] Example 51. The method according to any one of examples 1-50, further comprising intravenously administering a systemic anticancer chemotherapeutic agent prior to the endovascular advancing of the applicator.

[0426] Example 52. The method according to any one of examples 1-51, wherein the electroporation is a reversible electroporation.

[0427] Example 53. The method according to any one of examples 1-52, wherein the electroporation is an irreversible electroporation.

[0428] Example 54. The method according to any one of examples 1-53, wherein the electrode is biased toward expansion, and wherein the method further comprises constraining the second electrode in a compressed state for advancement into the blood vessel, and / or expanding the second electrode within the blood vessel by unconstraining the second electrode.

[0429] Example 55. The method according to any one of examples 1-54, wherein clearing the margin of the tumor comprises clearing the margin of the tumor by driving the electroporation pulses unidirectionally through the blood vessel wall.

[0430] Example 56. A method for transvascular treatment of a tumor in an organ of a subject, the method comprising: (i) endovascularly advancing an electrode of an applicator to an intravascular site adjacent the tumor; (ii) conducting an electroporation of the tumor by driving the electrode to apply a series of electroporation pulses from the intravascular site transvascularly to the tumor; and / or (iii) subsequently, resecting at least some of the tumor.

[0431] Example 57. The method according to example 56, further comprising intravenously administering a systemic anticancer chemotherapeutic agent prior to electroporation of the tumor.

[0432] Example 58. The method according to any one of examples 56-57, wherein the electroporation is a reversible electroporation.

[0433] Example 59. The method according to any one of examples 56-58, wherein the electroporation is an irreversible electroporation.

[0434] Example 60. A method, comprising: (i) endovascularly advancing an electrode of an applicator to an intravascular site adjacent a tumor of a subject; (ii) driving the electrode to apply a series of electroporation pulses from the intravascular site transvascularly to the tumor; (iii) determining an effect that the electroporation pulses had on the tumor; and / or (iv) responsively to the determining, identifying the subject as being a candidate for resection of at least some of the tumor.

[0435] Example 61. The method according to example 60, further comprising, responsively to the identifying, resecting at least some of the tumor.

[0436] Example 62. A method, comprising: (i) identifying a subject as having had a series of electroporation pulses applied from an intravascular site transvascularly to a tumor of the subject; and / or (ii) responsively to the identifying, resecting at least some of the tumor.

[0437] Example 63. The method according to example 62, further comprising, prior to the identifying, driving an endovascular electrode to apply the series of electroporation pulses from the intravascular site transvascularly to the tumor.

[0438] Example 64. A method for transvascular treatment of a tumor in an organ of a subject, the method comprising: (i) endovascularly advancing an applicator to an intravascular site adjacent the tumor; (ii) at the intravascular site, expanding a first electroporation electrode of the applicator into contact with a vascular wall; (iii) at the intravascular site, positioning a second electroporation electrode of the applicator medially from the vascular wall; and / or (iv) while the applicator remains at the intravascular site, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between the first electrode and the second electrode.

[0439] Example 65. The method according to example 64, further comprising intravenously administering a systemic anticancer chemotherapeutic agent prior to the endovascular advancing of the applicator.

[0440] Example 66. The method according to any one of examples 64-65, wherein the second electroporation electrode has a surface area that is greater than that of the firstelectroporation electrode, and wherein applying the electroporation pulses transvascularly to the tumor comprises driving the electroporation pulses between (i) the first electroporation electrode, and (ii) the second electroporation electrode that has the surface area that is greater than that of the first electroporation electrode.

[0441] Example 67. The method according to any one of examples 64-66, wherein the second electroporation electrode has an axial length that is greater than that of the first electroporation electrode, and wherein applying the electroporation pulses transvascularly to the tumor comprises driving the electroporation pulses between (i) the first electroporation electrode, and (ii) the second electroporation electrode that has the axial length that is greater than that of the first electroporation electrode.

[0442] Example 68. The method according to any one of examples 64-67, further comprising intracorporeally adjusting an axial length of the first electrode.

[0443] Example 69. The method according to any one of examples 64-68, wherein applying the electroporation pulses transvascularly to the tumor comprises applying the electroporation pulses radially through the vascular wall.

[0444] Example 70. The method according to any one of examples 64-69, wherein applying the electroporation pulses transvascularly to the tumor comprises applying the electroporation pulses unidirectionally through the vascular wall.

[0445] Example 71. The method according to any one of examples 64-70, wherein applying the electroporation pulses transvascularly to the tumor comprises applying the electroporation pulses omnidirectionally through the vascular wall.

[0446] Example 72. The method according to any one of examples 64-71, wherein the tumor is a stage 2 tumor, and wherein endovascularly advancing the applicator to the intravascular site adjacent the tumor comprises endovascularly advancing the applicator to an intravascular site adjacent the stage 2 tumor.

[0447] Example 73. The method according to any one of examples 64-72, wherein the tumor is a stage 3 tumor, and wherein endovascularly advancing the applicator to the intravascular site adjacent the tumor comprises endovascularly advancing the applicator to an intravascular site adjacent the stage 3 tumor.

[0448] Example 74. The method according to any one of examples 64-73, wherein the tumor is a pancreatic tumor, and wherein endovascularly advancing the applicator to theintravascular site adjacent the tumor comprises endovascularly advancing the applicator to an intravascular site adjacent the pancreatic tumor.

[0449] Example 75. The method according to any one of examples 64-74, wherein the tumor is a locally advanced tumor, and wherein endovascularly advancing the applicator to the intravascular site adjacent the tumor comprises endovascularly advancing the applicator to an intravascular site adjacent the locally advanced tumor.

[0450] Example 76. The method according to any one of examples 64-75, further comprising determining an effect of the electroporation pulses on the tumor.

[0451] Example 77. The method according to example 76, further comprising responsively to the determining, resecting at least some of the tumor.

[0452] Example 78. The method according to example 76, further comprising responsively to the determining, identifying the subject as being a candidate for resection of at least some of the tumor.

[0453] Example 79. The method according to example 78, further comprising responsively to the identifying, resecting at least some of the tumor.

[0454] Example 80. A system for treatment of a tumor adjacent to a blood vessel of a subject, the system comprising: (i) a tool, comprising: (a) a flexible shaft, (b) at a distal part of the shaft, an applicator, advanceable into the blood vessel, and comprising: (I) an expandable first electroporation electrode, expandable into contact with a wall of the blood vessel; and / or (II) a second electroporation electrode, configured such that expansion of the first electroporation electrode into contact with the wall biases the second electroporation electrode medially away from the wall; and / or (ii) at a proximal part of the shaft, a connector assembly comprising: (a) a first connector, electrically connected to the first electroporation electrode; and / or (b) a second connector, electrically connected to the second electroporation electrode; and / or (iii) a pulse generator: (a) comprising a first terminal to which the first connector is connectable, and a second terminal to which the second connector is connectable; and / or (b) configured to electroporate cells of the tumor by, via the first terminal connected to the first connector and the second terminal connected to the second connector, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between (i) the first electroporation electrode in contact with the wall, and (ii) the second electroporation electrode disposed medially from the wall.

[0455] Example 81. The system according to example 80, wherein the second electroporation electrode has a surface area which is greater than that of the first electroporation electrode.

[0456] Example 82. The system according to any one of examples 80-81, wherein the second electroporation electrode has an axial length which is greater than that of the first electroporation electrode.

[0457] Example 83. The system according to any one of examples 80-82, wherein the first electroporation electrode is proximal from the second electroporation electrode.

[0458] Example 84. The system according to any one of examples 80-83, wherein the first electroporation electrode is distal from the second electroporation electrode.

[0459] Example 85. The system according to any one of examples 80-84, wherein the second electroporation electrode is advanceable through the first electroporation electrode.

[0460] Example 86. The system according to any one of examples 80-85, wherein the first electroporation electrode is advanceable through the second electroporation electrode.

[0461] Example 87. The system according to any one of examples 80-86, wherein the applicator is operable to intracorporeally adjust an effective axial length of the first electroporation electrode.

[0462] Example 88. The system according to any one of examples 80-87, wherein the applicator is configured such that the electroporation pulses are applied radially through the vascular wall.

[0463] Example 89. The system according to any one of examples 80-88, wherein the applicator is configured such that the electroporation pulses are applied unidirectionally through the vascular wall.

[0464] Example 90. The system according to any one of examples 80-89, wherein the applicator is configured such that the electroporation pulses are applied omnidirectionally through the vascular wall.

[0465] Example 91. The system according to any one of examples 80-90, wherein the first electrode is biased toward expansion, and the applicator is configured to: (a) constrain the first electrode compressed for advancement into the blood vessel, and / or (b) expand the first electrode within the blood vessel by unconstraining the first electrode.

[0466] Example 92. The system according to example 91, wherein the applicator comprises an insulator that insulates at least part of the first electrode, and wherein the applicator is configured to unconstrain the first electrode by deploying the first electrode out of the insulator.

[0467] Example 93. The system according to example 92, wherein the insulator is a sleeve.

[0468] Example 94. The system according to example 92, wherein the distal part of the shaft serves as the insulator.

[0469] Example 95. The system according to example 92, wherein the first electrode is biased to form a helix upon expansion.

[0470] Example 96. The system according to example 92, wherein the first electrode is biased to form a tube upon expansion.

[0471] Example 97. The system according to example 92, wherein the first electrode is biased to define, upon expansion, a lumen through which blood can flow.

[0472] Example 98. The system according to example 91, wherein the second electrode is non-expandable.

[0473] Example 99. The system according to example 91, wherein the second electrode is biased toward expansion, and the applicator is configured to: (a) constrain the second electrode compressed for advancement into the blood vessel, and / or (b) expand the second electrode within the blood vessel by unconstraining the second electrode.

[0474] Example 100. The system according to example 99, wherein the first electrode is distal from the second electrode.

[0475] Example 101. The system according to example 100, wherein the shaft has a lateral opening, disposed proximally to the first electrode, and the second electrode is configured to: (a) be constrained, while advanced, inside the shaft, and / or (b) emerge through the lateral opening when expanding.

[0476] Example 102. The system according to example 100, wherein the second electrode is biased to form a helix upon expansion, the helix encircles the shaft.

[0477] Example 103. The system according to example 101, wherein the second electrode is biased to define, upon expansion, a lumen through which blood can flow.

[0478] Example 104. A system for treatment of a tumor adjacent to a blood vessel of a subject, the system comprising: (i) a tool, comprising: (a) a flexible shaft, defining an axial axis along the shaft, (b) a first conductive wire extending along the shaft, (c) a second conductive wire extending along the shaft, and / or (d) at a distal part of the shaft, an applicator, advanceable into the blood vessel, and comprising: (I) a first electroporation electrode, (II) a second electroporation electrode, and / or (III) a non-conductive centering mechanism radially expandable into contact with a vascular wall of the blood vessel in a manner that: (A) supports the first and second electrodes medially from the vascular wall, and / or (B) allows blood within the blood vessel to flow past the applicator, and (ii) at a proximal part of the shaft, a connector assembly comprising: (a) a first connector, electrically connected to the first electrode via the first wire; and / or (b) a second connector, electrically connected to the second electrode via the second wire; and / or (iii) a pulse generator: (I) comprising a first terminal to which the first connector is connectable, and a second terminal to which the second connector is connectable; and / or (II) configured to electroporate cells of the tumor by, via the first terminal connected to the first connector and the second terminal connected to the second connector, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between the first electrode and the second electrode while the first electrode and the second electrode are supported medially from the vascular wall by the centering mechanism.

[0479] Example 105. The system according to example 104, wherein the centering mechanism: (i) comprises a tube having a plurality of slots aligned with the shaft axis to define a corresponding plurality of bendable ribs, (ii) has a delivery state in which the ribs have a low profile; and / or (iii) is reversibly expandable into a centering state in which the ribs bend radially outwardly away from the shaft to contact the vascular wall.

[0480] Example 106. The system according to any one of examples 104-105, wherein the centering mechanism: (i) comprises a plurality of axial ribs, (ii) has a delivery state in which the ribs are substantially flat against the shaft, and / or (iii) is reversibly expandable into a centering state in which the ribs bend radially outwardly away from the shaft to contact the vascular wall.

[0481] Example 107. The system according to any one of examples 104-106, wherein the centering mechanism is biased toward expanding.

[0482] Example 108. The system according to any one of examples 104-107, wherein the centering mechanism is biased toward contracting.

[0483] Example 109. The system according to any one of examples 104-108, wherein the centering mechanism expands by rotating the mechanism in one direction, and retracts, after expanding, by rotating in an opposite direction.

[0484] Example 110. The system according to any one of examples 104-109, wherein: (i) the centering mechanism is disposed axially between the first and second electrodes, (ii) the first electrode is proximal from the second electrode, (iii) the second electrode is slidably mounted on the shaft, and serves as an actuator of the centering mechanism such that sliding the second electrode proximally along the shaft toward the first electrode expands an expandable structure of the centering mechanism into contact with the vascular wall.

[0485] Example 111. The system according to example 110, wherein the second wire is: (i) mechanically attached to the second electrode, (ii) slidable axially within the shaft, and / or (iii) is sufficiently strong in tension that the expandable structure is expandable by the second electrode being slid proximally along the shaft toward the first electrode via pulling the wire proximally.

[0486] Example 112. The system according to example 111, wherein the tool is configured such that the centering mechanism is medially contractible by the second electrode being slid distally along the shaft away from the first electrode via pushing the wire distally.

[0487] Example 113. The system according to example 110, wherein the applicator further comprises a stopping mechanism, the stopping mechanism comprising: (i) a spring, attached to the second electrode at a first spring-end, and fixed, at a second spring-end, to the shaft, the spring biases the second electrode to rest distally; and / or (ii) a stopper, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end, configured: (a) to limit spring extension, and / or (b) to slide along with the second electrode, and wherein the stopping mechanism is configured to stop the sliding of the second electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

[0488] Example 114. The system according to example 113, wherein the second electrode is proximal from the stopper and the spring is extended, closing the gap.

[0489] Example 115. The system according to example 113, wherein the stopper is proximal from the second electrode and the spring is compressed, opening the gap.

[0490] Example 116. The system according to example 113, wherein the spring and the second electrode are formed from a single material such that the spring serves as a continuation of the second electrode in applying electroporation pulses to the tumor.

[0491] Example 117. The system according to example 113, wherein the stopper and the second electrode are formed from a single material such that the stopper serves as a continuation of the second electrode in applying electroporation pulses to the tumor.

[0492] Example 118. The system according to example 113, wherein the entire stopping mechanism is formed from a single material such that the entire stopping mechanism serves as the second electrode in applying electroporation pulses to the tumor.

[0493] Example 119. The system according to example 113, wherein the system further comprises, at shaft proximal end, an extracorporeal unit, operatively coupled to the second electrode mechanism; and wherein the extracorporeal unit is configured to slide the second electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

[0494] Example 120. The system according to example 119, wherein: (i) the extracorporeal unit further comprises a connector, electrically connected to the second electrode, and / or (ii) the system further comprises a pulse generator, comprising a terminal to which the connector is connectable, the pulse generator is configured to apply, via the connector connected to the second electrode, electroporation pulses transvascularly to the tumor.

[0495] Example 121. The system according to example 110, wherein: (i) the applicator comprises a third electroporation electrode, slidably mounted on the shaft axially between the first electrode and the second electrode, (ii) the expandable structure is a first expandable structure, and is disposed axially between the third electrode and the second electrode, (iii) the centering mechanism further comprises a second expandable structure, disposed axially between the first electrode and the third electrode, and / or (iv) sliding the second electrode proximally along the shaft toward the third and first electrodes: (a) expands the first expandable structure into contact with the vascular wall, and / or (b) slides the third electrode proximally along the shaft toward the first electrode in a manner that expands the second expandable structure.

[0496] Example 122. The system according to example 103, wherein the centering mechanism comprises a balloon configured to: (a) expand into contact with the vascular wallof the blood vessel, and / or (b) while expanded, to prevent blood flow through the blood vessel.

[0497] Example 123. The system according to example 122 wherein the shaft further comprises an opening in a lateral wall of the shaft, the opening is configured to allow drug delivery to the adjacent blood vessel.

[0498] Example 124. The system according to example 122 wherein the centering mechanism is self-expandable.

[0499] Example 125. The system according to example 122 wherein the centering mechanism expands by rotating the mechanism in one direction, and retracts, after expanding, by rotating in an opposite direction.

[0500] Example 126. The system according to example 122 wherein the centering mechanism expands via inflation of the balloon.

[0501] Example 127. The system according to example 126, wherein the centering mechanism is configured to become stable upon inflation even in an absence of maintenance of inflation pressure.

[0502] Example 128. The system according to example 126, wherein the centering mechanism is configured to be deflated via application of a vacuum.

[0503] Example 129. The system according to example 126, wherein the centering mechanism is configured to deflate in an absence of maintenance of inflation pressure.

[0504] Example 130. The system according to example 122 wherein the first electrode is proximal and the second electrode is distal, and the centering mechanism is disposed axially between the first electrode and the second electrode.

[0505] Example 131. The system according to example 122 wherein the centering mechanism expands and retracts periodically during the treatment, such that, while retracted, the blood vessel is not occluded and blood is allowed to flow through the blood vessel.

[0506] Example 132. The system according to example 122 wherein: (a) the first electrode is proximal, (b) the second electrode is distal, (c) the balloon is a first balloon, and is disposed axially proximally from the first electrode, (d) the centering mechanism further comprises a second balloon, disposed axially distally from the second electrode; and / or (e) the second balloon is configured to: (i) expand into contact with the vascular wall of the blood vessel, and / or (ii) while expanded, to prevent blood flow through the blood vessel.

[0507] Example 133. The system according to example 132, wherein the second balloon is expandable independently of the expansion of the first balloon.

[0508] Example 134. The system according to example 132, wherein the second balloon expansion is dependent on the expansion of the first balloon.

[0509] Example 135. The system according to example 132, wherein the second balloon expands simultaneously with the expansion of the first balloon.

[0510] Example 136. The system according to example 132, wherein the second balloon expands separately from the expansion of the first balloon.

[0511] Example 137. A system for treatment of a tumor adjacent to a blood vessel of a subject, the system comprising a tool that comprises: (i) a flexible shaft, and / or (ii) at a distal part of the shaft, an applicator, advanceable into the blood vessel, and comprising: (a) an expandable first electroporation electrode, expandable into contact with a wall of the blood vessel; and / or (b) a second electroporation electrode, configured such that expansion of the first electroporation electrode into contact with the wall biases the second electroporation electrode medially away from wall, wherein the system is configured to electroporate cells of the tumor by applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between (i) the first electroporation electrode in contact with the wall, and (ii) the second electroporation electrode disposed medially from the wall.

[0512] Example 138. A system for treatment of a tumor adjacent to a blood vessel of a subject, the system comprising: (i) a tool, comprising: (a) a flexible shaft, and / or (b) at shaft distal end, an electrode mechanism, comprising: (I) an electroporation electrode, slidable along the shaft, (II) a spring, attached to the electrode at a first spring-end, and fixed, at a second spring-end, to the shaft, the spring biases the electrode to rest distally; and / or (III) a stopper, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end; configured: (A) to limit spring extension, and / or (B) to slide along with the electrode, (ii) at shaft proximal end, an extracorporeal unit, operatively coupled to the electrode mechanism, comprising a connector, electrically connected to the electroporation electrode; and / or (iii) a pulse generator, comprising a terminal to which the connector is connectable, the pulse generator is configured to apply, via the connector connected to the electrode, electroporation pulses transvascularly to the tumor, wherein the extracorporeal unit is configured to slide the electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

[0513] Example 139. The system according to example 138, wherein the electrode is proximal from the stopper and the spring is extended, closing the gap.

[0514] Example 140. The system according to any one of examples 138-139, wherein the stopper is proximal from the electrode and the spring is compressed, opening the gap.

[0515] Example 141. The system according to any one of examples 138-140, wherein the tool further comprises a centering mechanism proximally from the electrode mechanism along the shaft, the centering mechanism is configured to bias the electrode medially away from a wall of the blood vessel, and wherein the electrode sliding actuates the centering mechanism.

[0516] Example 142. The system according to example 141, wherein: (i) the system further comprises a second electroporation electrode proximally from the centering mechanism along the shaft, (ii) the connector is a first connector, (iii) the extracorporeal unit is operatively coupled to the second electrode and comprising a second connector that is connectable to the terminal and electrically connected to the second electroporation electrode; and / or (iv) the pulse generator is configured to apply, via the second connector connected to the second electrode, electroporation pulses transvascularly to the tumor.

[0517] Example 143. The system according to any one of examples 138-142, wherein the spring and the electrode are formed from a single material such that the spring serves as a continuation of the electrode in applying electroporation pulses to the tumor.

[0518] Example 144. The system according to any one of examples 138-143, wherein the stopper and the electrode are formed from a single material such that the stopper serves as a continuation of the electrode in applying electroporation pulses to the tumor.

[0519] Example 145. The system according to any one of examples 138-144, wherein the entire electrode mechanism is formed from a single material such that the entire electrode mechanism serves as the electrode in applying electroporation pulses to the tumor.

Claims

CLAIMS1. A method for transvascular treatment of a tumor in an organ of a subj ect, the method comprising:endovascularly advancing an electrode of an applicator into a blood vessel adjacent the tumor;clearing a margin of the tumor adjacent the blood vessel by driving the electrode to apply a series of electroporation pulses to the tumor from within the blood vessel; and subsequently, resecting at least some of the tumor.

2. The method according to claim 1, wherein:the applicator is at a distal part of a flexible shaft, the shaft defining an axial axis along the shaft,a first conductive wire extends along the shaft,a second conductive wire extends along the shaft,the electrode is a first electroporation electrode,the applicator further comprises:a second electroporation electrode, anda non-conductive centering mechanism radially expandable into contact with a vascular wall of the blood vessel, andthe method further comprises expanding the centering mechanism in a manner that:supports the first and second electrodes medially from the vascular wall, and allows blood within the blood vessel to flow past the applicator.

3. The method according to claim 2, wherein:the centering mechanism is disposed axially between the first and second electrodes, the centering mechanism comprises an expandable structure,the first electrode is proximal from the second electrode,the second electrode is slidably mounted on the shaft, and serves as an actuator of the centering mechanism; andexpanding the centering mechanism comprises expanding the centering mechanism by sliding the second electrode proximally along the shaft toward the first electrode such that the expandable structure of the centering mechanism expands into contact with the vascular wall.

4. The method according to claim 3, wherein the applicator further comprises a stopping mechanism, the stopping mechanism comprising:a spring, attached to the second electrode at a first spring-end, and fixed, at a second spring-end, to the shaft, the spring biases the second electrode to rest distally; anda stopper, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end; configured:to limit spring extension, andto slide along with the second electrode;and wherein sliding the second electrode proximally along the shaft comprises sliding the second electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

5. The method according to claim 4, wherein the second electrode is proximal from the stopper, and wherein sliding the second electrode proximally along the shaft is sliding the second electrode proximally along the shaft such that the spring is extended, thereby closing the gap.

6. The method according to claim 4, wherein the stopper is proximal from the second electrode, and wherein sliding the second electrode proximally along the shaft is sliding the second electrode proximally along the shaft such that the spring is compressed, thereby opening the gap.

7. The method according to claim 2, wherein:the centering mechanism comprises a tube having a plurality of slots aligned with the shaft axis to define a corresponding plurality of bendable ribs,the centering mechanism has a delivery state in which the ribs have a low profile, andthe centering mechanism is reversibly expandable into a centering state; and expanding the centering mechanism comprises expanding the centering mechanism such that the ribs bend radially outwardly away from the shaft to contact the vascular wall.

8. The method according to claim 2, wherein:the centering mechanism comprises a plurality of axial ribs,the centering mechanism has a delivery state in which the ribs are substantially flat against the shaft,the centering mechanism is reversibly expandable into a centering state, andexpanding the centering mechanism comprises expanding the centering mechanism such that the ribs bend radially outwardly away from the shaft to contact the vascular wall.

9. The method according to claim 2, wherein the centering mechanism is biased toward expanding, and wherein expanding the centering mechanism comprises expanding the centering mechanism by unconstraining the centering mechanism.

10. The method according to claim 2, wherein the method further comprises contracting the centering mechanism.

11. The method according to claim 10, wherein the centering mechanism is biased toward contracting, and wherein contracting the centering mechanism comprises contracting the centering mechanism by constraining the centering mechanism.

12. The method according to claim 10, wherein expanding the centering mechanism comprises expanding the centering mechanism by rotating the mechanism in one direction, and wherein contracting the centering mechanism comprises contracting the centering mechanism, after expanding, by rotating in an opposite direction.

13. The method according to claim 3, wherein the second wire is:mechanically attached to the second electrode,slidable axially within the shaft, andis sufficiently strong in tension;and wherein sliding the second electrode proximally along the shaft comprises sliding the second electrode proximally along the shaft by pulling the wire proximally that the expandable structure expands into contact with the vascular wall.

14. The method according to claim 13, wherein the method further comprising medially contracting the centering mechanism by sliding the second electrode distally along the shaft away from the first electrode.

15. The method according to claim 14, wherein sliding the second electrode comprises sliding the second electrode by pushing the wire distally.

16. The method according to claim 3, wherein:the applicator comprises a third electroporation electrode, slidably mounted on the shaft axially between the first electrode and the second electrode,the expandable structure is a first expandable structure, and is disposed axially between the third electrode and the second electrode,the centering mechanism further comprises a second expandable structure, disposed axially between the first electrode and the third electrode;and wherein sliding the second electrode proximally along the shaft comprises sliding the second electrode proximally along the shaft toward the third and first electrodes, such that:the first expandable structure expands into contact with the vascular wall, and the third electrode slides proximally along the shaft toward the first electrode in a manner that expands the second expandable structure.

17. The method according to claim 2, wherein:the centering mechanism comprises a balloon; andexpanding the centering mechanism comprises expanding the centering mechanism into contact with the vascular wall of the blood vessel, such that, while expanded, blood flow through the blood vessel is prevented.

18. The method according to claim 17, wherein the shaft further comprises an opening in a lateral wall of the shaft, and wherein the method further comprises opening the opening to allow drug delivery to the adjacent blood vessel.

19. The method according to claim 17, wherein the centering mechanism is selfexpandable, and wherein expanding the centering mechanism comprises expanding the centering mechanism via unconstraining the centering mechanism.

20. The method according to claim 17, wherein expanding the centering mechanism comprises expanding the centering mechanism by rotating the mechanism in one direction.

21. The method according to claim 20, wherein the method further comprises, subsequently to expanding the centering mechanism, retracting the centering mechanism by rotating in an opposite direction.

22. The method according to claim 17, wherein expanding the centering mechanism comprises expanding the centering mechanism by inflating the balloon.

23. The method according to claim 22, wherein inflating the balloon comprises inflating the balloon non-continuously, such that the centering mechanism becomes stable upon inflation even in an absence of maintenance of inflation pressure.

24. The method according to claim 22, wherein the method further comprises, subsequently to inflating the balloon, deflating the balloon via application of a vacuum.

25. The method according to claim 22, wherein the method further comprises, subsequently to inflating the balloon, deflating the balloon via absence of maintenance of inflation pressure.

26. The method according to claim 17, wherein:the first electrode is proximal and the second electrode is distal, andthe centering mechanism is disposed axially between the first electrode and the second electrode, andthe method further comprises, subsequently to expanding the centering mechanism, stabilizing the orientation of the applicator.

27. The method according to claim 17, wherein the method further comprises, subsequently to expanding the centering mechanism, retracting and expanding the mechanism periodically during the treatment, such that, while retracted, the blood vessel is not occluded and blood is allowed to flow through the blood vessel.

28. The method according to claim 17, wherein:the second electrode is distal to the first electrode,the balloon is a first balloon, and is disposed proximally from the first electrode, the centering mechanism further comprises a second balloon, disposed distally from the second electrode, andthe method further comprises expanding the second balloon into contact with the vascular wall of the blood vessel, such that, while expanded, blood flow through the blood vessel is prevented.

29. The method according to claim 28, wherein expanding the second balloon comprises expanding the second balloon independently of the expansion of the first balloon.

30. The method according to claim 28, wherein expanding the second balloon comprises expanding the second balloon in dependance on the expansion of the first balloon.

31. The method according to claim 28, wherein expanding the second balloon comprises expanding the second balloon simultaneously with the expansion of the first balloon.

32. The method according to claim 28, wherein expanding the second balloon comprises expanding the second balloon separately from of the expansion of the first balloon.

33. The method according to claim 2, wherein, subsequently to expanding the centering mechanism, clearing a margin of the tumor is clearing a margin of the tumor by driving thefirst electrode to apply a series of electroporation pulses between the first electrode and the second electrode while the first electrode and the second electrode are supported medially from the vascular wall by the centering mechanism.

34. The method according to claim 1, wherein the electrode is expandable, and subsequently to advancing the electrode into a blood vessel, the method further comprises expanding the electrode into contact with a wall of the blood vessel.

35. The method according to claim 34, wherein the electrode is biased toward expansion, and the applicator is configured to constrain the first electrode compressed for advancement into the blood vessel, and wherein expanding the electrode comprises expanding the electrode by unconstraining the electrode.

36. The method according to claim 35, wherein the applicator comprises an insulator that insulates at least part of the electrode, and wherein unconstraining the electrode comprises unconstraining the electrode by deploying the electrode out of the insulator.

37. The method according to claim 36, wherein the insulator is a sleeve, and wherein unconstraining the electrode comprises unconstraining the electrode by deploying the first electrode out of the sleeve.

38. The method according to claim 36, wherein the applicator is at a distal part of a shaft and the distal part of the shaft serves as the insulator, and unconstraining the electrode comprises unconstraining the electrode by deploying the electrode out of the distal end of the shaft.

39. The method according to claim 35, wherein the electrode is biased to form a helix upon expansion, and unconstraining the electrode comprises unconstraining the electrode to form a helix upon expansion.

40. The method according to claim 35, wherein the electrode is biased to form a tube upon expansion, and unconstraining the electrode comprises unconstraining the electrode to form a tube upon expansion.

41. The method according to claim 35, wherein the electrode is biased to define, upon expansion, a lumen through which blood can flow, and unconstraining the electrode comprises unconstraining the electrode such that blood can flow through the lumen defined by the expanded electrode.

42. The method according to claim 34, wherein:the electrode is a first electrode,the applicator further comprises a second electrode, configured such that expansion of the first electroporation electrode into contact with the wall positions the second electroporation electrode medially from the wall, andthe method further comprises positioning the second electroporation electrode medially from the wall when expanding the first electrode.

43. The method according to claim 42, wherein subsequently to positioning the second electrode, and wherein clearing a margin of the tumor comprises clearing a margin of the tumor by driving the first electrode to apply a series of electroporation pulses between the first electroporation electrode and the second electroporation electrode.

44. The method according to claim 43, wherein the second electrode is non-expandable, and wherein clearing a margin of the tumor comprises clearing a margin of the tumor by driving the first electrode to apply a series of electroporation pulses between the first electroporation electrode and the non-expandable electroporation electrode.

45. The method according to claim 43, wherein the second electrode is expandable, and the method further comprises expanding the second electrode.

46. The method according to claim 45, wherein the second electrode is biased toward expansion and the applicator is configured to constrain the second electrode compressed for advancement into the blood vessel, and wherein expanding the second electrode comprises expanding the second electrode by unconstraining the second electrode.

47. The method according to claim 46, wherein the first electrode is distal from the second electrode, and wherein unconstraining the second electrode comprises unconstraining the second electrode proximally to the first electrode.

48. The method according to claim 47, wherein the applicator is at a distal part of a shaft, and the shaft has a lateral opening, disposed proximally to the first electrode, and the second electrode is configured to be constrained, while advanced, inside the shaft, and wherein unconstraining the second electrode comprises unconstraining the second electrode to emerge through the lateral opening when expanding.

49. The method according to claim 47, wherein the second electrode is biased to form a helix upon expansion, the helix encircles the shaft, and wherein unconstraining the second electrode comprises unconstraining the second electrode to form a helix upon expansion.

50. The method according to claim 49, wherein the second electrode is biased to define, upon expansion, a lumen through which blood can flow, the helix encircles the shaft, and wherein unconstraining the second electrode comprises unconstraining the second electrode such that blood can flow through the lumen defined by the expanded second electrode.

51. The method according to claim 1, further comprising intravenously administering a systemic anticancer chemotherapeutic agent prior to the endovascular advancing of the applicator.

52. The method according to claim 1, wherein the electroporation is a reversible electroporation.

53. The method according to claim 1, wherein the electroporation is an irreversible electroporation.

54. The method according to claim 1, wherein the electrode is biased toward expansion, and wherein the method further comprises constraining the second electrode in a compressed state for advancement into the blood vessel, andexpanding the second electrode within the blood vessel by unconstraining the second electrode.

55. The method according to claim 1, wherein clearing the margin of the tumor comprises clearing the margin of the tumor by driving the electroporation pulses unidirectionally through the blood vessel wall.

56. A method for transvascular treatment of a tumor in an organ of a subject, the method comprising:endovascularly advancing an electrode of an applicator to an intravascular site adjacent the tumor;conducting an electroporation of the tumor by driving the electrode to apply a series of electroporation pulses from the intravascular site transvascularly to the tumor; and subsequently, resecting at least some of the tumor.

57. A method, comprising:endovascularly advancing an electrode of an applicator to an intravascular site adjacent a tumor of a subject;driving the electrode to apply a series of electroporation pulses from the intravascular site transvascularly to the tumor;determining an effect that the electroporation pulses had on the tumor; and responsively to the determining, identifying the subject as being a candidate for resection of at least some of the tumor.

58. The method according to claim 57, further comprising, responsively to the identifying, resecting at least some of the tumor.

59. A method, comprising:identifying a subject as having had a series of electroporation pulses applied from an intravascular site transvascularly to a tumor of the subject; andresponsively to the identifying, resecting at least some of the tumor.

60. The method according to claim 59, further comprising, prior to the identifying, driving an endovascular electrode to apply the series of electroporation pulses from the intravascular site transvascularly to the tumor.

61. A method for transvascular treatment of a tumor in an organ of a subj ect, the method comprising:endovascularly advancing an applicator to an intravascular site adjacent the tumor; at the intravascular site, expanding a first electroporation electrode of the applicator into contact with a vascular wall;at the intravascular site, positioning a second electroporation electrode of the applicator medially from the vascular wall; andwhile the applicator remains at the intravascular site, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between the first electrode and the second electrode.

62. A system for treatment of a tumor adjacent to a blood vessel of a subject, the system comprising:a tool, comprising:a flexible shaft,at a distal part of the shaft, an applicator, advanceable into the blood vessel, and comprising:an expandable first electroporation electrode, expandable into contact with a wall of the blood vessel; anda second electroporation electrode, configured such that expansion of the first electroporation electrode into contact with the wall biases the second electroporation electrode medially away from the wall; andat a proximal part of the shaft, a connector assembly comprising: a first connector, electrically connected to the first electroporation electrode; anda second connector, electrically connected to the second electroporation electrode; anda pulse generator:comprising a first terminal to which the first connector is connectable, and a second terminal to which the second connector is connectable; andconfigured to electroporate cells of the tumor by, via the first terminal connected to the first connector and the second terminal connected to the second connector, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between (i) the first electroporation electrode in contact with the wall, and (ii) the second electroporation electrode disposed medially from the wall.

63. A system for treatment of a tumor adjacent to a blood vessel of a subject, the system comprising:a tool, comprising:a flexible shaft, defining an axial axis along the shaft,a first conductive wire extending along the shaft,a second conductive wire extending along the shaft, andat a distal part of the shaft, an applicator, advanceable into the blood vessel, and comprising:a first electroporation electrode,a second electroporation electrode, anda non-conductive centering mechanism radially expandable into contact with a vascular wall of the blood vessel in a manner that:supports the first and second electrodes medially from the vascular wall, andallows blood within the blood vessel to flow past the applicator andat a proximal part of the shaft, a connector assembly comprising:a first connector, electrically connected to the first electrode via the first wire; anda second connector, electrically connected to the second electrode via the second wire; anda pulse generator:comprising a first terminal to which the first connector is connectable, and a second terminal to which the second connector is connectable; andconfigured to electroporate cells of the tumor by, via the first terminal connected to the first connector and the second terminal connected to the second connector, applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between the first electrode and the second electrode while the first electrode and the second electrode are supported medially from the vascular wall by the centering mechanism.

64. A system for treatment of a tumor adjacent to a blood vessel of a subject, the system comprising a tool that comprises:a flexible shaft, andat a distal part of the shaft, an applicator, advanceable into the blood vessel, and comprising:an expandable first electroporation electrode, expandable into contact with a wall of the blood vessel; anda second electroporation electrode, configured such that expansion of the first electroporation electrode into contact with the wall biases the second electroporation electrode medially away from wall,wherein the system is configured to electroporate cells of the tumor by applying electroporation pulses transvascularly to the tumor by driving the electroporation pulses between (i) the first electroporation electrode in contact with the wall, and (ii) the second electroporation electrode disposed medially from the wall.

65. A system for treatment of a tumor adjacent to a blood vessel of a subject, the system comprising:a tool, comprising:a flexible shaft, andat shaft distal end, an electrode mechanism, comprising:an electroporation electrode, slidable along the shaft,a spring, attached to the electrode at a first spring-end, and fixed, at a second spring-end, to the shaft, the spring biases the electrode to rest distally; anda stopper, disposed unattached at the second spring-end, and elongates along the spring to attach to the first spring-end; configured:to limit spring extension, andto slide along with the electrode;at the shaft proximal end, an extracorporeal unit, operatively coupled to the electrode mechanism, and comprising a connector that is electrically connected to the electroporation electrode; anda pulse generator, comprising a terminal to which the connector is connectable, the pulse generator is configured to apply, via the connector connected to the electrode, electroporation pulses transvascularly to the tumor,wherein the extracorporeal unit is configured to slide the electrode proximally along the shaft at a maximal displacement defined by a gap between the stopper and the second spring-end.

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