WO2000028913A1 - Appareil et technique permettant d'encapsuler des tumeurs malignes, de les tuer et de les enlever - Google Patents

Appareil et technique permettant d'encapsuler des tumeurs malignes, de les tuer et de les enlever Download PDF

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Publication number
WO2000028913A1
WO2000028913A1 PCT/US1999/023595 US9923595W WO0028913A1 WO 2000028913 A1 WO2000028913 A1 WO 2000028913A1 US 9923595 W US9923595 W US 9923595W WO 0028913 A1 WO0028913 A1 WO 0028913A1
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Prior art keywords
capsule
tissue
iron
agent
channel
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PCT/US1999/023595
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English (en)
Inventor
Robert G. Carroll
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Oncology Innovations, Inc.
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Application filed by Oncology Innovations, Inc. filed Critical Oncology Innovations, Inc.
Priority to AU11078/00A priority Critical patent/AU1107800A/en
Priority to DE19983750T priority patent/DE19983750T1/de
Publication of WO2000028913A1 publication Critical patent/WO2000028913A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00234—Surgical instruments, devices or methods, e.g. tourniquets for minimally invasive surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491—Surgical glue applicators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00867—Material properties shape memory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22082—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance

Definitions

  • This invention relates to the treatment of tumors within an organism, and more specifically, to encapsulating, destroying and removing malignant tumors from an organism.
  • New possibilities for concentrating rare circulating tumor cells from the peripheral blood and possibilities for detection of rare tumor cells m marrow may allow adequate certainty to proceed with lumpectomy as biopsy, avoiding one tumor shedding exposure. If clinical presentation and diagnostic images are shown to be more than 90 percent predictive m defined circumstances, biopsy may also be bypassed with adequate informed consent. In cases where biopsy cannot be eliminated, strategies for minimizing tumor shedding should be evaluated. Broadly, both physical and chemical methods are possible.
  • Physical methods include blockade of lymphatics using injection of substances around the full three dimensional perimeter of the tumor (peritumoral injection) m order to clog or constrict the lymphatics.
  • peritumoral injection of the patient's fresh whole blood which has been freshly hemolyzed by addition of sterile water for injection is a physiologically attractive maneuver. Not only are the lymphatics obstructed by red cells, but tissue clotting mechanisms are activated and small veins may clot. Edema should further close off lymphatics and small veins. Local macrophage activation may result in destruction of some tumor cells.
  • Peritumoral blockade is probably not adequate by itself to eliminate tumor shedding in cases where the tumor itself is surgically entered, rather than only pierced by a biopsy needle. If we want to excise small tumors with minimal invasion, we need a truly robust way to contain and kill spilled tumor cells.
  • Primary and metastatic malignant tumors can be treated by a variety of methods, including surgical excision, chemotherapy and radiation therapy.
  • a primary goal of all of these therapeutic methods is to remove and/or inactivate the tumor while causing as little collateral damage as possible to healthy tissues within the organism being treated.
  • Surgical excision of a tumor with a minimum of collateral damage to healthy tissues has been facilitated by advances in the arts of microsurgery, endoscopic surgery and real-time imaging.
  • surgical techniques using surgical/imaging devices enable surgeons to precisely distinguish in real-time between tissues to be removed and tissues to be preserved intact within an organism.
  • Unfortunately it has been found that the very act of surgically excising a tumor from an organism, no matter how precise the surgical technique, can cause the tumor to metastasize, thus causing collateral damage to healthy tissues which may not become clinically apparent for months or years, but which will almost always progress to kill the patient.
  • U.S. Patent No. 5,458,597 deals with creation of a diffusion barrier of heat coagulated tissue proteins in order to restrict the outflow of locally injected chemotherapeutic agents from the thermally created tumor crater. Necrotic tissues and the coagulation capsule are left behind, where they are at substantial risk of becoming infected.
  • U.S. Patent No. 5,472,441 teaches providing a radio-frequency induced tissue coagulation barrier around a tumor to contain locally injected chemotherapy. Only metastatic cancers with no prospect for cure would be suitable for such a palliative nonsurgical approach where the additional risk of shedding tumor cells by piercing the tumor is irrelevant because of the short lifespan of patients with metastatic disease. Failure to remove the killed tissues as taught in this patent places the patient at risk for infection.
  • Radiation sensitizers have been sought to selectively increase damage to malignant tissues while sparing healthy tissues. Unfortunately, these radiation sensitizers can themselves be toxic to healthy tissues when injected at levels high enough to achieve their radiation enhancing effect, and/or might not persist in the area of the tumor for a time sufficient to enhance the effect of radiation on the tumor.
  • the instant invention addresses at least the foregoing deficiencies of the prior art by providing methods for conducting an operation on a living organism, said method comprising: providing a channel around a tissue of said organism; and infusing into said channel an encapsulating composition to encapsulate said tissue in a capsule, wherein said capsule impedes materials encapsulated therein from migrating to other tissue outside said capsule.
  • the invention also provides an improved method of radiation therapy comprising administering a radiation enhancing agent in or near a tissue to be treated.
  • the radiation therapy method can conducted with or without encapsulation.
  • Figs. 1A, IB and 1C are sequential side views of a double hollow needle blade embodiment of the apparatus of the invention being deployed through a trocar;
  • Fig. 2 is a side view of a deployed single hollow needle blade embodiment of the apparatus of the invention
  • Fig. 3 is a side view of an ultrasonic tissue destruction and removal probe of the invention.
  • Fig. 4 is a front view of the probe of Fig. 3.
  • Fig. 5 is a front view of an alternative embodiment of a tissue destruction and removal probe of the invention.
  • the invention provides a method and an apparatus for creating a capsule which contains tissue to be treated, destroyed and/or removed, e.g., a tumor with adequate margins.
  • the invention also provides a method and an apparatus for treating tissues with radiation-enhancing agents, particularly residual tissues remaining when total tumor removal is impossible .
  • the invention is not limited thereto.
  • the invention encompasses the isolation, treatment, destruction, and/or removal of other tissues as well.
  • a capsule surrounding a malignant or potentially malignant tumor can be provided, which prevents significant collateral damage by metastasis to tissues outside of the capsule, and optionally allows the tumor within the capsule to be treated more aggressively, yet safely, using minimal invasive surgical techniques, including ultrasonic tissue ablation, resectoscope, chemical digestion, and the like.
  • minimal invasive surgical techniques including ultrasonic tissue ablation, resectoscope, chemical digestion, and the like.
  • Such aggressive treatment can include the provision of radiation enhancing agents to any unresectable tumor residue and/or to the tissues surrounding the capsule which are at risk of harboring viable tumor cells.
  • a preferred method of a tumor treating method of the invention comprises:
  • the fresh tissues exposed by removal of the capsule can by examined for residual tumor cells. If residual tumor cells are detected, a new, larger capsule is created, evacuated and removed, as above. If complete surgical tumor excision is impossible, residual tumor is treated by local infiltration of radiation sensitizers and/or therapeutic deposition of radiation sensitizers and other tumor killing agents in a timed release artificial capsule.
  • the blood flow into and out of the cancerous tumor is blocked in a minimally invasive manner.
  • the arteries supplying the tumor and the veins draining the tumor area are selectively coagulated outside the boundaries of the tumor by radio- frequency diathermal heat, preferably with a coaxial bipolar needle electrode.
  • Use of Doppler ultrasound aids identification of blood flow in feeding arteries and draining veins and documents cessation of blood flow with successful diathermy heat coagulation.
  • With successful devascularization including vessels deep to the cancer, only the peritumoral lymphatic flow and flow in small veins remains to be blocked by chemical and or physical agents and processes, as discussed immediately below.
  • Flow in tumor area lymphatics and veinules is further decreased by injection-infiltration of materials causing sludging, clogging, constriction, compression and coagulation.
  • Peritumoral blockage of lymphatic flow and flow in small veins may be achieved by injection of appropriate substances such as combinations of the patient's own whole blood, which has been freshly hemolyzed by addition of sterile water for injection, the patients own fresh plasma, vasoconstrictors, and substances which greatly increase local interstitial fluid viscosity prior to cutting and encapsulation. These measures can further reduce tumor cell shedding by sludging, clogging, constricting, compressing and coagulating peritumoral lymphatics and venules during the cutting process.
  • Red blood cells average 7 microns in diameter, which is relatively large for lymphatic channels. When sterile water for injection is added to blood, the red cells burst (hemoiysis), creating abundant debris of smaller sizes more suited for clogging lymphatic channels.
  • Peritumoral tissue preparation prior to cutting and encapsulation, can be accomplished by injecting:
  • any sclerosing solution such as are used to sclerose varicose veins, including adrenaline, norepinephrine, 95% ethyl alcohol, thrombin, ethanolamine oleate, ethanolamine oleate iopamidole, oleic acids, aethoxysclerol, polyethylene glycols, polydocanol, prolamine (Ethibloc) , minocycline solution, doxycycline solution, tetracycline solution, erythromycin solution, silver nitrate, bleomycin, talc, quinacrine colloids, quinacrine solutions, quinacrine-ionic copper solution, phenol, phenol almond oil, sodium tetradecyl sulfate and OK432.
  • tissue factor, fibrinogen or fibrin to induce clotting.
  • polyethylene glycol including co-polymers and photo-initiating agent, to dramatically raise extracellular fluid viscosity and induce transient tissue solidification.
  • Mechanisms of action include pharmacologic vasoconstrictions, physical tamponade, chemical sclerosis, tissue dehydration, edema and thro bogenesis .
  • One or more cutting devices e.g., blades, needle blades, lasers, wires, cords, torches, particle beams, etc.
  • the artificial capsule is created by providing (e.g., forming, cutting, etc.) a channel between the tumor and the surrounding healthy tissue.
  • a channel can be provided between the tumor-bearing tissue and surrounding healthy tissue by inserting at least one, and preferably an array, of shape memory metallic hollow side cutting blades or needles into the periphery of a tumor under real-time ultrasound, MRI, isotopic, x-ray guidance or combinations thereof.
  • the array comprises a plurality of deployable hollow radio-frequency or microwave antenna or laser or ultrasound energy activated needle blade elements.
  • the array is expanded using cutting radio- frequency or microwave or laser or ultrasound power and rotating 1 to 20 energy depositing elements to cut and define a common onion-shaped, spherical or cylindrical surface, thus isolating a core of tumor-bearing tissue from adjacent healthy tissues, hopefully without tumor at the margins.
  • every other (i.e., alternating) radio-frequency peripheral hollow element can be active or ground, producing a circumferential rather than a radial radio-frequency energy field.
  • This blade design eliminates the need to pierce the actual cancer until after capsule formation, minimizing the chance to dislodge cells.
  • Figs. 1A, IB, 1C and 2 show needle blades 10 which create such a channel when deployed and manipulated through a trocar 12.
  • advanced imaging and/or marking means to precisely distinguish between malignant and healthy tissues when creating the channel surrounding the tumor.
  • the individual blades 10 may be of reshaped spring steel, and may also be fabricated using a metal with shape memory or a bimetallic spring material, wherein shape alters as a function of temperature to cause bending in response to applied energy activation.
  • the channel is filled with an encapsulating composition to form a capsule wall.
  • the encapsulating composition is extruded into the channel through the hollow blades 10.
  • the capsule of the invention does not consist primarily of rigid, brittle heat denatured local tissue components, but rather consists predominantly of injected materials which mix with the patient's own wound blood to form a tough, flexible capsule.
  • the capsule is preferably created by chemical reactions between naturally-occurring components of the patient's own blood, such as plasminogen and fibrinogen, and components of a capsule-forming composition comprising substances (e.g., collagen) that combine with the patient's body chemistry to create a tough, flexible capsule.
  • the capsule may be created with a capsule-forming composition comprising a barrier-forming or film-forming substance, which forms the capsule without chemically reacting with naturally-occurring molecules.
  • the encapsulating composition preferably transforms from liquid to (a preferably elastic) solid form after being injected into the channel.
  • Ultraviolet chemical curing lights such as are commonly used for curing dental materials, may be used to initiate photopolymerization of capsule forming materials which have been doped with suitable photoinitiator compounds.
  • Covalent cross-linking of non-toxic biocompatable polymers has been accomplished in living animals with continuous films of good mechanical strength. See, e.g., West et al . , "Comparison of covalently and physically cross-linked polyethylene glycol- based hydrogels for the prevention of postoperative adhesions in a rat model.” Biomaterials 16:1153-1156, 1995. West et al .
  • the encapsulating composition is adapted to provide a capsule which prevents migration of tumor cells into regional lymphatics and into veins during surgical manipulation and during surgical removal of the abnormal tissue.
  • the encapsulating composition is adapted to provide a capsule which contains the chemical and physical tumor sterilization-destruction-digestion-fragmentation process, protecting adjacent tissues from chemical and physical damage attendant to tumor removal.
  • the encapsulating composition is preferably designed in view of the desired curing method.
  • Curing i.e., solidifying
  • the composition can comprise: components that react with each other to polymerize within a predictable amount of time after mixing; components that melt at a temperature above body temperature (i.e., > 37°C) , are applied as a hot melt and cool to form a solid capsule at body temperature; components that react with naturally prevailing molecules in the patient to form solids or semi-solids; and/or components that polymerize in response to radiation (e.g., ultraviolet radiation applied after injection into the channel) .
  • radiation e.g., ultraviolet radiation applied after injection into the channel
  • Suitable encapsulating compositions are formulated to provide capsules with properties that enhance or are complementary to the particular activities being performed within the capsule.
  • a biocompatible polymer that is resistant to the mechanical and/or chemical means for destroying the tumor is preferably selected.
  • the encapsulating composition can comprise a combination of materials selected for their various advantageous properties. Materials potentially useful in artificial capsule formation can be found in the book Surgical Adh esi ves and Sealants Current Technology and Appli ca ti ons, edited by David Sierra et al . (Technomic Publishing 1996, Library of Congress #95-61620) .
  • the encapsulating composition is adapted to provide a capsule which prevents migration of tumor cells into regional lymphatics and into veins during surgical manipulation and during surgical removal of the abnormal tissue.
  • the encapsulating composition is adapted to provide a capsule which contains the chemical and physical tumor sterilization-destruction-digestion-fragmentation process, protecting adjacent tissues from chemical and physical damage attendant to tumor removal.
  • the encapsulating composition is preferably physiologically compatible, although in certain circumstances physiological incompatibility is tolerable. For example, localized toxicity is acceptable when the method is employed as a palliative measure in terminal patients.
  • a marking agent e.g., an imaging ultrasound, x-ray, magnetic resonance or combined marking agent
  • an imaging ultrasound, x-ray, magnetic resonance or combined marking agent e.g., an imaging ultrasound, x-ray, magnetic resonance or combined marking agent
  • the capsule is to be removed after its evacuation, it is advantageous to provide an elastic capsule which does not adhere to body tissues.
  • the capsule typically extends to and bonds with the perimeter of the introducing needle or trocar, forming a sealed system, sealed to the outer skin, open to the outside of the body.
  • the length of the capsule to trocar seal may be increased by advancing the trocar further into the tumor while partly retracting blades 10 after the encapsulating composition has been freely applied within the channel .
  • the capsule provided by the methods and devices of the invention has at least the following beneficial effects.
  • First, the capsule prevents materials inside the capsule from contacting and damaging tissues outside the capsule.
  • Second, the capsule can enhance the anti-tumor effectiveness of the therapy by maintaining the focus of the therapy within a confined area surrounding the tumor.
  • any combination of chemical, physical and/or mechanical means of tissue destruction are employed to destroy the contents of the capsule.
  • desiccants such as absolute ethyl alcohol
  • cell bursting agents such as distilled water
  • free- radical catalysts such as iron and copper ions
  • free-radical chemical reaction initiators such as hydrogen peroxide and hypochlorite bleach solution
  • halogenators such as iodine tincture.
  • Enzymes such as colligenase, chondroitin sulfate, and DNAase, as well as proteolytic enzymes, such as trypsin, which are physiologically secreted by the pancreas, may be used to digest tissues. Papain and other common biochemical enzymes may also be used. Use of radio-frequency cutting and coagulation as well as adaptation of the common resectoscope normally used for transurethral resection of the prostate are also appropriate. Ultrasound, laser, microwave or radio-frequency energy can be deposited in the tissue to be destroyed using tumor penetrating probes or through skin or nearby tissues such as the vagina, bowel wall, oral cavity or other energy transmission site external to the capsule.
  • Ultrasound energy can be very effective in tumor destruction-digestion-fragmentation. Ultrasound has been used in cataract emulsification and in brain tumor debulking. Ultrasound energy induces local hyperthermia which is beneficial in tumor killing and lysis. Local hyperthermia significantly increases the rate of all chemical reactions.
  • the invention enables complete removal of large tumors from anywhere in an organism through a small, minimal access puncture, by liquefaction and removal of the contents of the artificial capsule.
  • Liquefaction is preferably accomplished by physical means, such as comminuting the tissue with a moving (e.g., rotating, reciprocating, etc.) slicing means (e.g., a spinning cord or blade) to which the capsule walls are resistant, and/or chemical means.
  • the contents of the artificial capsule are liquefied using ultrasonic energy, preferably having a wavelength of about 20 to about 40 kilohertz, transmitted through a titanium wand incorporating irrigation and suction functions.
  • Use of radio-frequency cutting and coagulation as well as adaptation of the common resectoscope normally used for transurethral resection of the prostate is also appropriate.
  • Tumor tissues may be particularly sensitive to destruction by high power ultrasound, even in the absence of pretreatment with hypotonic solutions, because tumor cells generally exhibit higher intracellular pressures than are found in normal cells.
  • Pretreatment with absolute ethyl alcohol sucks water out of cells and injures cell membranes. Sterile distilled water subsequently administered rushes into the dehydrated cells, bursting them.
  • Membrane destruction may be done with physical energy, such as 20 to 40 kilohertz frequency high energy ultrasound, or by chemical means, or preferably by a combination of chemical pretreatment, metallic colloid treatment, augmented by subsequent 20 to 40 kilohertz frequency high energy ultrasound.
  • High power 20 to 40 kilohertz ultrasound bursts cell membranes especially well if prior exposure to a hypotonic solution has caused cells to swell.
  • Such high energy ultrasound also focally heats tissues, and vastly increases chemical and catalytic reactivity of metallic powders or colloids which may have been previously deposited in said tissues.
  • Conventional 20 to 40 kilohertz frequency high power ultrasound titanium probes which have heretofore been used for fat reduction surgery can be adapted for tumor removal.
  • Zocchi Ultrasonic Liposculpting, " Aesth. Plast. Surg. 16:287-298, 1992.
  • Zocchi advocates infiltration of large volumes of a physiologic salt solution 50% diluted with distilled water to render the cells vulnerable to ultrasound energy induced cell bursting.
  • Zocchi also uses the enzyme chondroitin sulfate. As shown in Figs. 3 and 4, improvements over Zocchi ' s design (which more closely resembles the alternative embodiment of the invention depicted in Fig.
  • a central passage 14 for irrigant and a coaxial suction cannula 16 adjustably positioned around a multi-edge, preferably titanium, ultrasound energy transmitting probe.
  • Further improvements over Zocchi include use of absolute ethyl alcohol, followed by distilled water, as well as free-radical reaction catalysts, such as iron and copper ions, free-radical chemical reaction initiators, such as hydrogen peroxide and hypochlorite bleach solution, and halogenators, such as iodine tincture. Powders and colloids of iron and copper may provide significant chemical catalytic free-radical mediated tissue destruction by chemical and physical increase in reactive surface as documented by Suslick et al . , "On the origin of sonoluminescence and sonochemistry, " Ultrasonics 28(5) 280-290, September 1990.
  • a rigid tube may be inserted which has rows of orifices along its circumference through which cords, wires or blades are radially deployed into the adjacent tissue. Multiple rows of radial elements are deployed into the encapsulated tissues in this manner to transmit ultrasound, microwave, diathermy or other energy forms into the tissue. The degree of destructive energy can be modulated to achieve the desired degree of cell killing and/or liquefaction.
  • a multiplicity of fine wires may be deployed, which are hollow at their core, thereby allowing hypodermic injection of selected chemical or biochemical substances throughout the volume of the tumor to selectively increase the tissue destruction either by more efficient coupling with the energy field being deposited, or in order to propagate chemical reactions that are induced by the deposition of energy.
  • free-radical reactions can be supported by the presence in tissue of elemental iron or copper, especially of selected valences.
  • the tumor can be macerated within the artificial capsule with a grinder suction probe modeled on "rotorooters” used to remove atherosclerotic plaque, a side cutting tissue auger with attached suction probe.
  • Mechanical tumor removal can also proceed by more conventional mechanical tumor removal by resectoscope, side-cutting or end-cutting minimally invasive surgical instruments such as the ABBYTM or BIOPSYSTM systems, vacuum assisted auger or "rotorooter” tissue extraction, or various means of mechanical tissue maceration.
  • the capsule contents can also be removed by endoscopic or direct visually guided dissection.
  • Wires, cords and/or fibers can be introduced and rapidly rotated like a WEED WACKERTM gardening device.
  • Such rotatable elements can effectively mince tissue, allowing the suction removal of tissues that have been destroyed.
  • encysting and appropriate biochemical treatment of the tumor prior to mechanical mincing may be valuable.
  • thin metallic blades are advanced to extend beyond the diameter of the trocar in order to engage tissue.
  • the needle shaft in its entirety, or just the portion of the needle shaft that has the blade elements projecting therefrom, is then rapidly rotated coaxially with the needle shaft.
  • an approximately cylindrical volume of tissue is minced in si tu .
  • Application of irrigation solution and application of suction facilitates the removal of the debris, leaving only healthy tissues behind.
  • tissues can be mechanically minced or destroyed by movement of elements designed to whip, shred, or mince tissues.
  • a roughly spherical volume of tissue destruction can be readily achieved.
  • roughly cylindrical volumes of tissue destruction seem readily achievable.
  • more specialized volumes and shapes can be achieved by modification or repositioning of the tissue destructive elements emanating from the placement needles.
  • Micromotors exist which can individually drive the tissue destructive elements so that the individual elements can rotate as well as be moved by the movement of the shaft of the needle. That is, the elements can be rotated about their own axis or whipped about similar to a WEED WACKERTM while at the same time the shaft of the needle upon which they are mounted is also rotating on its own axis. In such a way, more extensive tissue destruction is rapidly achieved.
  • One advantage of mincing, liquefying and removing the cancerous tumor is to assure that complete tissue destruction has, in fact, occurred. If the tumor is simply destroyed in its location and allowed to remain, a palpable lump persists. If the tumor, having been killed, is then minced, liquefied and withdrawn from the body, it is possible that healing may occur without production of a palpable area of scar tissue. Thus, assurance that the tumor is not regrowing would be provided.
  • Every other alternating diathermy peripheral element is either active or ground, producing a circumferential rather than a radial diathermy energy field.
  • the diathermy coagulation power can preferably be applied using the same alternating active or ground elements. For this use, cutting power is applied to the antenna array as it is pulled back from the created capsule wall, to a position about 2/3 the capsule diameter. To maintain clearance from the capsule wall closest to the surface, the trocar may be pushed further forward under ultrasound control. Much higher coagulation diathermy power is then applied under real-time ultrasound visualization to heat, kill, and shrink the tumor bearing tissues within the capsule, without injury to the capsule wall or to tissues beyond the capsule wall.
  • a bipolar diathermy system with a central needle serving as ground electrode plus 1 to 20 wire antennas radiating to surround the central ground can be inserted into the encapsulated tumor to define a spherical or cylindrical diathermy field.
  • the configuration may resemble antennas deployed on space satellites.
  • Chemical tumor sterilization and destruction-digestion- fragmentation means include: dehydration by absolute ethyl alcohol, optionally followed by povodine-iodine, and then by osmotic cell bursting using distilled water or other hypotonic solutions; enzymatic degradation, including digestion by collaginase and/or pappain; acid and/or base degradation; applying sodium hypochlorite solutions, applying hypertonic salt solutions, applying local hyperthermia, and applying tincture of iodine.
  • Final sterilization of the tumor bed and instrument track can be achieved by providing chemical sterilization agents within the capsule's interior.
  • Suitable chemical sterilization agents include free-radical catalysts, such as iron and copper ions, initiators, such as hydrogen peroxide and hypochlorite bleach solution, halogenators, such as iodine tincture, desiccants, such as absolute ethyl alcohol, and cell bursting agents, such as distilled water causing osmotic rupture. Physical heat from diathermy or cell membrane bursting from high power ultrasound is useful for final sterilization of the capsule interior, capsule exterior, and instrument track.
  • free-radical catalysts such as iron and copper ions
  • initiators such as hydrogen peroxide and hypochlorite bleach solution
  • halogenators such as iodine tincture
  • desiccants such as absolute ethyl alcohol
  • cell bursting agents such as distilled water causing osmotic rupture. Physical heat from diathermy or cell membrane bursting from high power ultrasound is useful for final sterilization of the capsule interior, capsule exterior, and instrument track.
  • the sterilized capsule wall is safely removed by peeling with a suitable tool, by resectoscope (e.g., as commonly used in prostate surgery) , by endoscopic or direct surgical dissection, or by side-cutting or end-cutting minimally invasive surgical instruments, such as the ABBYTM or BIOPSYSTM systems.
  • Capsule wall removal technique can mimic opening a sardine can by peeling the capsule membrane onto a key like tool. Removal of the capsule wall eliminates a palpable residue that could mask local tumor recurrence.
  • Final treatment of the cavity after removal of the capsule wall by installation of residual action locoregional tumor bed and lymphatic treatment agents can be performed.
  • suitable sustained-release materials can be incorporated into the created capsule wall.
  • suitable sustained-release materials include, e.g.: chemotherapeutic agents; sterilization agents; biological response modifying agents, such as histamine, cytokines, and anti-growth factor blockers; and radiation-enhancing agents, such as ferric lactate.
  • the capsule interior can be examined by standard optical or video endoscopic or laparoscopic or other minimal access surgical tools.
  • Exposed fresh tissues are examined for residual tumor cells.
  • pathology touch preparations are obtained from the freshly exposed tissue walls after the capsule has been removed from the patient. If margins are tumor positive, the procedure is repeated to encapsulate a larger volume of tissue, or a side lobe of tissue.
  • an enlarged capsule is formed around a temporary support structure provided by a balloon expanded within the void created by evacuation of the contents of the original capsule.
  • Iron and copper compounds and colloids can be infiltrated into at- ⁇ sk tissues by multiple closely spaced injections, or introduced into the retained capsule wall in order to potentiate other therapies such as systemic chemotherapy, non-ionizing radiation, ionizing radiation, and ultrasound energy deposition.
  • Radiation sensitizers include atoms having atomic numbers higher than the atoms m tissue, favoring greater interaction with the x-ray beam. A 30° increase m tumor radiation sensitivity allows much higher cancer cure rates with much lower damage to normal tissues.
  • iron and copper are intrinsically highly catalytic for free-radical reactions, especially when ionized by incident x-rays. These metals may also be activated by ultrasound energy, and potentially by laser energy.
  • iodine compounds used for conventional x-ray contrast can be reformulated as colloids or small particles which can remain m the tissues long enough to facilitate-radiation therapy treatments lasting many weeks.
  • Tumor killing effectiveness of each unit of absorbed radiation can be greatly enhanced by maximizing formation and propagation of the free-radical reactions initiated when ionizing radiation knocks electrons off target molecules.
  • Iron and copper are potent catalysts for free-radical reactions withm the living body. Iron and copper also have atomic numbers greater than tissue, increasing the likelihood of interaction with the radiation therapy beam.
  • the invention also encompasses the prophylaxis and treatment of local and regional lymphatic vessels and nodes with extended release forms of biological response modifiers, iron and copper compounds, and extended release forms of conventional cancer chemotherapeutics, infiltrated into tissues surrounding the removed capsule wall or slowly released from biodegradable resorbable capsule wall.
  • the artificial capsule can be formulated to include a wide range of physical, chemical and/or biological therapeutic agents which are slowly released (i.e., sustained-release agents) to provide local tissue treatment and locoregional lymphatic treatment.
  • Radiation sensitizers have been sought to selectively increase damage to malignant tissues while sparing healthy tissues. Unfortunately, these radiation sensitizers can themselves be toxic to healthy tissues when injected at levels high enough to achieve their radiation enhancing effect, and/or might not persist in the area of the tumor -for a time sufficient to enhance the effect of radiation on the tumor.
  • transition metals including Cu
  • Cu 2+ associates with the guanine-cytosine base pair of DNA to create local free-radical damage to the DNA characteristic of attack by hydroxyl ion.
  • Copper is a powerful promoter of free-radical damage to lipids, proteins, and especially to DNA and its bases. See Aruoma, "Copper ion- dependent damage to the bases in DNA in the presence of hydrogen peroxide," Biochemical Journal 1991, 273: 601-4.
  • Iron-catalyzed injury results in damage to cell constituents, including oxidative damage to lipid membranes, proteins, nucleic acids, mitochondria, lysosomes, and the sarcolemmal membrane. Many pathological events are thought to be associated with peroxidation of lipids in biological membranes. This peroxidation proceeds by a free-radical chain reaction (1 - 3) :
  • the initiation reaction (1) is one of the key steps. Iron is a well-known catalyst of initiation step (1), and iron-oxygen species have been suggested to be responsible for initiation of peroxidation. However, it has been pointed out that since biochemical membrane systems always contain traces of preformed lipid peroxide (LOOH) , added iron is more likely to stimulate peroxidation by decomposing lipid peroxide to the alkoxy radical (LO*) (4) than by generating initiating species.
  • LOOH preformed lipid peroxide
  • LO* alkoxy radical
  • LOOH-dependent lipid peroxidation plays an important part in oxidative deterioration of biological membranes.
  • Treatment of locoregional lymphatics may be performed by inclusion of therapeutic colloids and slow release chemical formulations within the materials forming the capsule wall and/or by direct injection of therapeutic materials outside the capsule wall.
  • therapeutic substances may include conventional antineoplastic agents, including colloidal forms of such agents designed for sustained-release and preferential lymph node targeting.
  • Suitable therapeutic substances include colloidal radioactive agents, hormonal agents, biological growth modifiers, growth factor blocking agents, DNA transacting viral probes, and free-radical catalytic chemical means.
  • Iron dextran is a U.S. Food and Drug Administration approved injectable agent formulated for intravenous or intramuscular injection.
  • a suitable dose is about 100 milligrams of iron in 1 milliliter of volume.
  • direct tissue iron toxicity, and local radiation sensitization within the diffusion zone surrounding the persistent iron dextran significantly increased tumor control can be achieved.
  • Addition of systemically administered iron chelating agents by periodic intravenous administration provides protection against the metastasis growth promoting effects of elevated systemic iron levels.
  • tumors which kill primarily by local invasion, such as brain glioblastoma multiforme and pancreatic cancer, and in which the role of metastatic disease is minimal.
  • Such carefully selected tumors may benefit from local tissue iron toxicity and local radiation sensitization, without the necessity of systemically administered iron chelating agents.
  • Tumors with any metastatic potential are best treated with systemically administered iron chelating agents.
  • the radiation enhancing material is, for example, injected directly into the prostate gland through the rectal wall, the prostate would be diffusely labeled and some iron dextran would flow out into lymphatics draining the prostate.
  • the intra prostate cancer area as well as the lymphatics that may harbor spread of prostate cancer can both receive the benefits of enhanced radiation therapy effectiveness when those areas are treated.
  • iron dextran or other persisting iron/copper compounds are directly injected into lung cancers or other solid tumors through CT, MR or ultrasound guided needles in a technique resembling needle biopsy, the benefits of this radiation sensitization technique could extend to all solid tumors .
  • Iron dextran or other persisting iron/copper compounds can also be deposited into tumors through bronchoscopic methods, or by angiographic injection into feeding arteries. Injection into the portal veins of the liver may be useful for some tumors. Direct lymphatic injections may also be useful.
  • Ferricenium salts can act as radiosensitizers of hypoxic cells. The toxicity of these metal complexes, but not their radio-sensitizing ability, is reduced by including serum albumin in the medium. See, e.g., Joy et al . , in J. Radiation Oncology Biol. Phys., 16: 1053-56, 1989 and Teicher, et al . , in Radiation Research 109: 36-46, 1987.
  • U.S. Patent 5,246,726 discloses oral administration of an essential fatty acid along with oral administration of iron. It does not mention the possibility of intravenous preparations of fatty acids in which appropriate daily doses are given by intravenous administration of fatty acid emulsions coupled with daily doses of iron given either in the same preparation or by another route, for example, iron dextran or iron sorbitol preparations for intramuscular injection in the treatment of persons suffering from cancer.
  • the patent discloses that the cancer cell killing effect of fatty acids is dramatically enhanced when the fatty acids are provided to cancer cells in the presence of iron within a culture. There is no use of ionizing radiation in the patent.
  • Iron bound to negatively charged ligands including citrate, ammonium citrate, nitrofluoracetic acid, or adenosine diphosphate has increased solubility which enhances the redox-cycling of iron, allowing iron to catalyze oxidative
  • O2 ⁇ ascorbate results in the release of iron into pools that can catalyze oxidative injury.
  • hydrogen peroxide can release iron from hemeproteins, exacerbating oxidative damage.
  • Ischemia causes approximately a 10-20 nM increase in cytosolic iron.
  • Acidic environments caused by ischemia or inflammation can result in the release of iron from Tf, even at physiologic levels of iron saturation.
  • Redox-cycling by iron between Fe 2+ and Fe3+ damages biomolecules, causing cell injury.
  • Fe reacts with super oxide anion and hydrogen peroxide via the Haber-Weiss mechanism to generate the very reactive hydroxyl radical.
  • the second reaction between Fe 2+ and hydrogen peroxide that generates *OH is the Fenton reaction.
  • Iron-catalyzed hydroxyl radical formation requires at least one aqueous coordination site in the iron coordination sphere.
  • Iron ligands such as EDTA, sugars, citrate, and nucleotides (including ATP and ADP) allow water in the iron coordination complex and catalyze subsequent iron-catalyzed *OH formation.
  • *OH causes oxidative damage to DNA, membrane lipids, and proteins.
  • Protein damage can involve protein sulfhydryl oxidation, carbonyl group formation, or oxidative bond cleavage. Protein damage leads to enzyme inactivation, structural protein alteration, and often accelerated proteolysis. Oxidative DNA damage causes strand breaks and cross-linking, as well as the hydroxylation of bases, the latter providing a marker of oxidative damage to DNA. By any of these mechanisms, oxidative damage to DNA increases the incidence of mutations. Iron can both initiate and propagate lipid peroxidation, leading to altered membrane fluidity, inactivation of membrane-bound enzyme complexes, and eventual membrane disruption. Fe 2+ bound to ADP and ATP is an especially good catalyst for *OH generation, and of potential physiologic importance as well. The Fenton reaction between Fe 2+ , -ADP and hydrogen peroxide clearly damages tissues.
  • Fe Fe ratios of 1:1 to 7:1 result in the highest rates of lipid peroxidation.
  • Fe 2+ -ADP is an efficient initiator, but does not result m propagation.
  • Fe 2+ -EDTA is an efficient propagator of lipid peroxidation.
  • iron could be involved m damage to cell membrane lipids m at least three ways: (1) iron-generated
  • Mitochondrial calcium release initiates subtle cycles of calcium uptake and release from mitochondria that consume energy and impair cellular calcium homeostasis, predisposing to cell damage.
  • Hydrogen peroxide can diffuse across cell membranes, while super oxide can traverse anion channels. This finding is consistent with results m cell culture that target cells provide the mtracellular iron for their own destruction, even
  • Iron-catalyzed injury results in damage to cell constituents, including mitochondria, lysosomes, and the sarcolemmal membrane. These mechanisms of iron-mediated damage are involved in the pathogenesis or organ dysfunction in primary hemochromatosis, transfusion-related iron overload, ischemia- reperfusion injury and cardiac anthracycline toxicity.
  • DNA, cellular proteins, lipid membranes, mitochondria and other cellular organelles are targets for molecular damage caused by either covalent binding of primarily electrophilic, but in some cases free-radical, reactive intermediaries and direct free-radical initiated oxidative stress resulting in target oxidation.
  • Fujii et al. recently reported on site-specific mechanisms of initiation by chelated iron and inhibition by alpha- tocopherol of lipid peroxide dependent lipid peroxidation in charged micelles. See Archives of Biochemistry and Biophysics 284: 120-126. 1991.
  • Al ions m aqueous solution undergo extensive hydrolysis at pH 7.4. Qumlan et al . hypothesize that Al binds to the membrane surface, thus causing a localized freezing of phospholipid movement, facilitating the propagation of peroxidation. This work suggests that aluminum sulfate in concentrations of 10 mM to 400 mM m conjunction with ferrous ammonium sulfate at 100 mM produces catalytic effects.
  • Phagocytic cells such as monocytes and macrophages, may become activated by contact with foreign compounds and foreign particles m the treated tissue. Activated phagocytic cells produce toxic metabolites of oxygen coupled with the release of granular enzymes and the formation of highly reactive metabolites such as hypochlorite.
  • the entire range of white cells including polymorphonuclear leukocytes, T-cells, basophils, eosinophiles, monocytes and macrophages, can be involved in tissue injury reactions. Such reactions may serve to initiate further propagation of oxidative free-radical injury.
  • Hydroxyl radicals are produced in living organisms by at least two mechanisms: (1) reaction of transition metal ions with hydrogen peroxide, and (2) homolytic fission of water caused by ionizing radiation. Hydroxyl radicals are extraordinarily reactive and attack all biologic molecules, usually setting off free-radical chain reactions. Transition metals, including i _ ⁇ _ i 4- 4-
  • Organisms take great care in the handling of iron, using both transferring transport protein and ferritin and hemosiderin storage proteins to minimize the amount of "free" iron within cells and in extra-cellular fluids. This sequestration of transition metals is a very important contribution to antioxidant defenses.
  • oxidative stress itself can provide iron for free-radical reactions. *02 can mobilize iron from ferritin, and hydrogen peroxide can degrade. Copper is a powerful promoter of free-radical damage to lipids, proteins, and especially to DNA and its bases. See Aruoma "Copper ion- dependent damage to the bases in DNA in the presence of hydrogen peroxide.” Biochemical Journal 1991, 273: 601-604.
  • tissue injury has been initiated by a free-radical cascade, additional injury mediators, such as prostaglandins, leukotrienes, interleukins, interferons, and tumor necrosis factors, may all play additional roles.
  • an object of this invention in addition to providing artificial capsules for treating tumors is to selectively increase tissue destruction either by more efficient coupling with the energy field being deposited or m order to propagate chemical reactions that are induced by the ⁇ eposition of ionizing radiation.
  • free-radical reactions can be propagated by the presence in tissue of elemental iron or copper, especially of selected valences. Iron or copper ions and/or colloids can serve to profoundly alter the electromagnetic characteristics of tissue, thereby allowing more effective coupling of the ionizing radiation energy with the volume of tissue containing such increased concentrations of selected high atomic number catalytic materials.
  • a particularly preferred method of the invention comprises:
  • F Filling the channel with the patient's fresh plasma, possibly with added collagen and the patient's concentrated fibrmogen.
  • G Inspecting the capsule thus formed by imaging ultrasound, and thickening any apparently thin areas.
  • H Injecting absolute ethyl alcohol to kill and dehydrate cells within the created capsule, followed by povodine-iodine to further sterilize the contents.
  • touch preparations are positive, the following options are appropriate: a. Re-excision of a larger volume, possibly after purse string sutures to obliterate the cavity. b. Local infiltration of persistent radiation sensitizers such as colloids of iron and copper. c. Deposition of a therapeutic capsule wall providing long term timed release of radiation sensitizers, such as colloids of iron and copper.

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Abstract

Cette invention a trait à des techniques d'intervention sur un organisme vivant et, notamment, des techniques dans le cadre desquelles on constitue un canal autour d'un tissu et l'on introduit une composition d'encapsulation dans le canal pour encapsuler le tissu dans une capsule. La capsule permet d'éviter que la matière encapsulée ne migre vers d'autres tissus. On soumet le patient à une nouvelle radiothérapie améliorée, dans le cadre de laquelle un agent renforçant un rayonnement persistant localement, du fer dextran par exemple, est introduit dans le tissu à traiter ou à proximité de celui-ci. L'invention porte également sur une double lame d'aiguille creuse (10) avec trocart (12).
PCT/US1999/023595 1998-11-18 1999-10-08 Appareil et technique permettant d'encapsuler des tumeurs malignes, de les tuer et de les enlever WO2000028913A1 (fr)

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AU11078/00A AU1107800A (en) 1998-11-18 1999-10-08 Apparatus and method to encapsulate, kill and remove malignancies
DE19983750T DE19983750T1 (de) 1998-11-18 1999-10-08 Vorrichtung zur Herstellung von Kapseln

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Cited By (10)

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US6405733B1 (en) 2000-02-18 2002-06-18 Thomas J. Fogarty Device for accurately marking tissue
US7846108B2 (en) 2002-04-16 2010-12-07 Vivant Medical, Inc. Localization element with energized tip
US8068921B2 (en) 2006-09-29 2011-11-29 Vivant Medical, Inc. Microwave antenna assembly and method of using the same
US8292880B2 (en) 2007-11-27 2012-10-23 Vivant Medical, Inc. Targeted cooling of deployable microwave antenna
US8690868B2 (en) 1999-06-17 2014-04-08 Covidien Lp Needle kit and method for microwave ablation, track coagulation, and biopsy
US8808282B2 (en) 2002-04-16 2014-08-19 Covidien Lp Microwave antenna having a curved configuration
US9192441B2 (en) 2011-02-17 2015-11-24 Covidien Lp Energy-delivery device including ultrasound transducer array and phased antenna array, and methods of adjusting an ablation field radiating into tissue using same
US10154880B2 (en) 2001-11-02 2018-12-18 Covidien Lp High-strength microwave antenna assemblies
US10405921B2 (en) 2003-07-18 2019-09-10 Covidien Lp Devices and methods for cooling microwave antennas
CN111012520A (zh) * 2019-12-18 2020-04-17 华中科技大学同济医学院附属协和医院 一种腹腔镜肿瘤手术无瘤装置、制作方法及使用方法

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US5246726A (en) * 1986-03-21 1993-09-21 Efamol Ltd. Iron-containing composition and method for treatment of cancer
US5458597A (en) * 1993-11-08 1995-10-17 Zomed International Device for treating cancer and non-malignant tumors and methods
US5472441A (en) * 1993-11-08 1995-12-05 Zomed International Device for treating cancer and non-malignant tumors and methods

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US5246726A (en) * 1986-03-21 1993-09-21 Efamol Ltd. Iron-containing composition and method for treatment of cancer
US5458597A (en) * 1993-11-08 1995-10-17 Zomed International Device for treating cancer and non-malignant tumors and methods
US5472441A (en) * 1993-11-08 1995-12-05 Zomed International Device for treating cancer and non-malignant tumors and methods

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8690868B2 (en) 1999-06-17 2014-04-08 Covidien Lp Needle kit and method for microwave ablation, track coagulation, and biopsy
US6564806B1 (en) 2000-02-18 2003-05-20 Thomas J. Fogarty Device for accurately marking tissue
US6405733B1 (en) 2000-02-18 2002-06-18 Thomas J. Fogarty Device for accurately marking tissue
US10154880B2 (en) 2001-11-02 2018-12-18 Covidien Lp High-strength microwave antenna assemblies
US7846108B2 (en) 2002-04-16 2010-12-07 Vivant Medical, Inc. Localization element with energized tip
US11045253B2 (en) 2002-04-16 2021-06-29 Covidien Lp Electrosurgical energy channel splitters and systems for delivering electrosurgical energy
US8808282B2 (en) 2002-04-16 2014-08-19 Covidien Lp Microwave antenna having a curved configuration
US10363097B2 (en) 2002-04-16 2019-07-30 Coviden Lp Ablation system having multiple energy sources
US10039602B2 (en) 2002-04-16 2018-08-07 Covidien Lp Electrosurgical energy channel splitters and systems for delivering electrosurgical energy
US10143520B2 (en) 2002-04-16 2018-12-04 Covidien Lp Microwave antenna guide assembly
US10405921B2 (en) 2003-07-18 2019-09-10 Covidien Lp Devices and methods for cooling microwave antennas
US9333032B2 (en) 2006-09-29 2016-05-10 Covidien Lp Microwave antenna assembly and method of using the same
US8068921B2 (en) 2006-09-29 2011-11-29 Vivant Medical, Inc. Microwave antenna assembly and method of using the same
US8292880B2 (en) 2007-11-27 2012-10-23 Vivant Medical, Inc. Targeted cooling of deployable microwave antenna
US9192441B2 (en) 2011-02-17 2015-11-24 Covidien Lp Energy-delivery device including ultrasound transducer array and phased antenna array, and methods of adjusting an ablation field radiating into tissue using same
CN111012520A (zh) * 2019-12-18 2020-04-17 华中科技大学同济医学院附属协和医院 一种腹腔镜肿瘤手术无瘤装置、制作方法及使用方法

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