WO2003011130A2 - A method for detection of cancer using a thermal enhancement agent, and non-invasive thermal monitoring - Google Patents
A method for detection of cancer using a thermal enhancement agent, and non-invasive thermal monitoring Download PDFInfo
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- WO2003011130A2 WO2003011130A2 PCT/IL2002/000620 IL0200620W WO03011130A2 WO 2003011130 A2 WO2003011130 A2 WO 2003011130A2 IL 0200620 W IL0200620 W IL 0200620W WO 03011130 A2 WO03011130 A2 WO 03011130A2
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- WIPO (PCT)
- Prior art keywords
- thermal
- tissue
- temperature
- enhancing agent
- monitoring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
- A61B5/414—Evaluating particular organs or parts of the immune or lymphatic systems
- A61B5/415—Evaluating particular organs or parts of the immune or lymphatic systems the glands, e.g. tonsils, adenoids or thymus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
- A61B5/015—By temperature mapping of body part
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
- A61B5/414—Evaluating particular organs or parts of the immune or lymphatic systems
- A61B5/418—Evaluating particular organs or parts of the immune or lymphatic systems lymph vessels, ducts or nodes
Definitions
- the present invention generally relates to a method for detection of malignant lesions within human tissue.
- the present invention is especially useful for detection of breast cancer.
- Non-invasive detection and assessment of malignancy remains one of the great targets in the field of cancer, especially in breast cancer.
- Breast cancer is the most common malignancy in women affecting almost one in nine individuals.
- Early detection of breast cancer has been widely acknowledged as the key to the successful treatment of this disease in women.
- the best way to cure women diagnosed with breast cancer is to detect the tumor in time.
- Studies of breast cancer identify several stages in the evolution of a tumor. The stage of the detection has a crucial effect on the survival chances and/or healing possibilities for the breast cancer patient.
- early detection of breast cancer is considered to be detection in the period spanning from the end of stage one (tumors smaller than 2cm) through the beginning of stage two (tumors larger than 2cm, with one lymph node).
- breast cancer may be detected using several methods.
- an initial breast examination involves breast palpation, performed by the woman herself and/or her physician. If breast palpation uncovers a potential tumorous growth or another abnormality, a test such as mammography, MRI, or an ultrasound examination is advised. These are performed in a hospital or a large medical center. When a tumor is positively detected by any of these means, a biopsy or fine needle aspiration is utilized to determine whether or not the tumor is cancerous.
- Mammography is the breast imaging technique most commonly used when an abnormality is suspected, and is also widely used as a preventative screening tool.
- mammography MRI, or ultrasound.
- Mammography is essentially an x-ray technique that locates dense spots or tiny specks of calcium in breast tissue, that may be an early sign of cancer.
- Mammography necessitates administration of ionizing radiation, which can cause cumulative damages upon repeated exposure.
- Mammography testing is costly, since the equipment is expensive, a trained technician must be on hand to operate the equipment, and medical personnel must evaluate the results.
- An optimal imaging tool for detection and diagnosis of breast cancer should be noninvasive and more widely available in gynecologic clinics, should not involve harmful irradiation and should be accurate for women in all age groups.
- a major goal of breast imaging is differentiation between benign and malignant lesions in a noninvasive and reliable manner.
- Thermal monitoring has been considered for use in diagnosing cancer.
- Classical thermal monitoring makes use of the slight variations in temperature that exist in different tissues in order to generate a thermal map from which information can be gleamed.
- these internal temperature differences are so minor as to be difficult to detect non-invasively .
- One way of overcoming this problem is to chill the tissue undergoing evaluation, then allow it to re-perfuse, in order to create a dynamic situation. This enhances the temperature differences and may provide additional information.
- US Patent No. 6,077,228 discloses an array of thermoresistors and conductors which can be used to measure breast temperature after the breasts have been chilled, then re-perfused. Chilling and re-perfusion of tissues enhances the temperature differences, but does not improve the sensitivity of the method. In spite of the fact that re-perfusion creates a dynamic situation which is easier to measure, the measurements are too lengthy, and the thermal effect, which is slight to begin with, usually dissipates before it can be noted.
- Neoplastic lesions are associated with an enhanced blood supply.
- the blood vessels at the lesion are dense and their permeability is different than that of the vessels in normal tissue, so that there is leakage from the pathological vascular bundles into the tumor.
- vascularature has many characteristics not found in the microcirculation of normal tissues. These characteristics include:
- a large extracellular fraction -a large fraction of volume which is not occupied by cells or vascularization and accessible for agent that cannot enter cells.
- Perfluorocarbon (herein PFC) compounds are common organic compounds, in which hydrogen atoms have been substituted by flourine atoms. Carbon-flourine compounds are highly inert, and are therefore bio-compatible and non-toxic. Perfluorocarbons have been used in implants and in drugs, and have been investigated for use as blood substitutes. PFC's have a high affinity for gasses, and are able to dissolve 20 times more oxygen that water, for example. Gas-loaded perfluorocarbons absorb sound energy due to the presence of the dissolved gas, and this results in heating of the area that contains the compounds. US Patent No.
- 5,149,319 discloses a method for destroying a tumor by heat, in which a gas or a perflourocarbon compound is first administered to a patient and then ultrasonic energy is applied to the tissue, causing the temperature in the tissue to rise to 43 °C, at which temperature, cell death is assured.
- US Patent No. 5,158,536 discloses a similar method for treating lung cancer, in which a patient's lungs are temporarily filled with a perfluorocarbon liquid, then ultrasound is applied until a temperature of 41-50°C is reached and the tumor cells are assumed to have been killed.
- PFC's can be utilized in detection of cancer.
- the method disclosed in the present invention does not require trained persomiel to administer testing, and so may be made available in any outpatient clinic. It is the object of the present invention to provide a method for detection of malignant lesions in humans, which utilizes thermal monitoring, yet has improved sensitivity and success over prior art methods.
- thermal magnitude refers to the temperature, heat flux, or radiance.
- Thermal measurements include for example, temperature measurements, heat flux, or radiance measurements
- a thermal enhancing agent refers to a material which, when injected into human tissue, absorbs energy from an external energy source, and releases heat in response. The amount of heat released is considerably greater than the amount that would have been released by the tissue alone, should the thermal enhancing agent not have been present. This phenomenon is based on the ability of thermal enhancing agents to convert the energy absorbed to heat which enhances the thermal magnitude and therefore the sensitivity of the thermal monitoring and detection.
- gaseous precursors refers to materials that form a gas after being triggered to do so.
- the trigger can be, for example, a change in pH, such as is achieved, upon injection of the material into the bloodstream, causing modification and breakdown of the precursor, resulting in release of a gas.
- the present invention is based on the ability of thermal enhancing agents to produce heat upon absorption of energy, emitted from an external energy source, for thermal monitoring and detection of malignant lesions in human tissue.
- the method of the present invention is especially useful for detection of breast cancer.
- a thermal enhancing agent for example a gas-loaded perfluorocarbon compound, or a solution containing a precursor to a gas
- the material injected accumulates in a tumor, should such a lesion be present, at a higher concentration than in the normal tissue, due to the above-mentioned circulatory abnormalities associated with tumors.
- a beam of an external energy source is directed towards the area undergoing evaluation, such as the breast.
- the thermal enhancing material that was injected absorbs this energy and generates heat, which can be measured externally on the skin.
- the surrounding normal tissue emits less heat than the tumorous area, due to the differences in the concentration of the thermal enhancing agent in each of these areas.
- thermal monitoring can be used to generate a map of non-invasive thermal magnitude measurements which correspond to different areas on the tissue, and this map reflects the presence or absence of a neoplasm.
- the present invention provides a method for detection of malignant lesions in humans, which utilizes thermal monitoring, yet has improved sensitivity and success over prior art methods.
- the present invention relates to a method for detecting a malignant lesion within a human tissue, comprising: a) administering a thermal enhancing agent, and said thermal enhancing agent generates heat upon activation from an external energy source, to a human; b) submitting the human tissue undergoing evaluation, to a predetermined amount of energy emitted from an external energy source; c) monitoring the temperature or other thermal magnitude, on the skin, in a plurality of points on the tissue; d) analyzing the results of said monitoring; e) detecting specific points on the tissue having abnormal thermal magnitudes (such as temperatures or other thermal magnitudes), in comparison to other points on the tissue or to predetermined data.
- Various thermal enhancing agents can be utilized, along with any external energy source appropriate for activation of said thermal enhancing agents.
- the thermal enhancing agent is a perfluorocarbon.
- the perfluorocarbon is selected from cis-perfluordecaline, trans-perfluorodecaline, perfluorohexane, or perfluoro-2-butyl-tetr-thydrofurane.
- the perfluorocarbon prior to administration is loaded with a gas selected from carbon dioxide or oxygen.
- the thermal enhancing agent is a gaseous precursor.
- the gaseous precursor is selected from sodium bicarbonate, aminomalonate, diazonium or methylactete.
- the human tissue is the female breast.
- the predetermined amount of energy to which the tissue is submitted is emitted from the external energy source at a plurality of levels of intensity, and wherein said emission is constant or time-dependant.
- the amount of thermal enhancing agent administered and the amount of energy the tissue is submitted to are such that will produce a maximal internal tissue temperature of 41°C.
- the thermal magnitude of the tissue is measured non-invasively on the skin.
- the agent injected is enclosed within liposomes.
- the agent injected is in the form of an emulsion.
- the emulsion has a particle size of 10-lOOnm.
- the energy to which the tissue is submitted is ultrasonic energy. Still further, in accordance with a preferred embodiment of the present invention, the ultrasonic energy to which the tissue is submitted to, has a frequency of 0.3-lOMHz.
- the external energy is emitted in several pulses having predetermined intervals between said pulses.
- at least one of the pulses is characterized by a varying level of pulse intensity within said pulse.
- the external energy source is activated in a continuous manner.
- the method further comprises the step of comparing results of said monitoring, with an image obtained using an imaging technique other than thermal magnitude monitoring.
- the thermal magnitudes are monitored using an infrared-based camera.
- the thermal magnitudes, (such as the temperature) are monitored using at least one temperature-sensing probe, a sensor array, or a plurality of thermistors. If the temperature or other thermal magnitudes are monitored in a plurality of points, these readings can be taken simultaneously.
- a temperature-sensing probe or a thermal magnitude-sensing probe (such as a probe measuring the heat flux or the radiance), is used.
- the thermal magnitude-sensing probe is located within or on the external energy source in general, and on an ultrasonic transducer specifically.
- analyzing of the results of said measurements is performed using an prediction algorithm.
- This computation aids in mapping of the thermal monitoring results, and correlating them with specific areas on the tissue.
- Another algorithm can also be used to shorten the length of the thermal monitoring; by calculating and predicting the steady-state temperature value after only a brief amount of time. This prevents premature dissipation of the thermal effect before it can be measured.
- administration of the thermal enhancing agent is performed by intravenous injection.
- Figure 1 illustrates a graph of temperature elevations obtained in Example 1.
- Figure 2 illustrates a schematic presentation of the experiment protocol of Example 2.
- Figure 3 illustrates thermal images captured after bovine tissue was injected with perfluorodecalin and subjected to ultrasound, as performed in Example 2.
- the present invention discloses a method of detecting malignancies within a human, especially within the human breast.
- a gas-loaded perfluorocarbon compound is used as an example of the thermal enhancing agent, and the external energy source described is an ultrasound transducer.
- various thermal enhancing agents may be used other than gas-loaded perfluorocarbons or gaseous precursors, and various external energy sources may be utilized.
- an external energy source Upon selection of a specific thermal agent, an external energy source must be selected as well, so that the energy source selected is one that is capable of activating the specific thermal enhancing agent.
- a perfluorocarbon compound is loaded with a gas, for example, carbon dioxide gas or oxygen, and emulsified into a water-soluble micro-emulsion.
- a gas for example, carbon dioxide gas or oxygen
- the emulsion is administered intravenously to a patient undergoing screening or detection of breast cancer.
- the emulsion tends to accumulate in a neoplastic lesion, if one is present, due to the abnormal vasculature present in such lesions, as described above.
- Ultrasound energy is directed towards the breast area, the energy is absorbed by the gas in the perfluorocarbon emulsion, and heat is generated as a result.
- An array of sensors is brought in contact with the skin in the breast area, and the temperature is measured on a plurality of points on the breast.
- the operation mode of the external energy source can be continuous or pulsed. In the continuous mode the energy source is switched on for a predetermined time period. During this time, the intensity might be constant or time dependent. In the pulsed mode the energy source is switched ON and OFF alternately. The duration of time in which the energy source is switched "ON” and the duration of time in which the energy source is switched “OFF”, can be controlled and is changeable. The "ON" time period followed by the "OFF” time period is defined as a cycle. In the pulsed mode, the number of cycles can be controlled.
- the intensity of energy can be controlled and may vary during the application period.
- One or more pulses may have a higher level of intensity than the remainder of the pulses, or the level of intensity can vary even within a single pulse, so that for example, the pulse may begin at one intensity level, and end at another intensity level.
- Cumulatively all the parameters such as operation mode (continuous or pulsed), duration times, intensity form (constant or time dependent) comprises the operation profile.
- the control unit of the energy source may contain many operation profiles.
- the method of the present invention grants control over the dynamics of the thermal effect, by controlling the duration and the timing of application of the external energy source.
- the timing of the monitoring is controllable in the present invention, more so than in prior art. Use of a thermal enhancing agent, and controlling the dynamics of the process, enhances the differences in thermal magnitude on the one hand, and avoids dissipation of the thermal effect on the other hand, by improving the timing of the monitoring.
- thermal magnitude measurements are plotted and a thermal map is generated and analyzed by computer.
- a point of abnormally elevated thermal magnitude corresponds to a suspected lesion in that area on the breast.
- thermal magnitude measurements are compared to data previously accumulated from the same patient.
- the thermal magnitudes are monitored over a period of time, so that several measurements are taken for each point on the breast.
- the amount of material injected is calibrated to be sufficient enough to receive a detectable change the thermal magnitude reading on the skin, from material accumulated in a tumor at a typical depth of 2.5cm within the breast.
- the temperature reached within the breast should not be higher than 41°C, a maximum temperature suited for diagnostics. This is assured by injecting the proper amount of material, by calibrating the intensity of the energy administered towards the breast, and the length of time for which it is applied.
- the thermal magnitudes are measured in one embodiment with an array of sensors, (which are, for instance, thermistors), and the distance between the sensors determines the resolution of the thermal map which is generated.
- the method of the present invention aims to detect lesions of a minimum size of 0.4cm (which correlates to a developmental stage of malignancy of up to stage 1), and thus in a preferred embodiment, the maximum distance between the sensors in the array is 0.2cm .
- the thermal magnitudes are measured using a thermal camera, from which a gray scale, or a colored scale, thermal map is generated. The infrared-based camera is directed towards the breast, or the sensor array is brought in contact with the breast, either before, during or after the external energy is applied. Thermal magnitude measurements can then be taken before, after, or in parallel to application of the external energy, or in any combination of timing thereof.
- the amount of time necessary to measure the thermal magnitudes of the breast may be shortened if a prediction algorithm is used.
- the algorithm can aid in shortening the measurement time by calculating the steady-state temperature value instead of waiting for skin temperature to reach steady state.
- the material to be injected is enclosed within liposomes.
- it is emulsified using a carrier, until it is a water-soluble micro-emulsion with a particle diameter ⁇ 100nm, so that the emulsion can diffuse out of the blood vessels and into a lesion, should a lesion be present.
- the material to be injected is a gaseous precursor, for example sodium bicarbonate, aminomalonate, or methylactete. These materials will form a gas after a change in pH, such as is achieved, for example, upon injection into the bloodstream, or when they reach a hypoxic, acidic tumor.
- a temperature rise can be generated when a thermal enhancing agent (at concentrations as low as are expected in tumors) is activated by an external energy source.
- the temperature rise generated deep within the tissue, in the presence of a thermal enhancing agent, can be measured on the skin.
- test tubes Two test tubes were chosen, containing saline (0.9M NaCl). Perflourodecalin was repeatedly added to one of the test tubes so as to obtain ten-fold increases in perflourodecalin concentration. After each new concentration was reached, the test tube was subjected to ultrasound energy, having a frequency of 1MHz, with an intensity of 100 mW/cm 2 for a period of three minutes. The temperature was then read via a temperature probe inserted into the test tube. The temperature was similarly measured in the remaining test tube , which contained saline only, and functioned as a control. The results are depicted in Figure 1.
- the temperature is shown in both test tubes over the course of the experiment.
- the upper line on the graph represents the test tube to which perfluorodecalin was added in increasing amounts, and the lower line represents the test tube which contained saline.
- Each peak on the graph represents a rise in temperature at a specific time in the experiment.
- the first peak on the left (peak 0) represents a time-point where both test tubes contained only saline, and application of ultrasound raised the temperature in both test tubes to 33°C.
- the concentration of perfluorodecalin was continuously raised in one of the test tubes, represented by the upper line on the graph.
- Bovine tissue was subjected to several cycles, in which in each cycle the tissue was injected with a ten-fold increased concentration of a perfluoro- decalin solution, then immediately subjected to ultrasonic energy having a frequency of 1MHz, with an intensity of 100 mW/cm 2 for a period of three minutes. Then the tissue was imaged using an infrared-based camera. Between each injection and subsequent application of ultrasound, the tissue was allowed to return to the baseline temperature.
- a schematic presentation of the experiment protocol is shown.
- the bovine tissue was first injected with saline (0.9M NaCl) (0) at a depth of 2.7 cm within the tissue. This depth was chosen since it represents a typical depth at which a tumor can be found within a human breast.
- Ultrasound was applied to the tissue, at the intensity described above, for three minutes, after which thermal mapping was performed using an infrared-based camera. A delay of five minutes allowed the tissue to return to the baseline temperature, then 0.01% perfluorodecalin (1) diluted in saline was injected, and after three minutes of ultrasonic energy was applied, the tissue was imaged once again.
- Fig. 3 depicts images taken by an infrared-based camera after injection of various concentrations of perfluorodecalin to bovine tissue.
- the percentage of injected perfluorodecalin is noted in the left-hand corner of each box within the figure. Light-colored areas in the gray scale represent higher temperatures, while darker areas represent lower temperatures.
- perfluorodecalin When saline was injected instead of perfluorodecalin (box 3a), the application of ultrasound lead to a minimal rise in temperature at the site of injection, which is represented by a light-colored area on the dark gray background. Even the lowest percentage of perfluorodecalin used in this experiment, 0.01% (box 3b), enhances the rise in temperature obtained when ultrasound is applied to the tissue. At 0.1%perfluorodecalin (box 3c), the rise in temperature is greatly enhanced. This concentration, and concentrations greater than it, are shown to significantly intensify the thermal effect that application of ultrasound has on tissue (see boxes 3c, 3d, 3e and 3f). Therefore, perfluorocarbons can be administered to a tissue and after application of ultrasound, a diagnostic thermal image can be obtained that clearly depicts areas of perfluorocarbon accumulation.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IL14466101A IL144661A0 (en) | 2001-07-31 | 2001-07-31 | A method for detection of cancer using a thermal enhancement agent, and non-invasive thermal monitoring |
IL144661 | 2001-07-31 |
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WO2003011130A2 true WO2003011130A2 (en) | 2003-02-13 |
WO2003011130A8 WO2003011130A8 (en) | 2003-08-14 |
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PCT/IL2002/000620 WO2003011130A2 (en) | 2001-07-31 | 2002-07-25 | A method for detection of cancer using a thermal enhancement agent, and non-invasive thermal monitoring |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013186735A2 (en) * | 2012-06-14 | 2013-12-19 | Bar-Ilan Research And Development Company Ltd. | Photothermal detection |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5149319A (en) | 1990-09-11 | 1992-09-22 | Unger Evan C | Methods for providing localized therapeutic heat to biological tissues and fluids |
US5158536A (en) | 1989-08-28 | 1992-10-27 | Biopulmonics, Inc. | Lung cancer hyperthermia via ultrasound and/or convection with perfiuorochemical liquids |
US6077228A (en) | 1998-11-04 | 2000-06-20 | Schonberger; Milton | Breast temperature scanner |
-
2001
- 2001-07-31 IL IL14466101A patent/IL144661A0/en unknown
-
2002
- 2002-07-25 WO PCT/IL2002/000620 patent/WO2003011130A2/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5158536A (en) | 1989-08-28 | 1992-10-27 | Biopulmonics, Inc. | Lung cancer hyperthermia via ultrasound and/or convection with perfiuorochemical liquids |
US5149319A (en) | 1990-09-11 | 1992-09-22 | Unger Evan C | Methods for providing localized therapeutic heat to biological tissues and fluids |
US6077228A (en) | 1998-11-04 | 2000-06-20 | Schonberger; Milton | Breast temperature scanner |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013186735A2 (en) * | 2012-06-14 | 2013-12-19 | Bar-Ilan Research And Development Company Ltd. | Photothermal detection |
WO2013186735A3 (en) * | 2012-06-14 | 2014-02-20 | Bar-Ilan Research And Development Company Ltd. | In-vivo tissue imaging by photothermal detection |
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Publication number | Publication date |
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WO2003011130A8 (en) | 2003-08-14 |
IL144661A0 (en) | 2002-05-23 |
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