EP3562551A1 - Dispositif pour le traitement d'affections malignes à l'aide d'impulsions mécaniques détruisant les tumeurs (tmi) - Google Patents

Dispositif pour le traitement d'affections malignes à l'aide d'impulsions mécaniques détruisant les tumeurs (tmi)

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Publication number
EP3562551A1
EP3562551A1 EP16831817.8A EP16831817A EP3562551A1 EP 3562551 A1 EP3562551 A1 EP 3562551A1 EP 16831817 A EP16831817 A EP 16831817A EP 3562551 A1 EP3562551 A1 EP 3562551A1
Authority
EP
European Patent Office
Prior art keywords
tumor
pulse
treatment
cells
tmi
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP16831817.8A
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German (de)
English (en)
Inventor
Axel Erich Theuer
Irmengard Theuer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
THEUER, AXEL ERICH
THEUER, IRMENGARD
Original Assignee
Richard Wolf GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richard Wolf GmbH filed Critical Richard Wolf GmbH
Publication of EP3562551A1 publication Critical patent/EP3562551A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • 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
    • A61B17/22004—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 using mechanical vibrations, e.g. ultrasonic shock waves
    • A61B17/22012—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 using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement
    • A61B17/22022—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 using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement using electric discharge
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0808—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0825—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the breast, e.g. mammography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/13—Tomography
    • A61B8/14—Echo-tomography
    • 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
    • A61B17/225—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 for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves
    • A61B17/2251—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 for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves characterised by coupling elements between the apparatus, e.g. shock wave apparatus or locating means, and the patient, e.g. details of bags, pressure control of bag on patient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00022—Sensing or detecting at the treatment site
    • A61B2017/00106—Sensing or detecting at the treatment site ultrasonic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00137—Details of operation mode
    • A61B2017/00154—Details of operation mode pulsed
    • A61B2017/00172—Pulse trains, bursts, intermittent continuous operation
    • A61B2017/00176—Two pulses, e.g. second pulse having an effect different from the first one
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00137—Details of operation mode
    • A61B2017/00154—Details of operation mode pulsed
    • A61B2017/00181—Means for setting or varying the pulse energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00137—Details of operation mode
    • A61B2017/00154—Details of operation mode pulsed
    • A61B2017/00194—Means for setting or varying the repetition rate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00743—Type of operation; Specification of treatment sites
    • A61B2017/00796—Breast surgery
    • A61B2017/008—Removal of tumors
    • 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
    • A61B17/22004—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 using mechanical vibrations, e.g. ultrasonic shock waves
    • A61B17/22012—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 using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement
    • A61B2017/22025—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 using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement applying a shock wave
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/10—Computer-aided planning, simulation or modelling of surgical operations
    • A61B2034/101—Computer-aided simulation of surgical operations
    • A61B2034/105—Modelling of the patient, e.g. for ligaments or bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2505/00—Evaluating, monitoring or diagnosing in the context of a particular type of medical care
    • A61B2505/05—Surgical care

Definitions

  • the invention relates to a device for the treatment of malignant diseases using tumor-destructive mechanical impulses (TMI) and defines the operation and control of this device.
  • TMI tumor-destructive mechanical impulses
  • Apparatus for the treatment of diseased cells in living bodies by means of sonic and / or ultrasonic waves have been known for several decades.
  • DE 44 14 239 A1 describes a device in which a sound source for the selective destruction of cells pathological appearance, such as tumor cells, for the generation of sound and / or ultrasound waves with a typical cell type, these cells destructive resonant frequency spectrum is designed.
  • WO 2009/156156 A1 discloses an arrangement for destroying tumor cells, in which an ultrasound generator for generating a thermally active, high-frequency oscillation comprises a plurality of low-frequency ultrasound generators, each generating a different frequency, and a controller connected to a radiofrequency oscillator. Ultrasonic generator is connected so that the tumor cells with a high-frequency, the tumor cells thermally acting vibration and a low-frequency oscillation can be acted upon, in addition to a biopsy device is provided with multiple individual images for tissue samples.
  • WO 2010/020406 A1 discloses a device for destroying tumor cells or pathogens in the blood circulation, in which at least one ultrasonic frequency generator and a device for forming an extracorporeal blood circulation are provided, wherein the device comprises at least one heat exchanger, a blood pump and a treatment container to receive Includes blood, wherein the treatment tank is arranged downstream of the heat exchanger, forms a treatment space and is connected to at least one ultrasonic oscillating head.
  • the ultrasonic oscillating head is coupled to the ultrasonic frequency generator, so that a low-frequency ultrasonic vibration can be introduced in the treatment space.
  • a medical device for the treatment of tumor tissue which comprises a surgical instrument insertable into a body with a housing, in which a vibration element is arranged, which is operable to generate an ultrasonic vibration.
  • the vibration element is associated with a transmission region which at least partially comprises a wall of the housing, which is arranged in use facing the tumor tissue to be treated.
  • the transmission range is adapted, in use, to transfer the ultrasonic vibration into the tumor tissue to be treated.
  • the transmission area cooperates with at least one tempering device.
  • a device for the vibration-induced, selective treatment of malignant diseases by means of mechanical vibrations and / or sound waves in which by means of a targeted selection those cells can be taken, which are to be treated with the aid of the device .
  • a microsurgical device which has a vibration generator. It is an object of the invention to provide a TMI device for the treatment of malignant diseases by means of mechanical impulses or to define the operation and control of the device, compared to the known from the prior art devices or methods, a further improvement of the Treatment is achieved and extendable to other forms of therapy.
  • This object is solved by the features of claims 1 and 17, respectively. Further advantageous embodiments of the invention are each the subject of the dependent claims. These can be combined in a technologically meaningful way. The description additionally characterizes and specifies the invention.
  • TMI device for the treatment of malignant diseases using tumor-destructive mechanical impulses uses a cell biologically optimized, optimally destructive and tumor-selective patient-specific pulse shape and / or pulse sequences resulting from the mechanical, visco-elastic properties of the tumor cells and the intertumoral or tumor-surrounding extracellular matrix (ECM) results or is or is adapted to it.
  • ECM extracellular matrix
  • a method for operating and controlling the TMI device comprises determining an optimal pulse shape and / or pulse sequence and / or further operating parameters before use of the device in a cell experiment on cells removed from a patient or by means of a tissue assay or from a database for cell experiments and tissue tests, whereby measurements, in particular AFM (Atomic Force Microscopy) measurements, physical properties of the extracted cells are determined and integrated into FEM (Finite Element) simulation models.
  • the device can be designed to apply a cell biologically optimized, optimally destructive and tumor-selective pressure pulse train.
  • a cell biologically optimized, optimally destructive and tumor-selective delay time can be set or adjustable between the pulses. It can be provided that the device is designed to dilute tumor-activated fibroblasts by expanding a target volume impinged by the pulses into healthy tissue.
  • the device may comprise at least one pressure sounding head and at least one control unit for controlling the pressure sounding head for generating the tumor-destructive mechanical impulses or pulse trains.
  • It can furthermore have at least one positioning mechanism for positioning the pressure-sounding head relative to a target volume impinged by the pulses, preferably in accordance with the control unit.
  • the pressure sounding head can be positioned or positioned and modulated or modulated in terms of its pulse output in such a way that tumor-destructive shearing forces arise in the target volume.
  • At least two pressure sounding heads or oppositely polarized piezo elements are provided in phased array technology for the generation of the tumor-selective pulse shapes and pulse sequences, preferably with corresponding positioning mechanisms.
  • At least three or more pressure sounding heads are provided with corresponding positioning mechanisms, wherein preferably the pressure sound heads are positioned or positionable and modulated or modulated with regard to their pulse output in such a way Tumor area tumor-destructive shear forces arise.
  • the positioning mechanisms may be controlled or controllable in such a way that a preferably punctiform focus area is first directed to a tumor edge and scans it, the pulse edges being deflected due to the high frequency of the tumor.
  • tumor-protective TAF tumor-dense fibroblasts
  • at the tumor edge preferably high frequency fractions of about 1 MHz to 10 MHz.
  • the positioning mechanisms can also be controlled in such a way that a preferably punctiform focus area is directed at the target volume and scans it, pulse edges having patient-specific low-frequency components, preferably at about 0.1 MHz-3 MHz.
  • the device may be configured to heat a target volume to about 39 ° C to 41 ° C, preferably about 40 ° C, by suitable pulses or pulse trains to further enhance its effectiveness.
  • the device may comprise at least one ballistic and / or at least one electrohydraulic or piezoelectric shock wave generator or corresponding treatment applicators, in particular for generating positive shock wave pulses.
  • the at least one ballistic shock wave generator can be provided for generating second shock wave pulses with specific, tumor-destructive properties.
  • the device may comprise at least two shock wave generators and a control unit, wherein the shock wave generators are successively controlled or controlled by the control unit such that the respective pressure maxima of the shock wave pulses follow one another at a time interval which is smaller than the pulse duration of the shock wave pulses.
  • the device can be equipped with at least one diagnostic unit for continuously monitoring a treatment success, in particular for monitoring an ultrasound echo image (frequency spectrum) of a tumor area, a number of circulating tumor cells in the blood and / or immune parameters.
  • a diagnostic unit for continuously monitoring a treatment success, in particular for monitoring an ultrasound echo image (frequency spectrum) of a tumor area, a number of circulating tumor cells in the blood and / or immune parameters.
  • lethal pulse forms and pulse sequences are determined with the aid of individual patient numerical simulation models and experimentally validated.
  • TMI central treatment center
  • TF decentralized treatment facilities
  • the TMI device can be used simultaneously with the use of immunomodulators.
  • the TMI device comprises treatment applicators or pressure sound heads, which serve for the application of mechanical impulses or shock waves.
  • the treatment applicators preferably also have a possibly centrally arranged diagnostic unit. Between the treatment pulses thus ultrasonic noise waves can be evaluated and short pulses in the low intensity range for excitation and evaluation of the pulse echo (spectral analysis) are sent.
  • the TMI device may further comprise one or more pulse generators. Depending on the intended use, ultrasound generators or shock wave generators are used, in which the me- chanical impulses are generated ballistically, piezoelectrically, electromechanically or electro-hydraulically. In the case of multiple shock wave or pulse generators, it may be useful if different shock wave generators, such as a ballistic and an electro-hydraulically operating shock wave generator, are present.
  • Piezoelectric pulse generators are designed to be planar or focused according to the type of tumor and the position of the tumor area.
  • tumor-destructive pulse fields can take place with the aid of a series of capacitive discharges or with the aid of tumor-specific pulsed sinusoidal oscillations in the high intensity range (60.0 - 200.0 MPa).
  • the components of the treatment applicators include, in addition to focused electromagnetic or piezoelectric pulse generators, low frequency (20-30 kHz) planar pulse generators, a diagnostic unit, positioning mechanisms, and a transmission medium.
  • the focused pulse generators may preferably generate continuous or pulsed high-intensity sinusoidal oscillations, which apply pressure pulse impulses in the focus area through the division of the sine wave, or low-intensity pulsed sinusoidal oscillations, which induce resonance phenomena in the tumor area. It is advantageous to vary the power of the TMl pulse generators to apply sequentially positioned surge pressure pulses and continuous sinusoidal vibrations.
  • a coupling surface is preferably present, which can be applied, for example, to a body region of a patient to be treated.
  • the coupling surface may be, for example, a cavity of the treatment applicator filled with transfer fluid.
  • a baffle plate preferably made of metal, onto which a projectile is fired, wherein the the shot direction of the projectile side facing away from the baffle plate forms the coupling surface (however, there may be more intermediate elements).
  • the device in a preferred embodiment, comprises a control unit, which is signal-connected to the at least one pulse generator.
  • a control unit is referred to here in simplified terms, this is to be understood as a unit which is suitable for controlling and / or regulating.
  • the control unit can be designed so that the pulse generators generate pulses with a pulse frequency of 0.5 Hz to 600 Hz, a maximum pressure with an absolute value of 0.01 MPa to 300 MPa and a rise time of 2 ns to 4000 ns without the invention would be limited to these values.
  • TMI device With such a TMI device, it is possible to selectively destroy tumor cells, in particular therapy-resistant tumor cells, such as those resistant to vemurafenib, a protein kinase inhibitor, ie without or at most with slight damage to healthy tissue or cells by necrosis and / or initiation of apoptotic processes. It is particularly crucial for the tumor-destructive action that the pulse frequency and the pulse sequence according to the invention are adapted to the respective type of tumor and thus in tumorous tissue in particular the effect can be generated that one of the shock wave generated by the TMI device stretched cell or cell organelles a subsequent shock wave is / are applied before the cell or the Zellorganellen has returned to its original state / are.
  • tumor cells in particular therapy-resistant tumor cells, such as those resistant to vemurafenib, a protein kinase inhibitor, ie without or at most with slight damage to healthy tissue or cells by necrosis and / or initiation of apoptotic processes.
  • the mechanical impulses generated by the TMI device can be both positive and negative or inverted impulse waves, where a pulse train of shock waves can have both types of pressure waves.
  • modulated shockwaves or pressure waves For example, particularly high and destructive shear forces on tumor cells and tumor cell organelles can be produced.
  • selective, tumor-destroying pulse forms and pulse trains are determined from tumor-specific viscoelastic properties of malignant cells and the intertumoral or tumor-surrounding extracellular matrix (ECM), preferably outside the body after appropriate sampling.
  • Tumor cells have concise, tumor-specific mechanical properties. Particularly relevant are the viscoelastic properties of malignant protein structures.
  • the rigidity of cells is determined primarily by the cytoskeleton and the size and consistency of the cell organelles.
  • the cytoskeleton consists of a variety of different protein structures and determines the overall rigidity of the cell.
  • actin filaments, microtubules, microfilaments and interfilaments characterize the overall cellular stiffness and determine the mechanical properties and dynamic behavior of cellular structures.
  • Actin filaments determine the dynamic deformation behavior of the cells. They support the cell membranes. In most of the malignant cells, especially on the inside of the cortical bone, filaments of filaments are almost absent, less concentrated, and can not fulfill their physiological protective protective function of malignant cell membranes.
  • the rigid cortical actin filament of healthy, non-degenerated cells supports the membranes of healthy cells and has a membrane-protective effect for them.
  • the invention describes tumor-specific impulses and tumor-specific pulse sequences. Pulse trains are determined by the pulse frequency and the number of pulses. Relevant to the invention is the visco-elastic delay behavior of malignant cell structures. After the impact of the first pulses or pulse fields, significant elongations occur in malignant cells. These are more concise than in normal cells. The second, temporally subsequent pulse fields amplify the already established strain fields. As a result, the strains continue to build until they reach lethal levels and lead to lethal damage in malignant cells and cell organelles. Healthy, non-degenerated cells are - as already stated - much stiffer than malignant cells and require longer time intervals to lethal To reach strains. For short pulse sequences, they remain below critical, cell destructive values and survive the treatment without damage.
  • selectively acting mitochondria also have destructive pulse fields.
  • the mitochondria of malignant cells are significantly more pressure sensitive than mitochondria of healthy cells. They are embedded in an unbundled, relatively soft actin filament. They are torn apart by the applied impulses and pulse sequences and cause the release of cytochrome c. Cytochrome c binds to the APAF-1 protein which oligomerizes and activates the initiator caspase 9 and subsequently the effector caspase 3. It is the so-called death receptors that lead to an apoptotic failure of the tumor cells.
  • the inertia of the cells and cell organelles is too large to build lethal strain fields.
  • the cells and cell organelles can not follow the pulse front and remain as a whole. But at the mitochondrial level, the pulse front first encounters mitochondrial outer membranes. At the time of impact, the opposite mitochondrial membrane is unloaded in ultrashort pulses. Thus, mitochondrial membranes are exposed to extreme pressure differences. They cause complex mitochondrial signaling cascades and the release of free radicals (NO and hydroxyl OH). These are assigned an important role as signal and modulators in the formation of heat shock proteins. In malignant cells apoptotic processes are triggered.
  • CAFs tumor-dense fibroblasts
  • CAFs tumor-dense fibroblasts
  • specific pulse fields for the selective destruction of tumor-dense fibroblasts (CAFs) in the tumor area are applied concomitantly or with a time delay with appropriate embodiment of the invention.
  • CAF specific pulse fields can be determined in upstream FEM analyzes. The selectivity is given by CAF's specific material properties and the spindle shape of tumor-dense fibroblasts. These material properties of CAFs can be determined using AFM measurements.
  • tumor-destructive pulse fields used in a corresponding embodiment of the invention have the ability to activate photosensitizers.
  • Our own simulation analyzes and validating experiments have led to the finding that tumor-specific impulses have tumor-destructive properties even in tumors with a reduced rate of apoptosis, such as, for example, colon carcinoma, pancreatic carcinoma and hepatocellular carcinoma.
  • special impulses are capable of selectively destroying tumor stem cells, including chemo- and radiation-resistant tumor stem cells.
  • TMI tumor-destructive mechanical impulses
  • a development of the present invention preferably comprises a combination of the TMI treatment with PD1 inhibitors (eg nivolumab).
  • PD1 inhibitors are administered concomitantly or after TMI treatment.
  • the treatment is continued until no circulating metastatic cells (CM) can be detected in the patient's blood.
  • CM metastatic cells
  • a new acoustic method can be used in which ZM excited by short extracorporeal impulses to tumor-specific vibrations and then detected acoustically.
  • the invention may, with a corresponding development, comprise the following distinct steps:
  • tumor cells are taken from a patient on site and sent to the CTC.
  • MRI data from the tumor areas are transferred from the TF to the CTC and integrated into predefined, stable FEM models.
  • the treatment parameters include patient-individual Both control impulses and patient-specific position coordinates of the treatment applicators. This ensures that lethal pulse forms and pulse sequences are applied in the tumor area.
  • patient-related diagnostic patient data are continuously transferred to the CTC and evaluated by spectral analysis.
  • the treatment applicators preferably have a centrally located diagnostic unit. Between the pulses ultrasonic noise waves are evaluated and short pulses in the low intensity range are sent for excitation and evaluation of the pulse echo (spectral analysis).
  • TMI tumor-destructive mechanical impulses
  • diagnostic patient data of tumor-related lymph nodes are sent to the CTC. These are integrated into predefined stable FEM models and solved numerically. This results in patient-specific treatment parameters, which are transmitted to the CPU (central processing unit) of the TF.
  • the treatment parameters include patient-specific control pulses of the CPU and patient-specific position coordinates for the treatment of affected lymph nodes.
  • PD1 Inhibitors eg Nivolumab
  • TMI treatment a combination of TMI treatment with PD1 Inhibitors (eg Nivolumab) take place.
  • PD1 inhibitors are administered concomitantly or after TMI treatment.
  • CM metastatic cells
  • the components of the treatment applicators include in addition to focused electromagnetic or piezoelectric pulse generators, low frequency (20-30 kHz) planar pulse generators, a diagnostic unit, positioning mechanisms and a transmission medium ( Figure 2).
  • the focused pulse generators can preferably generate continuous or pulsed high-intensity sinusoidal oscillations which generate pressure impulse impulses in the focus area by dividing the sine wave or low-intensity pulsed sinusoidal oscillations which induce resonance phenomena in the tumor area. It is advantageous to vary the power of the TMI pulse generators in order to apply sequentially positioned surge pressure pulses and continuous sinusoidal vibrations (Figure 16).
  • tumor-destructive or treatment-specific pulse fields are also relevant to the invention.
  • Upstream or accompanying are visco-elastic FEM simulation models of the cellular structures and commercial areas to be treated.
  • the input parameters of the FEM simulation analyzes are physical properties of the cells and cell structures to be treated. These preferably result from AFM measurements or electrical measurements of living cells and cell organelles or are taken from a separate CTC database. Own calculations and analyzes have further led to the realization that sickle cells can also be led into apoptotic processes with the TMl therapy. In sickle cell diseases, cell-supporting, apoptotic processes are particularly important, since a necrotic destruction leads to possible adhesions of the cell fragments and the already difficult blood circulation is further worsened. In addition, ultrashort pulse fields due to the NO release have vasodilatory capabilities that play an eminently important role in sickle cell disease.
  • patient-specific tumor-destructive mechanical impulses of the TMI device and preferably its temporal variation, modulation, combination, diagnostic accompaniment and control define the essence of the invention.
  • Patient-specific viscoelastic FEM simulation models of the cellular structures and commercial areas to be treated can be placed in front of them.
  • the input parameters of the FEM simulation analyzes are physical properties of the cells and cell structures to be treated and are preferably determined via AFM measurements.
  • AFM measurements of the patient cells are carried out for the determination of the patient-specific physical properties. These are integrated into predefined, stable FEM models. This results in patient-specific lethal pulse forms and pulse sequences.
  • MRI / CT data from the tumor areas are integrated into predefined, stable FEM models. This results in patient-specific treatment parameters which are transmitted to the CPU (central processing unit) of the TMI device.
  • the treatment parameters include patient-individual control pulses and patient-specific position coordinates for the positioning mechanisms of the treatment applicators for the sequential scanning of the entire tumor area. This ensures that lethal pulse forms and pulse sequences are applied in the tumor area.
  • diagnostic MRI / CT patient data of tumor-affected lymph nodes are integrated into predefined stable FEM models and solved numerically. This results in patient-specific treatment parameters: These include patient-specific control impulses and patient-specific position coordinates for the TMI treatment of the affected lymph nodes of breast cancer.
  • Prostate cancer is by far the most commonly diagnosed malignant tumor of the man. In Germany, approximately 26,500 new men develop prostate cancer each year. Prostate cancer ranks second in cancer-related, organ-related mortality statistics in men Job.
  • the TMI device operates by means of mechanical pulse fields and comprises the pulse generators, a control device and treatment applicators, which, however, may have a different shape in this application.
  • the treatment applicators can be arranged on the positioning mechanism on an anatomically curved holding device. Pulses of the treatment applicators are transferred to the tumor area.
  • the treatment applicators flexibly integrated in the holding device are aligned with the tumor area and acted upon by the control unit with tumor-destructive pulse trains. Tumor nodules are treated by multiple, focused on the node treatment applicators.
  • Tissue-surrounding tissue with tumor-activated, fibroblasts (TAFS) activated by the tumor is scanned by punctiform lethal pulse forms and treated concomitantly or with a time delay.
  • TMI device for the treatment of prostate cancer and bone metastases of prostate cancer is explicitly treated also affected lymph nodes. It is a nature of the invention that also affected lymph nodes of prostate cancer are treated.
  • High-resolution MRI / CT patient data is integrated into predefined stable FEM models. These are solved numerically and the position of the treatment applicators is determined so that the pressure propagation is directed to the lymph nodes and in the lymph nodes lethal pulse shapes and pulse trains are applied.
  • the TMI device may also contain several different pulse generators for the treatment of prostate cancer.
  • the TMI device for the treatment of bone metastases of prostate cancer is preferably characterized by low frequency treatment applicators (30 kHz - 800 kHz) operating in the high intensity range (20.0 MPA - 200 MPA). Because tumor areas of bone metastases are primarily positioned on the inside of the highly absorbent compact, pulse shapes with low frequency components in the frequency spectrum and the treatment parameters described above are needed to overcome the highly absorbent compacts of the affected bone structures.
  • the cells of bone metastases behave largely like the cells of the primary tumor and have the same or very similar therapy-determining mechanical properties.
  • the physical properties of patient-specific metastatic cells are determined by AFM (Atomic Force Microscopy) measurements, integrated into FEM simulation models of non-linear pressure propagation through the tumor area and treatment parameters determined by means of comparative comparisons of the simulation results that lead to lethal lesions malignant Lead cells in the tumor area.
  • tumor-destructive pressure peaks can be built up.
  • a patient-specific positioning of the treatment applicators is required.
  • the results of FEM simulation analyzes of pressure propagation through absorbent bone structures result in tumor-destructive pulse shapes and pulse sequences. In this case, tumor-destructive pulse fields can be generated with the aid of a series of capacitive discharges or with the aid of pulsed sinusoidal oscillations.
  • both ballistic treatment applicators, piezoelectric treatment applicators or a combined construction of ballistic treatment applicators and piezoelectric treatment applicator can be used.
  • the Applicant has recognized that selective tumor-specific pulse shapes can be used for different tumor identities.
  • the selectivity, tumor-destructive pulse shapes result from the mechanical, visco-elastic properties of the tumor cells and the intertumoral or tumor-surrounding extracellular matrix (ECM).
  • ECM extracellular matrix
  • the propagation of tumor-specific pulse fields through the cells and cell organelles leads to an expansion of the cell membranes and cell organelles. If the value of the membrane strain (especially in the tangential direction) exceeds a lethal value, a necrotic failure occurs. The cell membrane ruptures and the cell plasma with the cell organelles contained therein flows into the surrounding ECM. Malignant cell fragments, malignant protein structures and especially mitochondrial fragments are released. This leads to a tumor-specific maturation of dendritic cells.
  • the invention preferably includes a tumor-specific pulse sequence in addition to the tumor-specific pulse shape.
  • the pulse train is determined by the pulse frequency and the number of pulses.
  • Significant here is the visco-elastic delay behavior of malignant cell structures. After the impact of the first impulse pulse occurs in malignant cells to significant strain fields. These are more concise than in normal cells.
  • the second impulse pulse amplifies the already established strain fields. As a result, the strains continue to build until they reach lethal levels and lead to necrotic destruction. Healthy, non-degenerated cells require longer time intervals to achieve lethal strains. For short bursts of pulses, they remain below the critical cell destructing values and survive the bursts without damage.
  • a positive pressure surge is followed by an equally high negative pressure surge, or that two positive pressure surges can be emitted, between which a defined delay time (time between the pressure surges) is set.
  • the variance of the delay time is used to search for an optimal pulse form for tumor destruction. We are looking for the time when the expansion fields in the tumor overlap and thus add up until they become lethal for the tumor cells.
  • Each tumor cell has an individual elongation characteristic, which is represented in the individual delay time. Healthy cells survive tumor-specific pulse propagation without damage. They have an intact actin filament.
  • the rigid cortical actin filament of healthy, non-degenerated cells supports the membrane healthier and has a membrane-protective effect.
  • the rigidity of the cells is determined primarily by the cytoskeleton.
  • the cytoskeleton consists of a variety of different protein structures, especially actin filaments, microtubules, microfilaments and interfilaments. A special role is played by actin filaments and microtubules. Actin filaments are responsible for the overall rigidity of the cells. They support the cell membranes. In most malignant cells, especially on the cortical inside of the cell membranes, actin filaments are almost non-existent, less concentrated and can not fulfill their physiological protective supporting function of the cell membrane. Due to the lower stiffness, the tumor cell can be better stretched and torn.
  • At least two pressure sound heads or oppositely polarized piezo elements are used in the phased array technique for the generation of the pulse sequences and a defined delay time between the pulses.
  • the TMI device can treat metastases of the skeleton, of the body trunk, of the liver, of the head, of the neck as well as tumor recurrences, operated and irradiated (treated) recurrences.
  • the invention relates to patient-specific destructive pulse shapes and pulse sequences in the tumor area.
  • tumor cells from the primary tumor or circulating metastatic cells are preferably taken from the patient.
  • the physical properties of the extracted cells can be determined and integrated into FEM simulation models.
  • the results of the simulation analyzes are patient-specific pulse shapes and pulse sequences, which can be applied after validating experiments in the tumor area.
  • patient-specific MRT data are preferably integrated into a stable, predefined FEM model, and the non-linear pressure propagation in the tumor area is determined.
  • the results of the FEM analyzes result in the relevant parameters and positions of the TMl treatment applicators, which can be used for sequential scanning of the entire tumor area.
  • FIG. 1 shows schematically the structure of a TMI device
  • FIG. 2 shows a schematic representation of a TMI treatment applicator
  • FIG. 3 shows the structure of a TMI Cancer Treatment Center (CTC);
  • FIG. 4 shows the AFM determination of the patient-specific cell data
  • FIG. 5 shows a validating comparison of TMI-treated melanoma cells
  • FIG. 6 shows a validating comparison of TMI-treated prostate carcinoma cells, vemurafenib-resistant melanoma cells and rhabdomiosarcoma cells;
  • FIG. 7 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (rabbits) and comparative comparison of the results (untreated animal with a strongly growing tumor);
  • FIG. 8 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (rabbits) and comparative comparison of the results (tumor regression after three TMI treatments);
  • FIG. 9 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (rabbits) and comparative comparison of the results (tumor regression after three TMI treatments in combination with nivolumab);
  • FIG. 10 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (rabbits) and comparative comparison of the results (increase in immune markers after three TMI treatments);
  • FIG. 11 shows a validating TMI treatment of tumor-bearing, immunocompetent animals (mice) and comparative comparison of the results (tumor progression in the untreated animals and the TMI-treated animals);
  • Figure 12 shows a TMI device for the treatment of brain metastases
  • FIG. 13 shows a TMI device for the treatment of brain metastases with unilateral placement of treatment applicators
  • Figure 14 shows a TMI device for the treatment of breast cancer in an overall view
  • FIG. 15 is a sectional view of a TMI device for the treatment of breast cancer
  • FIG. 16 shows tumor pulse pulse edges established in a TMI device for the treatment of breast cancer and continuous sinusoids
  • Figure 17 shows lethal pulse edges generated in the tumor area with a TMI device
  • FIG. 18 shows lethal pulse edges generated in the tumor area using a TMI device
  • Figure 19 shows schematically the effect of TMI treatment and response of the immune system
  • Figure 20 shows TMI treatment of affected lymph nodes and immune system response in combination with PD1 immunomodulators.
  • a TMI device comprises a central control unit or central processing unit (CPU) 1, a TMI pulse generator 2, positioning mechanisms 3, diagnostic units 4 and treatment applicators 5 with transmission medium.
  • CPU central control unit
  • TMI pulse generator central processing unit
  • diagnostic units 4 diagnostic units 4
  • treatment applicators 5 with transmission medium.
  • the treatment applicators 5 are equipped with corresponding positioning mechanisms 3 and a diagnostic unit 4. The alignment and positioning of the treatment applicators 5 is carried out with the positioning mechanisms 3.
  • the treatment applicators 5 are connected to the skin of a tissue area to be treated via a transfer medium (not shown) in the form of a coupling membrane or gel layer.
  • the control of the pulse generators 2 is designed so that tumor-destructive pulse shapes and pulse sequences are applied.
  • the flexible integrated treatment applicators 5, which are regularly in a treatment dome or a treatment ring (see Fig. 12), are aligned with the tumor area and acted upon by the control unit 1 with tumor-destructive pulse trains. Tumor nodules are treated via a plurality of treatment applicators 5 focused on the nodule. Tissue-surrounding tissue with tumor-activated, tumor-protective fibroblasts (TAFS) is scanned by punctiform lethal pulse forms and treated concomitantly or with a time delay.
  • TAFS tumor-protective fibroblast
  • TMI treatment applicators 5 with punctiform focus is advantageous.
  • the positioning mechanisms 3 are controlled with the aid of the diagnostic unit 4 such that the punctiform focus of the TMI device scans the entire tumor area.
  • a pulsed control of TMl treatment applicators 5 is advantageous.
  • a TMI treatment applicator is shown schematically by way of example. It comprises a positioning mechanism 1, a focused pulsed treatment applicator 2, a transmission medium 3 and a low frequency (20-30 kHz) treatment applicator.
  • FIG. 5 shows a diagram from which lethally damaged cells result from the TMI treatment. Shown are FM-human melanocytes, human fibroblasts and W3734 vemurafenibresistente melanoma cells.
  • FIG. 6 shows a diagram from which lethally damaged cells result from the TMI treatment. Shown are DU145 prostate carcinoma cells, Me1617 vemurafenibresistente melanoma cells and ZF rabdomyosarcoma cells.
  • FIG. 12 shows a TMI device (or TMI treatment device) BV for the selective, extracorporeal treatment of therapy-resistant cerebral metastases and primary cerebral tumor diseases by means of mechanical pulse fields.
  • the TMI device BV comprises a treatment ring BR to be fastened to the head of a patient, on which a number of treatment applicators BA are arranged.
  • Reference PM denotes a positioning mechanism associated with each treatment applicator BA.
  • the TMI device BV also includes at least one therapy-accompanying diagnostic unit (not shown) and a positioning mechanism or multiple positioning mechanisms.
  • the treatment applicators BA which are arranged in an adjustable manner, are attached thereto and are connected via a respective coupling device.
  • membrane (not shown), which is typically provided with a transfer gel that transmit mechanical pulse fields to the cranial bones.
  • the various treatment applicators BA are attached to a treatment ring BR and in the example shown to be directed to a tumor area.
  • the targeted control of the individual treatment applicators BA targeted mechanical pulse fields can be generated at the site of the tumor, which ensure destruction of the tumor.
  • FIG. 13 shows a variant of the TM1 treatment device from FIG. 12. Also shown are the skull bone SK of a patient and a tumor area TA located therein.
  • the treatment device BV according to FIG. 13 differs from that of FIG. 12 in that the treatment ring BR surrounds only a part of the cranial bone SK. This can, as shown in Fig. 13, be designed in the form of a semicircle, with other variants should not be excluded.
  • FIG. 13 shows a unilateral arrangement of the TMI treatment applicators BA. In this case, the treatment ring BR is executed completely circumferential, as shown in Fig. 13, but only one side of the treatment device BV is equipped with treatment applicators BA.
  • TMI treatment of cerebral metastases and primary cerebral cancers several, typically more than three, treatment applicators are positioned extracorporeally by means of positioning mechanisms and positioned on the skull through a coupling gel.
  • the cranial bone absorbs between 50 and 80% of the energy of the pulse fields.
  • the remaining impulse energy is so low that healthy brain areas are not damaged.
  • the superimposed and modulated pulse fields and pulse sequences are sufficient to cause lethal damage.
  • Particularly relevant here are the focused treatment of the tumor areas and the subsequent treatment of possible micrometastases by the uniform distribution of the pulse fields in the whole sound brain mass.
  • the pulse shape, the pulse train and the modulation of the pulse fields are selected accordingly.
  • TMI device for the extracorporeal, selective treatment of breast cancer is described below.
  • Such a treatment device may be constructed schematically similar to that shown in FIGS. 14 and 15.
  • the TMI device in Fig. 14 in turn, includes pulse generators, a controller, a plurality of treatment applicators, and imaging therapy-directing components.
  • the treatment applicators of the TMI device for the treatment of breast cancer induce tumor-destructive pulse shapes and pulse trains in the tumor area.
  • the focus is on a sharp increase in pressure.
  • the tissue is compressed.
  • Pressure surges can be induced via capacitive discharges in piezoelectric or electromagnetic applicators or applied to the tumor area via focused pulsed sinusoids (p-HIFU).
  • Such an arrangement is particularly advantageous for the selective, non-thermal treatment of breast cancer since own calculations and validating tumor experiments have led to the finding that tumor-destructive impulses have a maximum tumor-destructive effect when the tumor area is heated to 39-41 ° C. before the actual treatment becomes.
  • the device in Fig. 15 may include a plurality of different pulse generators. It may be useful piezoelectric, ballistic or electromagnetic pulse generators or a combination of the above Use pulse generators. From an organ-specific point of view, the arrangements of at least two electromagnetic or piezoelectric treatment applicators are preferred in the extracorporeal treatment of tumor areas of mammary carcinoma. These can be operated synchronously or asynchronously.
  • TMI device for the treatment of breast cancer are the focused treatment of the tumor areas and the subsequent treatment of possible micrometastases by the uniform distribution of the pulse fields in the entire area. Affected lymph nodes are not excised, but treated by TMI.
  • the TMI device for the treatment of mammary carcinoma is designed as a vacuum treatment bell and comprises a threaded ram 1, the bell wall 2, an ultrasonic lower part 3, piezo discs 4, a transmission medium 5, the ultrasonic threaded disc 8, a diaphragm 9 and applicators with positioning mechanisms 10.
  • Reference numeral 6 denotes the tumor area, 7 the breast tissue.
  • the construction of a negative-pressure treatment bell for the destruction of micrometastases in the breast tissue 7 shown in Figures 14 and 15 comprises integrated push-pull applicators 10 in the wall 2. The breast is sucked into the hollow-walled treatment bell. With the aid of an imaging diagnostic unit (not shown), the pressure impact applicators 10 are aligned with the tumor area 6.
  • Concomitant or delayed negative pressure vibrations are applied via the ultrasound converter in the entire breast tissue 7.
  • the selectively acting vibrations preferably 14-40 kHz
  • the frequency of the tumor-destructive vibrations is determined in upstream FEM analyzes. Healthy breast tissue 7 cells survive the treatment without damage.
  • 16 shows by means of a TMI device for the treatment of mammary carcinoma, in particular according to FIG. 14 or 15, generated pulse edges established in the tumor area (curve at reference numeral 11) and continuous sinusoidal oscillations (curve at reference numeral 12).
  • tumor-destructive pulse shapes and pulse sequences with sequentially applied pulses in the low-intensity range (-10 MPA-60 MPA) and high-intensity range (-20 MPa-120 MPA) are shown by way of example, as they can be generated with a device according to the invention or be generated.
  • the control of the device is designed so that before the actual treatment (tio-tn) a series of low-energy pulse forms (trt.2) is applied for the destruction of cellular binding proteins.
  • the pretreatment is required for the necrotic destruction of malignant tumor cells embedded in the extracellular matrix.
  • Fig. 18 Shown in Fig. 18 are combined bursts of burst pulse shapes (Vi) and ballistic pulse shapes (B-i) with sequentially applied inverted pulses (-0.20 MPA - 10.0 MPA) and ballistic pulses (0.0 MPA - 40.0 MPA).
  • the illustrated pulse train is relevant for the treatment of drug-resistant rabdomyosarcoma diseases.
  • malignant cell fragments are formed by the TMI treatment, which lead to a maturation of dendritic cells and the induction of tumor-toxic properties in T cells of the immune system.
  • metastatic cells, dendritic cells as well as T cells of the immune system are located in affected lymph nodes.
  • the targeted TMI treatment of affected lymph nodes can lead to a large number of tumor toxic T cells.
  • the simultaneous or time-delayed administration of PD1 immunomodulators blocks the tumor-protective binding sites of the numerous, newly formed tumor-toxic T cells and produces a systemic tumor-destroying effect.

Abstract

L'invention concerne un dispositif et un procédé pour traiter, de manière spécifique à chaque patient, des affections malignes à l'aide d'impulsions mécaniques détruisant les tumeurs (TMI) à effet sélectif. Les formes d'impulsions détruisant les tumeurs sont déterminées à l'aide de propriétés cellulaires physiques, spécifique à chaque patient, et le dispositif est commandé de façon à appliquer des champs d'impulsions létaux dans la zone de la tumeur.
EP16831817.8A 2016-02-09 2016-12-28 Dispositif pour le traitement d'affections malignes à l'aide d'impulsions mécaniques détruisant les tumeurs (tmi) Pending EP3562551A1 (fr)

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