EP3914312A1 - Système et méthodes pour une thérapie par perfusion sous hyperthermie extracorporelle (ehp) - Google Patents

Système et méthodes pour une thérapie par perfusion sous hyperthermie extracorporelle (ehp)

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Publication number
EP3914312A1
EP3914312A1 EP19745181.8A EP19745181A EP3914312A1 EP 3914312 A1 EP3914312 A1 EP 3914312A1 EP 19745181 A EP19745181 A EP 19745181A EP 3914312 A1 EP3914312 A1 EP 3914312A1
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EP
European Patent Office
Prior art keywords
blood
cancer
patient
temperature
disease
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
EP19745181.8A
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German (de)
English (en)
Inventor
Gerhard SIEBENHÜNER
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Siebenhuener Christine
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Siebenhuener Christine
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Publication date
Application filed by Siebenhuener Christine filed Critical Siebenhuener Christine
Publication of EP3914312A1 publication Critical patent/EP3914312A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/369—Temperature treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1698—Blood oxygenators with or without heat-exchangers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3687—Chemical treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3368—Temperature
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/36—General characteristics of the apparatus related to heating or cooling
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/36—General characteristics of the apparatus related to heating or cooling
    • A61M2205/366—General characteristics of the apparatus related to heating or cooling by liquid heat exchangers

Definitions

  • the present invention relates to a system for warming blood, in particular to carry out Extracorporeal Hyperthermia Perfusion (EHP) therapy. Further, the present invention relates to extracorporeal blood above normal body temperature for use in the treatment of a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis. Furthermore, the present invention relates to a combination of extracorporeal blood above normal body temperature and a chemotherapeutic agent for use in the treatment of cancer.
  • EHP Extracorporeal Hyperthermia Perfusion
  • cancer is the major cause of incidence of death increasing every day. Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development. Under current estimates, two in five people will have cancer at some point in their lifetime.
  • Hyperthermia is also a technique known to treat cancer.
  • doctors, treating cancer patients discovered that some patients who had developed fever themselves experienced spontaneous tumor regressions or even remissions. This led to the conclusion that cancer cells were more sensitive to heat than healthy cells.
  • diverse methods and devices have been developed to such an extent that various targeted applications have become possible in medical practice.
  • Hyperthermia has the advantage that it neglects or avoids the use of chemicals or harmful radiations.
  • the elevated body temperature can damage the cancerous cells with minimum injury to the normal cells.
  • Hyperthermia can also be combined with radiation therapy and/or chemotherapy in order to improve cancer treatment.
  • Numerous clinical trials have studied hyperthermia in combination with radiation therapy and/or chemotherapy. These studies have focused on the treatment of diverse types of cancer. Many of these studies have shown a significant reduction in tumor size when hyperthermia is combined with other treatments.
  • thermal treatment for cancer has typically been limited to superficial cancers.
  • three methods can be distinguished: local, regional, and whole-body hyperthermia. These methods have in common that individual body parts or body regions can be heated from the outside to a temperature between 40° and 44°C using electromagnetic waves, depending on the indication, in order to treat tumors.
  • Local hyperthermia is a method in which heat is applied to a small area, such as tumor in a tissue, using different techniques that deliver heat energy to the tumor. For this purpose, microwave, ultrasound, or radiofrequency may be used.
  • regional hyperthermia a body part such as limb or organ is heated. The body part can be heated by arrays of antennas by using different applicators. Sigma blade applicator is a widely used applicator that contains four pairs of dipole antennas in a ring around the patient.
  • Whole body hyperthermia is usually applied to treat metastatic tumor that has spread throughout the body. With the help of sedation of general anesthesia, the procedure is possible.
  • Body temperature of a patient can be raised from the outside of the body by using heating blankets, warm-water immersion (putting the patient in warm water), or thermal chambers (much like large incubators).
  • Side effects of local hyperthermia can be pain at the target site, bleeding, blood clots, infections, swelling, bums, blistering, and/or damage to skin, nerves and muscles around the treated area.
  • Side effects of regional and whole-body hyperthermia can be nausea, vomiting, and/or diarrhea. In severe cases, it leads to problems associated with heart, blood vessels, and other major organs.
  • the major disadvantage of whole-body heating is the systemic stress that results from a lack of preferential heating and the necessity of anesthesia with its negative side effects and risks.
  • the present inventor found that heating patient’s blood itself, and not by supplying heat from the outside to the patient, allows effective treatment of cancer, autoimmune diseases, infectious diseases, inflammatory diseases, and/or sepsis with low side-effects.
  • the present inventor has developed an improved device or system for removing patient’s blood from the blood circulation, warming said blood and returning said blood into the patient’s body.
  • This system further allows highly efficient blood purification and supply of the organism with necessary natural or chemical substances. It also allows the combination of blood purification, oxygen therapy, gentle chemotherapy, gentle radiotherapy, and/or surgery in one procedure/therapy approach which is most effective in the treatment of cancer.
  • the present inventor further found that the heat treatment of blood could increase the therapy success of surgery, radiation therapy, and/or chemotherapy of cancer patients.
  • the inventor further provides extracorporeal blood above normal body temperature for use in the treatment of a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the present invention relates to a system for warming blood, preferably configured for performing a method according to the fourth to seventh aspect, comprising:
  • a tube system comprising at least one inlet and at least one outlet, the tube system being configured to guide blood between the inlet and the outlet, and
  • At least one heat transfer device configured to transfer heat to blood in order to increase the blood temperature within the tube system
  • system is configured to raise a body temperature of a subject connectable to the tube system by receiving blood of the subject through the at least one inlet, guiding the blood through the tube system away from the at least one inlet to the at least one heat transfer device and guiding heated blood through the tube system away from the at least one heat transfer device to the at least one outlet in order to increase the body temperature by using heated blood as heat transfer medium.
  • the present invention relates to extracorporeal blood above normal body temperature for use in the treatment of a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the present invention relates to a combination of extracorporeal blood above normal body temperature and a chemotherapeutic agent for use in the treatment of cancer.
  • the terms used herein are defined as described in“A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • the term“comprise” or variations such as“comprises” or“comprising” according to the present invention means the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
  • the term“consisting essentially of’ according to the present invention means the inclusion of a stated integer or group of integers, while excluding modifications or other integers which would materially affect or alter the stated integer.
  • the term“consisting of’ or variations such as“consists of’ according to the present invention means the inclusion of a stated integer or group of integers and the exclusion of any other integer or group of integers.
  • haemoperfusion/hemoperfusion refers to a method of filtering blood extracorporeally (that is, outside the body) to remove one or more toxins.
  • the blood travels from the patient into a machine, gets filtered, and then travels back into the patient, typically by veno venous access (out of a vein and back into a vein).
  • Adsorbers filters
  • filters in particular macroporous resin beads, are preferably used, which allow an effective blood purification.
  • These adsorbers in turn may be combined with other therapy components, which regulate the metabolism and strengthen the immune system. In this way, drug strategies can take effect more effectively.
  • the present inventor worked with adsorbers which can, for example, eliminate heavy metal loads in only one treatment with EHP as effective as a large number of chelate infusions over a long period of time.
  • the heavy metals are chelated from the tissues into the blood, whereby the heat maximizes this process.
  • the heavy metals are then filtered out of the blood by the adsorbers without reabsorption in the kidneys. This increases the effectiveness to a maximum.
  • Adorbers can be used to eliminate sepsis, severe inflammations, cytokines, toxins as well as pesticides or drugs. Special adsorbers can also be used for borreliose, autoimmune diseases, cancer, suspected multi organ failure, liver diseases, kidney diseases, systemic inflammatory response syndrome (SIRS), or lung diseases such as ARDS (acute respiratory distress syndrome).
  • SIRS systemic inflammatory response syndrome
  • ARDS acute respiratory distress syndrome
  • hyperoxygenated haemoperfusion/hemoperfusion refers to the haemoperfusion/hemoperfusion as described above but extended by an oxygenator. This massively increases the oxygen content of the blood.
  • the hyperoxygenated haemoperfusion/hemoperfusion technology originates from cardiac surgery, but is now also used in other therapeutic disciplines. Through the supply of medical oxygen, it is possible to achieve a physical oxygen saturation of at least 400%, 500%, 600%, or 700%, preferably of at least 700%, within the tissue. In this way, the body's own repair and regeneration processes can be restarted. In addition, the formation of new blood vessels is stimulated and toxins can be better removed from the organism.
  • hyperthermia refers to a type of medical treatment in which body tissue is exposed to higher temperatures in an effort to treat cancer. This is achieved through the use of radio or electromagnetic waves, which heat the areas of the organism to be treated to 40°C to 44°C, depending on the indication.
  • hyperthermia treatment encompasses all procedures with which areas of the body are overheated in a targeted and controlled way.
  • Hyperthermia has the advantage that it neglects or avoids the use of chemicals or harmful radiations.
  • the elevated body temperature can damage the cancerous cells with minimum injury to the normal cells.
  • Hyperthermia can also be combined with radiation therapy and/or chemotherapy in order to improve cancer treatment.
  • Numerous clinical trials have studied hyperthermia in combination with radiation therapy and/or chemotherapy. These studies have focused on the treatment of diverse types of cancer. Many of these studies have shown a significant reduction in tumor size when hyperthermia is combined with other treatments. This effect is synergistic.
  • hyperthermia In the clinical application of hyperthermia, three methods can be distinguished: local, regional, and whole-body hyperthermia.
  • Local hyperthermia is a method in which heat is applied to a small area, such as tumor in a tissue, using different techniques that deliver heat energy to the tumor. For this purpose, microwave, ultrasound, or radiofrequency may be used.
  • regional hyperthermia a body part such as limb or organ is heated. The body part can be heated by arrays of antennas by using different applicators.
  • Whole body hyperthermia is usually applied to treat metastatic tumor that has spread throughout the body. With the help of sedation of general anesthesia, the procedure is possible.
  • Body temperature of a patient can be raised from the outside of the body by using heating blankets, warm-water immersion (putting the patient in warm water), or thermal chambers (much like large incubators).
  • Side effects of local hyperthermia can be pain at the target site, bleeding, blood clots, infections, swelling, bums, blistering, and/or damage to skin, nerves and muscles around the treated area.
  • Side effects of regional and whole-body hyperthermia can be nausea, vomiting, and/or diarrhea. In severe cases, it leads to problems associated with heart, blood vessels, and other major organs.
  • the major disadvantage of whole-body heating is the systemic stress that results from a lack of preferential heating and the necessity of anesthesia with its negative side effects and risks.
  • haemo/hemo-hyperthermia refers to a technique which does not heat the organism from the outside, but heats the blood itself, e.g. to between 39.0 and 44.0 °C, preferably to between 40.0 and 42.5 °C.
  • blood is removed from the patient’s blood circulation.
  • the extracorporeal blood is heated, e.g. to a temperature of between 39.0 and 44.0 °C, preferably to a temperature of between 40.0 and 42.5 °C, and the heated blood is then returned to the patient’s blood circulation.
  • haemo/hemo- hyperthermia an overall heating of the organism from the inside is achieved.
  • EHP therapy refers to a combination of“(hyperoxygenated) haemo/hemo-hyperthermia” and“perfusion therapy”.
  • cytostatic/chemotherapeutic drugs in much lower concentrations than with conventional chemotherapy can often even be directed directly to the affected target organs and b) at the same time the excess of cytostatic/chemotherapeutic drugs can be discharged from the organism at the end of the therapy, so that almost no side effects occur with improved effectiveness of the cytostatic drugs.
  • the EHP therapy is low in side effects and is usually well tolerated by the patient.
  • the EHP therapy is preferably used as an additive to chemotherapy and/or radiotherapy. In other words, EHP therapy is preferably used in combination with chemotherapy and/or radiotherapy.
  • the EHP therapy may be used for the treatment of cancer, numerous chronic diseases, autoimmune diseases such as rheumatism/rheumatic diseases, massive heavy metal exposure resulting diseases, infectious diseases such as borreliose, inflammatory diseases such as atherosclerosis or systemic inflammatory response syndrome (SIRS), sepsis, diseases associated with elevated cholesterol levels, lung diseases, liver diseases such as acute respiratory distress syndrome (ARDS), and/or kidney diseases.
  • autoimmune diseases such as rheumatism/rheumatic diseases, massive heavy metal exposure resulting diseases
  • infectious diseases such as borreliose
  • inflammatory diseases such as atherosclerosis or systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • sepsis diseases associated with elevated cholesterol levels
  • lung diseases such as acute respiratory distress syndrome (ARDS)
  • ARDS acute respiratory distress syndrome
  • kidney diseases preferably, the EHP therapy is used for the treatment of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and/or sepsis
  • disease refers to an abnormal condition that affects the body of an individual.
  • a disease is often construed as a medical condition associated with specific symptoms and signs.
  • a disease may be caused by factors originally from an external source, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune disease.
  • “disease” is often used more broadly to refer to any condition that causes pain, dysfunction, distress, social problems, or death to the individual afflicted, or similar problems for those in contact with the individual. In this broader sense, it sometimes includes injuries, disabilities, disorders, syndromes, infectious, isolated symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts and for other purposes these may be considered distinguishable categories.
  • the disease is selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • autoimmune disease refers to any disease in which the body produces an immunogenic (i.e. immune system) response to some constituent of its own tissue.
  • the immune system loses its ability to recognize some tissue or system within the body as self and targets and attacks it as if it were foreign.
  • Autoimmune diseases can be classified into those in which predominantly one organ is affected (e.g. hemolytic anemia and anti-immune thyroiditis), and those in which the autoimmune disease process is diffused through many tissues (e.g. systemic lupus erythematosus).
  • multiple sclerosis is thought to be caused by T-cells attacking the sheaths that surround the nerve fibers of the brain and spinal cord.
  • Autoimmune diseases are known in the art and include, for instance, Hashimoto's thyroiditis, Grave's disease, lupus, multiple sclerosis, rheumatism/rheumatic diseases, e.g. rheumatic arthritis, hemolytic anemia, anti-immune thyroiditis, systemic lupus erythematosus, celiac disease, Crohn's disease, colitis, diabetes, scleroderma, psoriasis, and the like.
  • rheumatism/rheumatic diseases caused by autoimmunity include, but are not limited to, ankylosing spondylitis, relapsing polychondritis, system lupus erythematosus, rheumatoid arthritis, gout, inflammatory arthritis, pseudogout, juvenile arthritis, Sjogren syndrome, scleroderma, polymyositis, dermatomyositis, Behcet’s disease, and psoriatic arthritis.
  • infectious disease refers to any disease which can be transmitted from individual to individual or from organism to organism, and is caused by a microbial agent (e.g. common cold).
  • Infectious diseases are known in the art and include, for example, a viral disease, a bacterial disease, or a parasitic disease. Said diseases are caused by a virus, a bacterium, and a parasite, respectively.
  • the infectious disease can be, for example, borreliose, hepatitis, sexually transmitted diseases (e.g.
  • chlamydia or gonorrhea tuberculosis, human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), diphtheria, hepatitis B, hepatitis C, cholera, severe acute respiratory syndrome (SARS), the bird flu, and influenza.
  • HIV human immunodeficiency virus
  • AIDS human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • diphtheria diphtheria
  • hepatitis B hepatitis C
  • cholera severe acute respiratory syndrome
  • SARS severe acute respiratory syndrome
  • the infectious disease is preferably borreliose.
  • inflammatory disease refers to a disease in which the immune system attacks the body’s own tissues, resulting in an inflammation.
  • the inflammatory disease is selected from the group consisting of atherosclerosis, an autoimmune disease, allergy, asthma, a coeliac disease, glomerulonephritis, hepatitis, and an inflammatory bowel disease.
  • the autoimmune disease is further specified above.
  • sepsis refers to a life-threatening condition that arises when the body’s response to an infection causes injury to its own tissues and organs. Sepsis is usually caused by an inflammatory immune response triggered by an infection. Most commonly, the infection is bacterial, but it may also be fungal, viral, or protozoan. Disease severity partly determines the outcome. The risk of death from sepsis is as high as 30%, from severe sepsis as high as 50%, and from septic shock as high as 80%.
  • cancer disease or “cancer”, as used herein, refer to or describe the physiological condition in an individual that is typically characterized by unregulated cell growth.
  • cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particularly, examples of such cancers include bone cancer, blood cancer lung cancer, liver cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, prostate cancer, uterine cancer, carcinoma of the sexual and reproductive organs, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the bladder, cancer of the kidney, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), neuroectodermal cancer, spinal axis tumors, glioma, meningioma, and pitu
  • the terms“individual” and“subject” can be used interchangeable herein.
  • the individual or subject may be any mammal, including both a human and another mammal, e.g. an animal. Human individuals or subjects are particularly preferred.
  • the individual may be a patient.
  • patient refers to any subject suffering from a disease, in particular suffering from cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and/or sepsis.
  • the patient may be treated and/or the response to said treatment may be evaluated.
  • the patient may be any mammal, including both a human and another mammal, e.g. an animal. Human subjects as patients are particularly preferred.
  • treatment refers to any therapy which improves the health status and/or prolongs (increases) the lifespan of a patient.
  • Said therapy may eliminate the disease in a patient, arrest or slow the development of a disease in a patient, inhibit or slow the development of a disease in a patient, decrease the frequency or severity of symptoms in a patient, and/or decrease the recurrence in a patient who currently has or who previously has had a disease.
  • a drug used in chemotherapy is a chemotherapeutic agent.
  • chemotherapeutic agent refers to a compound that is administered in the treatment of cancer. These agents or drugs are categorized by their mode of activity within a cell, for example, whether and at what stage they affect the cell cycle. Alternatively, an agent may be characterized based on its ability to directly cross-link DNA, to intercalate into DNA, or to induce chromosomal and mitotic aberrations by affecting nucleic acid synthesis.
  • the chemotherapeutic agent is preferably selected from the group consisting of alkylating agents, anthracyclines, cytoskeletal disruptors, epothilones, histone deacetylase inhibitors, inhibitors of topoisomerase I, inhibitors of topoisomerase II, kinase inhibitors, nucleotide analogs and precursor analogs, peptide antibiotics, platinium-based agents, and retinoids.
  • radiation therapy also called radiotherapy
  • radiation therapy refers to a cancer treatment that uses high doses of radiation to kill cancer cells and shrink tumors. At low doses, radiation is used in x-rays to see inside the body. At high doses, radiation therapy kills cancer cells or slows their growth by damaging their DNA. Cancer cells whose DNA is damaged beyond repair stop dividing or die. When the damaged cells die, they are broken down and removed from the body. Radiation therapy does not kill cancer cells right away. It takes days or weeks of treatment before DNA is damaged enough for cancer cells to die. Then, cancer cells keep dying for weeks or months after radiation therapy ends.
  • normal body temperature also known as normothermia or euthermia
  • euthermia refers to the typical temperature found in an individual. In humans, the normal body temperature is 37 °C. This value is, however, only an average. The normal body temperature may be slightly higher or lower. A number of factors can influence the body temperature, including age, sex, time of day, and activity level. In babies and children, for example, the average body temperature ranges from 36.6 °C to 37.2 °C. Among adults, the average body temperature ranges from 36.1 °C to 37.2°C.
  • the normal human body temperature range is, thus, typically stated as being between 36.1 °C and 37.5 °C, e.g. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0 37.1, 37.2, 37.3, 37.4, or 37.5 °C, in humans.
  • extracorporeal blood refers to blood removed/isolated from an individual’s blood circulation.
  • extracorporeal circuit refers to a procedure in which blood is taken from an individual’s circulation to have a process applied to it before it is returned to the circulation. All of the system carrying the blood outside the body is termed the extracorporeal circuit.
  • the blood is warmed/heated above normal body temperature before it is returned to the circulation.
  • the blood is not only warmed/heated above normal body temperature, it is also oxygenated, filtered, and/or supplemented with therapeutic agents such as chemotherapeutic agents before it is returned to the circulation.
  • systemic administration refers to the administration of the therapeutic agent, e.g. chemotherapeutic agent, such that said agent becomes widely distributed in the body of a patient in significant amounts and develops a biological effect.
  • Typical systemic routes of administration include administration by introducing the therapeutic agent, e.g. chemotherapeutic agent, directly into the vascular system or oral, pulmonary, or intramuscular administration wherein the therapeutic agent, e.g. the chemotherapeutic agent, enters the vascular system and is carried to one or more desired site(s) of action via the blood.
  • the systemic administration may be by parenteral administration.
  • parenteral administration refers to the administration of the therapeutic agent, e.g. chemotherapeutic agent, such that said compound does not pass the intestine.
  • parenteral administration includes intravenous administration, subcutaneous administration, intradermal administration, or intraarterial administration, but is not limited thereto.
  • heating patient’s blood itself and not by supplying heat from the outside to the patient allows effective treatment of cancer, autoimmune diseases, infectious diseases, inflammatory diseases, and/or sepsis with low side- effects.
  • the present inventor found that the heating of patient’s blood itself to a temperature between 40°C and 44°C has the following advantages in cancer therapy:
  • the temperature between 40°C and 44°C influences certain proteins in the cancer cells that are necessary for the formation of essential enzymes for cell function. Their destruction can trigger apoptosis of the cancer cells.
  • the heating of the blood also leads to a blockage of the blood vessels in the area of the tumor. This reduces oxygen and nutrients entering the cancer cells.
  • the heat shock causes that cancer cells form various“heat shock proteins” (HSP) as a defense reaction.
  • HSP heat shock proteins
  • the proteins which are located on the outer cell membranes, protect the cancer cells from the high temperatures and are initially not recognized by the body's immune system. However, these proteins are destroyed by the continuous heat treatment and the unmasked cancer cells are then eliminated by the immune system. In addition, the heat increases the blood flow to the tumor and, thus, increases the targeted absorption of drugs and active substances.
  • the present inventor has developed an improved device or system for removing patient’s blood from the blood circulation, warming said blood and returning said blood into the patient’s body.
  • This system further allows highly efficient blood purification and supply of the organism with necessary natural or chemical substances. It also allows the combination of blood purification, oxygen therapy, gentle chemotherapy, gentle radiotherapy, and/or surgery in one procedure/therapy approach which is most effective in the treatment of cancer.
  • the methods may use the system or its embodiments as discussed above.
  • the features, advantages and technical effects that are valid for the system and its embodiments may also be valid for the methods and other aspects and vice versa.
  • the system may comprise:
  • a tube system comprising at least one inlet and at least one outlet, the tube system being configured to guide blood between the inlet and the outlet, and
  • At least one heat transfer device configured to transfer heat to blood in order to increase the blood temperature within the tube system.
  • the system may be configured to raise a body temperature of a subject connectable to the tube system by receiving blood of the subject through the at least one inlet, guiding the blood through the tube system away from the at least one inlet to the at least one heat transfer device and guiding heated blood through the tube system away from the at least one heat transfer device to the at least one outlet in order to increase the body temperature by using heated blood as heat transfer medium.
  • the body may not be heated directly from outside but from inside using the blood vessels that are in the body. This is contrary to the classical hyperthermia method and allows new treatment methods.
  • Using the proposed system there is a heat transport from the outside of the body to the inside of the body using blood as a carrier medium.
  • the present invention relates to a system for warming blood, preferably configured for performing a method described/claimed herein, comprising:
  • a tube system comprising at least one inlet and at least one outlet, the tube system being configured to guide blood between the inlet and the outlet, and
  • At least one heat transfer device fluidly connected to the tube system and configured to transfer heat to blood in order to increase the blood temperature within the tube system
  • the system is configured to raise a body temperature of a subject connectable to the tube system by receiving blood of the subject through the at least one inlet, guiding the blood through the tube system away from the at least one inlet to the at least one heat transfer device and guiding heated blood through the tube system away from the at least one heat transfer device to the at least one outlet in order to increase the body temperature by using heated blood as heat transfer medium.
  • the heat transfer device may be fluidly connected to the tube system.
  • the inlet may for instance be located in or connected to the left femoral vein.
  • the output may for instance be located in or connected to the right femoral vein.
  • the right femoral vein may be connected with the inlet and the left femoral vein may be connected to the outlet of the tube system.
  • Jugular veins may be used instead of femoral veins as well. Furthermore, more than one inlet location and/or more than one outlet location may be used. It is also possible to use other locations of the blood vessels to connect the inlet and the outlet with the blood system of the person or with the blood system of the animal.
  • the subject may be a patient having a disease, for instance cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and/or sepsis and who needs a treatment involving the proposed system.
  • the subject may be a person, i.e. an individual, or an animal, preferably a mammalian.
  • the tube system may comprise flexible tubes or rigid tubes. T-fittings, valves, preferably three way valves or four-way valves, may be used in order to adapt the tube system to the needs.
  • the body temperature may be increased in the whole body, in at least 50 percent of volume or percent of mass of the body or in at least 75 percent of volume or percent of mass of the body.
  • more local treatments of the body are also possible using the system, the methods and the other aspects. It is for instance possible to heat less than 30 percent of volume or percent of mass of the body or less than 20 percent of volume or percent of mass of the body, e.g. only the tissue around a specific organ. This may be done be an appropriate placement of the inlet and the outlet of the system.
  • the system may be configured to increase the body temperature by at least 0.5 °C, at least 1 °C, by at least 2 °C, or by at least 3 °C.
  • the normal body temperature of a human is between 36.1 °C and 37.5 °C, e.g. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0 37.1, 37.2, 37.3, 37.4, or 37.5 °C.
  • a raise of the body temperature to at least 38, 38.5, 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5 °C, or 44 °C may, thus, be possible.
  • the body temperature is increased to between 40 °C and 44 °C. More preferably, the body temperature is increased to between 40 °C and 42.5 °C.
  • the method may also be used if the temperature of the body is higher, i.e. the person has fever or a higher temperature is reached by other methods, for instance using exogenic pyrogenes.
  • the increase of the body temperature that is reached by using the system may be smaller than 5 °C.
  • the system may comprise at least one blood pump that is connected to the tube system.
  • the pump may be a roller pump that creates pulsation from the outside on a tube, i.e. peristaltic pump, or other appropriate pump, for instance membrane pump, piston pump, centrifugal pump.
  • a centrifugal pump may be used if an oxygenator device is used in order to reach higher pressures and have higher pumping power, for instance if compared with the pressure or power of a peristaltic pump.
  • the heat transfer device may comprise a heat exchanger that is configured to use an auxiliary fluid, preferably water, preferably an auxiliary fluid having a temperature in the range of 42 °C to 47 °C or within the range of 44 °C to 46 °C or having a temperature of 45 °C.
  • the system may be configured such that the flow rate of the auxiliary fluid through the heat exchanger may be greater than of 2.5 liter per minute, preferably greater than 5 liter per minute. Changes of temperature are comparable slow if an auxiliary fluid is used, for instance if compared with an electrical heater. Using the auxiliary fluid, it is possible to prevent in a simple way overheating that would be dangerous for the health of the subject.
  • heat transfer device is the heat exchanger CSC14 from LivaNova former Sorin Group. However other heat transfer devices may also be used.
  • There may be a reservoir for the auxiliary fluid and a circular flow of the auxiliary fluid.
  • the flow of the auxiliary fluid may be created by a pump for pumping the auxiliary fluid.
  • a heater may heat the auxiliary fluid to an appropriate temperature, preferably an electric heater.
  • the heat exchanger may be a plate heat exchanger or a tube heat exchanger or another appropriate device.
  • the heat transfer device may comprise an electrical heater. There may be circuitry that prevents overheating or to fast heating of the blood.
  • the system may comprise an oxygenator device that is configured to provide additional oxygen within the blood that is transported through the tube system.
  • the oxygenator device may comprises an input port for oxygen. The combination of heating up the blood and enhancing the blood with oxygen gives the possibility for better medical treatments of many diseases.
  • An example of an oxygenator device is the oxygenator Inspire 8F or 8FM from LivaNova former Soring Group. However other oxygenator devices may also be used.
  • the oxygenator device may be fluidly connected to the tube system.
  • the oxygenator device may comprise the heat transfer device, preferably as an integral part. There may be a physical separation between the system of an auxiliary fluid that is used for heating or warming and the circulation system of blood within the oxygenator device.
  • the heat exchanger within the oxygenator device may be a plate heat exchanger or a tube heat exchanger or another appropriate device.
  • the system may comprise at least one adsorber unit comprising an inlet that is fluidly connected to the tube system and an outlet that is fluidly connected to the tube system, wherein the blood at the outlet has been filtered compared to the blood at the inlet.
  • the adsorber unit may comprise an adsorber, preferably for adsorbing inflammatory molecules, toxic molecules and/or other harmful molecules.
  • the adsorber unit may be for instance an adsorber unit from the company Biosun or Biosky, i.e. a MG Series disposable Hemoperfusion Cartridge. Additionally or alternatively a dialyzer device may be used, preferably for removal of small molecular toxins. Filtering of the blood may also have the technical effects that particles are removed that stem from the system itself, for instance particles that are rubbed-off from parts of the system.
  • the combination of heating blood, adding oxygen and filtering may result in very good results during the treatment of a disease, e.g. cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and/or sepsis. Self-healing forces of the subject may be strengthen considerably using this combination.
  • the adsorber units and/or adsorbers within the adsorber units may be individualized to the subject and/or to the disease of the subject. This, may allow further improvements of the system with regard to the results of the treatment that is performed using the system.
  • the system may comprise a control unit.
  • the control unit may be configured to control the heat that is generated or transferred by the heat transfer device and/or the control unit may be configured to control the heat that is transferred from the blood within the tube system to the body of the person or to the body of the animal, preferably by adaption of the flow rate of the blood within the tube system. Adjustments of the heat transfer of the heat transfer device are for instance possible by changing the temperature of an auxiliary fluid that is used for heating the blood and or by changing the flow rate of the auxiliary fluid. Alternatively, it is possible to adapt the electrical energy of an electrical heater that is used within the heat transfer device. In both cases, heat transfers may also depend on the flow rate of the blood within the system. This flow rate may also be adapted by the control unit to adjust the heat transfer.
  • no control device may be used and the system may be operated manually, for instance by a technician, preferably by a cardio technician that is supervised by a medical practitioner.
  • the medical practitioner may also operate the system manually by himself or by herself.
  • the system may comprise at least one of, a combination of or all of the following features:
  • an input functionality for setting a target temperature of the blood within the system preferably within the range of 39 °C to 44 °C, preferably within the range of 40 °C to 44 °C, more preferably within the range of 40 °C to 42.5 °C
  • an input functionality for setting a target temperature of the body preferably within the range of 38 °C to 44 °C, preferably within the range of 40 °C to 44 °C, more preferably within the range of 40 °C to 42.5 °C, and/or
  • an input functionality for setting a target flow rate of the blood preferably within a range of 1 liter per minute to 5 liters per minute, preferably within the range of 2 liters per minute to 4 liters per minute, more preferably within the range of 1.5 liters per minute to 3 liters per minute, and/or
  • an input functionality for setting a target time for operation of the system preferably within a range of 1 hour to 8 hours, preferably within the range of 2 hours to 6 hours, more preferably within the range of 3 hours to 5 hours.
  • the input functionalities may be realized by separate input elements or by a user digital interface, for instance a touch screen etc.
  • the input functionalities may be realized using the control unit mentioned above. Thus, automated operation of the system would be possible.
  • the inner diameter of the tubes of the tube system may be in the range of 5 to 10 millimeters or 15 French to 30 French. This enables the high flow rates.
  • the system may comprise a monitoring functionality that is configured to detect or to measure the temperature of the blood within the system and/or that is configured to detect or measure the temperature of the body of the subject, i.e. of a person or of an animal.
  • the control unit may control the system depending on the temperature of the blood detected or measured within the system. Alternatively or additionally, the control system may control the system depending on the temperature of the body. It may be possible to adjust a value of the blood temperature within the system to a first target value within the system or to adjust a temperature of the body to a second target value. The adjustment may be automated or done manually. Alternatively, it may be possible to hold one or both of these temperatures within a range that is defined by a lower value and by an upper value.
  • the system may comprise at least one, a combination of or all of the following features:
  • control device is configured to control the temperature of blood within the tube system, preferably using a closed loop control device, preferably a closed loop control that prevents overshooting of temperature above a target temperature value of the blood and/or a target temperature value of the body, and/or
  • control device is configured to control the temperature of the body, preferably using a closed loop control device, preferably a closed loop control that prevents overshooting of temperature above a target temperature value of the blood and/or a target temperature value of the body.
  • Preventing overshooting may mean that an asymptotical progression of the temperature is reached, i.e. with making sure that the target value is not exceeded. This may be relevant for the health of the subject.
  • the heat insulation may be done for instance using a foam material.
  • the heat insulation may be done for each tube separately, for groups of tubes or for parts of the tube system, for instance using an insulated casing.
  • the casing may be transparent in order to allow a quick check that all tubes are connected properly.
  • There may be an insulation against heat radiation and/or heat conduction and/or heat convection.
  • heated tubes may be used, for instance tubes that are heated by electrical energy or by an auxiliary fluid.
  • the system may comprise at least one port that is configured to receive a chemical or biochemical substance that is added to the blood within the tube system, preferably a substance used for a chemotherapy.
  • a chemical or biochemical substance that is added to the blood within the tube system, preferably a substance used for a chemotherapy.
  • a fourfold combination of treatment methods is possible using the system, i.e. heating blood, enhancing oxygen with in the blood, filtering of the blood and adding medicaments to the blood.
  • One kind of medicaments may be blood dilution substances that prevent agglutination if the blood is heated.
  • the port may be an inlet port for injections.
  • the inventor further provides extracorporeal blood above normal body temperature for use in the treatment of a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the present invention relates to extracorporeal/isolated blood above normal body temperature for use in the treatment of a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • extracorporeal/isolated blood above normal body temperature can be used for treating a disease associated with elevated cholesterol levels.
  • a patient suffering from a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis is treated with extracorporeal/isolated blood above normal body temperature.
  • the extracorporeal/isolated blood is from the patient suffering from a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the blood has been obtained/isolated from said patient and subsequently heated above the patient’s normal body temperature. Afterwards, the same patient is treated with said blood heated above normal body temperature.
  • the extracorporeal/isolated blood is from another subject, a blood donor.
  • the blood has been obtained/isolated from said donor and subsequently heated above the donor’s normal body temperature. Afterwards, the patient is treated with the donor’s blood heated above normal body temperature.
  • the donor does not suffer from a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis. It is noted that the normal body temperature of the donor is preferably comparable with the normal body temperature of the patient or higher than the normal body temperature of the patient. In a particular embodiment, the blood of the donor is heated above the normal body temperature of the patient.
  • the normal body temperature refers to the typical temperature found in an individual.
  • the normal human body temperature range for example, is typically stated as being between 36.1 °C and 37.5 °C, e.g. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0 37.1, 37.2, 37.3, 37.4, or 37.5 °C.
  • the extracorporeal blood has a temperature of between 39°C and 44°C, preferably of between 40°C and 44°C, and more preferably of between 40°C and 42.5°C, e.g. of between 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, or 44 °C.
  • the extracorporeal blood is oxygenated blood.
  • the extracorporeal blood has been oxygenated by external means, e.g. using an oxygenator.
  • the oxygenator enhances oxygen within the blood.
  • the oxygenated extracorporeal blood usually allows to achieve an oxygen saturation of the tissue of at least 400%, 500%, 600%, or 700%, preferably of at least 700%.
  • the blood is purified blood.
  • Extracorporeal blood purification is a treatment in which a patient’s/donor’s blood is passed through a device (e.g. membrane, sorbent) in which solute (e.g. waste products, toxins) and possibly also water are removed. When fluid is removed, replacement fluid is usually added.
  • purified blood does not comprise inflammatory, toxic molecules and/or other harmful molecules anymore or comprises a reduced amount of said molecules compared to unpurified blood.
  • Extracorporeal therapies designed to remove or filter substances from the circulation in order to purify blood include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies and combinations of any of the above.
  • the purified blood is filtered blood.
  • the purified blood is dialyzed blood.
  • Blood dialysis removes waste, salt, toxins, extra water to prevent them from building up in the body, keeps a safe level of certain chemicals in the blood such as potassium, sodium, and bicarbonate, and helps to control blood pressure.
  • the blood e.g. the purified, filtered, or dialyzed blood, is free of inflammatory or other harmful molecules.
  • the cancer is selected from the group consisting of skin cancer, nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squamous cell cancer, laryngeal cancer, retina cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bone cancer, lymphoma, and leukemia,
  • the autoimmune disease is selected from the group consisting of rheumatism/rheumatic disease, e.g. rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (lupus), Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, Myasthenia gravis, Vasculitis, Pernicious anemia, and Celiac disease,
  • rheumatism/rheumatic disease e.g. rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (lupus), Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, Myasthenia gravis, Vasculitis, Pernicious anemia, and Celiac disease
  • the infectious disease is selected from the group consisting of viral infection, preferably chronic or persistent viral infection, bacterial infection, parasitic infection, or
  • the inflammatory disease is selected from the group consisting of atherosclerosis, an autoimmune disease, allergy, asthma, a coeliac disease, glomerulonephritis, hepatitis, and an inflammatory bowel disease.
  • the viral infection is selected from the group consisting of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), rhinovirus (common cold), herpes simplex virus (HSV), and respiratory syncytial virus (RSV) infection,
  • HAV human immunodeficiency virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • RV rhinovirus
  • RSV respiratory syncytial virus
  • the bacterial infection is selected from the group consisting of Borrelia burgdorferi (Borreliose), Helicobacter pylori, Mycobacterium tuberculosis, Mycobacterium leprae, and Chlamydia trachomatis infection, or
  • the parasitic infection is selected from the group consisting of a Schistosoma mansoni, Taenia crassiceps, or Leishmania mexicana infection.
  • the rheumatism/rheumatic disease caused by autoimmunity is selected from the group consisting of ankylosing spondylitis, relapsing polychondritis, system lupus erythematosus, rheumatoid arthritis (RA), gout, inflammatory arthritis, pseudogout, juvenile arthritis, Sjogren syndrome, scleroderma, polymyositis, dermatomyositis, Behcet’s disease, and psoriatic arthritis.
  • the present invention relates to a combination of extracorporeal blood above normal body temperature and a chemotherapeutic agent for use in the treatment of cancer.
  • a patient suffering from cancer is treated with extracorporeal/isolated blood above normal body temperature.
  • the extracorporeal/isolated blood is from the patient suffering from cancer.
  • the blood has been obtained/isolated from said patient and subsequently heated above the patient’s normal body temperature. Afterwards, the same patient is treated with said blood heated above normal body temperature.
  • the extracorporeal/isolated blood is from another subject, a blood donor.
  • the blood has been obtained/isolated from said donor and subsequently heated above the donor’s normal body temperature. Afterwards, the patient is treated with the donor’s blood heated above normal body temperature. The donor does not suffer from cancer.
  • the normal body temperature of the donor is preferably comparable with the normal body temperature of the patient or higher than the normal body temperature of the patient.
  • the blood of the donor is heated above the normal body temperature of the patient.
  • the normal body temperature refers to the typical temperature found in an individual.
  • the normal human body temperature range for example, is typically stated as being between 36.1 °C and 37.5 °C, e.g. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0 37.1, 37.2, 37.3, 37.4, or 37.5 °C.
  • the extracorporeal blood has a temperature of between 39°C and 44°C, preferably of between 40°C and 44°C, and more preferably of between 40°C and 42.5°C, e.g. of between 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, or 44 °C.
  • the extracorporeal blood is oxygenated blood.
  • the extracorporeal blood has been oxygenated by external means, e.g. using an oxygenator.
  • the oxygenator enhances oxygen within the blood.
  • the blood is purified blood.
  • Extracorporeal blood purification is a treatment in which a patient’s/donor’s blood is passed through a device (e.g. membrane, sorbent) in which solute (e.g. waste products, toxins) and possibly also water are removed. When fluid is removed, replacement fluid is usually added.
  • purified blood does not comprise inflammatory, toxic molecules and/or other harmful molecules anymore or comprises a reduced amount of said molecules compared to unpurified blood.
  • Extracorporeal therapies designed to remove or filter substances from the circulation in order to purify blood include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies and combinations of any of the above.
  • the purified blood is filtered blood.
  • the purified blood is dialyzed blood.
  • Blood dialysis removes waste, salt, toxins, extra water to prevent them from building up in the body, keeps a safe level of certain chemicals in the blood such as potassium, sodium, and bicarbonate, and helps to control blood pressure.
  • the blood e.g. the purified, filtered, or dialyzed blood, is free of inflammatory or other harmful molecules.
  • the cancer is selected from the group consisting of skin cancer, nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squamous cell cancer, laryngeal cancer, retina cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bone cancer, lymphoma, and leukemia.
  • skin cancer nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squam
  • the chemotherapeutic agent is selected from the group consisting of alkylating agents, anthracy dines, cytoskeletal disruptors, epothilones, histone deacetylase inhibitors, inhibitors of topoisomerase I, inhibitors of topoisomerase II, kinase inhibitors, nucleotide analogs and precursor analogs, peptide antibiotics, platinium-based agents, and retinoids.
  • the chemotherapeutic agent is suitable to be administered such that said agent becomes widely distributed in the body of a patient in significant amounts and develops a biological effect (systemic administration).
  • systemic routes of administration include administration by introducing the chemotherapeutic agent directly into the vascular system or oral, pulmonary, or intramuscular administration wherein the chemotherapeutic agent enters the vascular system and is carried to one or more desired site(s) of action via the blood.
  • the systemic administration may be by parenteral administration.
  • the chemotherapeutic agent is suitable to be administered such that said agent does not pass the intestine (parenteral administration).
  • parenteral administration includes intravenous administration, subcutaneous administration, intradermal administration, or intraarterial administration, but is not limited thereto.
  • the chemotherapeutic agent is suitable to be administered topically, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intraocularly, intranasally, intravitreally, intravaginally, intrarectally, intramuscularly, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, orally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, via a catheter, or via a lavage.
  • the dose which can be administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the dose will be determined by the efficacy of the particular chemotherapeutic agent employed and the condition of the patient, as well as the body weight or surface area of the patient to be treated.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of the chemotherapeutic agent in a particular patient.
  • the chemotherapeutic agent is suitable to be administered in an amount of 0.1 to 10 mg/kg body weight, preferably 0.2 to 8 mg/kg body weight, more preferably 0.3 to 6 mg/kg body weight, more preferably 0.4 to 5 mg/kg body weight, more preferably 0.5 to 4 mg/kg body weight.
  • the present invention relates to a method for treating a disease in a patient comprising the step of:
  • the disease is selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • extracorporeal blood above normal body temperature can be administered for treating a disease associated with elevated cholesterol levels.
  • the patient suffers from a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the extracorporeal blood is from the patient suffering from a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the blood is obtained/isolated from said patient and subsequently heated above the patient’s normal body temperature. Afterwards, the blood heated above the patient’s normal body temperature is administered to the same patient.
  • the extracorporeal/isolated blood is from another subject, a blood donor.
  • the blood is obtained/isolated from said donor and subsequently heated above the donor’s normal body temperature. Afterwards, the blood heated above the donor’s normal body temperature is administered to the patient.
  • the donor does not suffer from a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the normal body temperature of the donor is preferably comparable with the normal body temperature of the patient or higher than the normal body temperature of the patient.
  • the blood of the donor is heated above the normal body temperature of the patient.
  • the normal body temperature refers to the typical temperature found in an individual.
  • the normal human body temperature range for example, is typically stated as being between 36.1 °C and 37.5 °C, e.g. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0 37.1, 37.2, 37.3, 37.4, or 37.5 °C.
  • the extracorporeal blood has a temperature of between 39°C and 44°C, preferably of between 40°C and 44°C, and more preferably of between 40°C and 42.5°C, e.g. of between 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, or 44 °C.
  • the extracorporeal blood is oxygenated before administration.
  • the extracorporeal blood is preferably oxygenated by external means, e.g. using an oxygenator.
  • the oxygenator enhances oxygen within the blood.
  • Extracorporeal blood purification is a treatment in which a patient’s/donor’s blood is passed through a device (e.g. membrane, sorbent) in which solute (e.g. waste products, toxins) and possibly also water are removed. When fluid is removed, replacement fluid is usually added. It is preferred that purified blood does not comprise inflammatory, toxic molecules and/or other harmful molecules anymore or comprises a reduced amount of said molecules compared to unpurified blood.
  • Extracorporeal therapies designed to remove or filter substances from the circulation in order to purify blood include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies and combinations of any of the above.
  • the purified blood is filtered blood. More preferably, the purified blood is dialyzed blood. Blood dialysis removes waste, salt, toxins, extra water to prevent them from building up in the body, keeps a safe level of certain chemicals in the blood such as potassium, sodium, and bicarbonate, and helps to control blood pressure. It is particularly preferred that the blood, e.g. the purified, filtered, or dialyzed blood, is free of inflammatory or other harmful molecules.
  • the technique of warming/heating of extracorporeal blood above normal body temperature is also designated as haemo/hemo-hyperthermia.
  • the technique of purification of blood is also designated as haemoperfusion/hemoperfusion.
  • this technique is also designated as hyperoxygenated haemoperfusion/hemoperfusion.
  • the combination of warming of extracorporeal blood above normal body temperature, filtering of extracorporeal blood and oxygenation of extracorporeal blood is also designated as Extracorporeal Hyperthermia Perfusion (EHP) therapy.
  • EHP Extracorporeal Hyperthermia Perfusion
  • the cancer is selected from the group consisting of skin cancer, nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squamous cell cancer, laryngeal cancer, retina cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bone cancer, lymphoma, and leukemia,
  • skin cancer nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squam
  • the autoimmune disease is selected from the group consisting of rheumatism/rheumatic disease, e.g. rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (lupus), Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, Myasthenia gravis, Vasculitis, Pernicious anemia, and Celiac disease,
  • rheumatism/rheumatic disease e.g. rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (lupus), Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, Myasthenia gravis, Vasculitis, Pernicious anemia, and Celiac disease
  • the infectious disease is selected from the group consisting of viral infection, preferably chronic or persistent viral infection, bacterial infection, parasitic infection, or
  • the inflammatory disease is selected from the group consisting of atherosclerosis, an autoimmune disease, allergy, asthma, a coeliac disease, glomerulonephritis, hepatitis, and an inflammatory bowel disease.
  • the viral infection is selected from the group consisting of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), rhinovirus (common cold), herpes simplex virus (HSV), and respiratory syncytial virus (RSV) infection,
  • HAV human immunodeficiency virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • RV rhinovirus
  • RSV respiratory syncytial virus
  • the bacterial infection is selected from the group consisting of Borrelia burgdorferi (Borreliose), Helicobacter pylori, Mycobacterium tuberculosis, Mycobacterium leprae, and Chlamydia trachomatis infection, or
  • the parasitic infection is selected from the group consisting of a Schistosoma mansoni, Taenia crassiceps, or Leishmania mexicana infection.
  • the rheumatism/rheumatic disease caused by autoimmunity is selected from the group consisting of ankylosing spondylitis, relapsing polychondritis, system lupus erythematosus, rheumatoid arthritis (RA), gout, inflammatory arthritis, pseudogout, juvenile arthritis, Sjogren syndrome, scleroderma, polymyositis, dermatomyositis, Behcet’s disease, and psoriatic arthritis.
  • RA rheumatoid arthritis
  • the disease is cancer and the method further comprises the step of administering a chemotherapeutic agent to the patient.
  • the chemotherapeutic agent is preferably administered such that said agent becomes widely distributed in the body of a patient in significant amounts and develops a biological effect (systemic administration).
  • systemic routes of administration include administration by introducing the chemotherapeutic agent directly into the vascular system or oral, pulmonary, or intramuscular administration wherein the chemotherapeutic agent enters the vascular system and is carried to one or more desired site(s) of action via the blood.
  • the systemic administration may be by parenteral administration.
  • the chemotherapeutic agent is administered such that said agent does not pass the intestine (parenteral administration).
  • parenteral administration includes intravenous administration, subcutaneous administration, intradermal administration, or intraarterial administration, but is not limited thereto.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the dose will be determined by the efficacy of the particular chemotherapeutic agent employed and the condition of the patient, as well as the body weight or surface area of the patient to be treated.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of the chemotherapeutic agent in a particular patient.
  • the chemotherapeutic agent is preferably administered in an amount of 0.1 to 10 mg/kg body weight, preferably 0.2 to 8 mg/kg body weight, more preferably 0.3 to 6 mg/kg body weight, more preferably 0.4 to 5 mg/kg body weight, more preferably 0.5 to 4 mg/kg body weight.
  • the chemotherapeutic agent is administered to the patient before the administration of the extracorporeal blood above normal body temperature to the patient, e.g. within one week or 1, 2, 3, 4, 5, 6, or 7 day(s) before the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent is administered to the patient after, in particular immediately after, the administration of the extracorporeal blood above normal body temperature to the patient, e.g. within one week or 1, 2, 3, 4, 5, 6, or 7 day(s) after the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent is administered to the patient during the administration of the extracorporeal blood above normal body temperature to the patient or at the same time as the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent can be administered to the patient either during the administration of the extracorporeal blood above normal body temperature to the patient (e.g. simultaneously or nearly simultaneous, for instance, within the time period of administration of the blood) or separately (e.g. administered at different times, typically more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or more hours apart).
  • the chemotherapeutic agent may be administered up to 6 or 12 hours before or after the blood is administered.
  • the disease is cancer and the method further comprises the step of performing radiation therapy on the patient or applying radiation therapy to the patient.
  • the amount of radiation used in photon radiation therapy is measured in grays (Gy), and varies depending on the type and stage of cancer being treated.
  • the typical dose for a solid epithelial tumor ranges from 60 to 80 Gy, while lymphomas are treated with 20 to 40 Gy for curative cases.
  • the radiation therapy may be an external beam radiation therapy (EBRT or XRT) or teletherapy, brachytherapy or sealed source radiation therapy or systemic radioisotope therapy or unsealed source radiotherapy.
  • EBRT external beam radiation therapy
  • XRT XRT
  • teletherapy brachytherapy or sealed source radiation therapy or systemic radioisotope therapy or unsealed source radiotherapy.
  • the radiation therapy may be performed before (e.g. 1 week before or 1, 2, 3, 4, 5, 6, or 7 day(s) before) or after (e.g. 1 week after or 1, 2, 3, 4, 5, 6, or 7 day(s) after) the administration of the extracorporeal blood above normal body temperature to the patient.
  • the radiation therapy may be performed simultaneously or nearly simultaneous with the administration of the extracorporeal blood above normal body temperature to the patient.
  • the administration of the extracorporeal blood above normal body temperature, the administration of the chemotherapeutic agent and the application of radiation therapy may take place simultaneously or nearly simultaneous
  • the administration of the chemotherapeutic agent and the application of radiation therapy may take place before or after the administration of extracorporeal blood above normal body temperature
  • the administration of the chemotherapeutic agent may take place before the administration of extracorporeal blood above normal body temperature and the radiation therapy may be applied after the administration of extracorporeal blood above normal body temperature, or
  • the radiation therapy may be applied before the administration of extracorporeal blood above normal body temperature and the chemotherapeutic agent may be applied after the administration of extracorporeal blood above normal body temperature.
  • cancer surgery may be applied in order to remove the cancer and nearby tissue and/or cancer metastases from the body in an operation. Cancer surgery may also be applied as an alternative to radiation therapy and/or chemotherapy. Preferably, cancer surgery is performed before administering to a patient in need thereof extracorporeal blood above normal body temperature. More preferably, cancer surgery is performed before administering to a patient in need thereof extracorporeal blood above normal body temperature and before conducting radiation therapy and/or chemotherapy.
  • the patient to whom extracorporeal blood above normal body temperature is administered has already received a cancer and/or cancer metastases surgery. This therapy has been applied before heat treatment.
  • the present invention relates to a method for treating cancer in a patient comprising the step of:
  • the patient suffers from cancer.
  • the extracorporeal blood is from the patient suffering from cancer.
  • the blood is obtained/isolated from said patient and subsequently heated above the patient’s normal body temperature. Afterwards, the blood heated above the patient’s normal body temperature is administered to the same patient.
  • the extracorporeal/isolated blood is from another subject, a blood donor.
  • the blood is obtained/isolated from said donor and subsequently heated above the donor’s normal body temperature. Afterwards, the blood heated above the donor’s normal body temperature is administered to the patient.
  • the donor does not suffer from cancer.
  • the normal body temperature of the donor is preferably comparable with the normal body temperature of the patient or higher than the normal body temperature of the patient.
  • the blood of the donor is heated above the normal body temperature of the patient.
  • the normal body temperature refers to the typical temperature found in an individual.
  • the normal human body temperature range for example, is typically stated as being between 36.1 °C and 37.5 °C, e.g. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0 37.1, 37.2, 37.3, 37.4, or 37.5 °C.
  • the extracorporeal blood has a temperature of between 39°C and 44°C, preferably of between 40°C and 44°C, and more preferably of between 40°C and 42.5°C, e.g. of between 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, or 44 °C. It is also preferred that the extracorporeal blood is oxygenated before administration.
  • the extracorporeal blood is preferably oxygenated by external means, e.g. using an oxygenator. The oxygenator enhances oxygen within the blood.
  • Extracorporeal blood purification is a treatment in which a patient’s/donor’s blood is passed through a device (e.g. membrane, sorbent) in which solute (e.g. waste products, toxins) and possibly also water are removed. When fluid is removed, replacement fluid is usually added. It is preferred that purified blood does not comprise inflammatory, toxic molecules and/or other harmful molecules anymore or comprises a reduced amount of said molecules compared to unpurified blood.
  • Extracorporeal therapies designed to remove or filter substances from the circulation in order to purify blood include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies and combinations of any of the above.
  • the purified blood is filtered blood. More preferably, the purified blood is dialyzed blood. Blood dialysis removes waste, salt, toxins, extra water to prevent them from building up in the body, keeps a safe level of certain chemicals in the blood such as potassium, sodium, and bicarbonate, and helps to control blood pressure. It is particularly preferred that the blood, e.g. the purified, filtered, or dialyzed blood, is free of inflammatory or other harmful molecules.
  • the technique of warming/heating of extracorporeal blood above normal body temperature is also designated as haemo/hemo-hyperthermia.
  • the technique of purification of blood is also designated as haemoperfusion/hemoperfusion.
  • this technique is also designated as hyperoxygenated haemoperfusion/hemoperfusion.
  • the combination of warming of extracorporeal blood above normal body temperature, filtering of extracorporeal blood and oxygenation of extracorporeal blood is also designated as Extracorporeal Hyperthermia Perfusion (EHP) therapy.
  • EHP Extracorporeal Hyperthermia Perfusion
  • the cancer is selected from the group consisting of skin cancer, nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squamous cell cancer, laryngeal cancer, retina cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bone cancer, lymphoma, and leukemia.
  • skin cancer nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squam
  • the chemotherapeutic agent is preferably administered such that said agent becomes widely distributed in the body of a patient in significant amounts and develops a biological effect (systemic administration).
  • systemic routes of administration include administration by introducing the chemotherapeutic agent directly into the vascular system or oral, pulmonary, or intramuscular administration wherein the chemotherapeutic agent enters the vascular system and is carried to one or more desired site(s) of action via the blood.
  • the systemic administration may be by parenteral administration.
  • the chemotherapeutic agent is administered such that said agent does not pass the intestine (parenteral administration).
  • parenteral administration includes intravenous administration, subcutaneous administration, intradermal administration, or intraarterial administration, but is not limited thereto.
  • the chemotherapeutic agent is preferably administered in an amount of 0.1 to 10 mg/kg body weight, preferably 0.2 to 8 mg/kg body weight, more preferably 0.3 to 6 mg/kg body weight, more preferably 0.4 to 5 mg/kg body weight, more preferably 0.5 to 4 mg/kg body weight.
  • the chemotherapeutic agent is administered to the patient before the administration of the extracorporeal blood above normal body temperature to the patient, e.g. within one week or 1, 2, 3, 4, 5, 6, or 7 day(s) before the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent is administered to the patient after, in particular immediately after, the administration of the extracorporeal blood above normal body temperature to the patient, e.g. within one week or 1, 2, 3, 4, 5, 6, or 7 day(s) after the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent is administered to the patient during the administration of the extracorporeal blood above normal body temperature to the patient or at the same time as the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent can be administered to the patient either during the administration of the extracorporeal blood above normal body temperature to the patient (e.g. simultaneously or nearly simultaneous, for instance, within the time period of administration of the blood) or separately (e.g. administered at different times, typically more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or more hours apart).
  • the chemotherapeutic agent may be administered up to 6 or 12 hours before or after the blood is administered.
  • the method further comprises the step of performing radiation therapy on the patient or applying radiation therapy to the patient.
  • the amount of radiation used in photon radiation therapy is measured in grays (Gy), and varies depending on the type and stage of cancer being treated.
  • the typical dose for a solid epithelial tumor ranges from 60 to 80 Gy, while lymphomas are treated with 20 to 40 Gy for curative cases.
  • the radiation therapy may be an external beam radiation therapy (EBRT or XRT) or teletherapy, brachytherapy or sealed source radiation therapy or systemic radioisotope therapy or unsealed source radiotherapy.
  • EBRT external beam radiation therapy
  • XRT XRT
  • teletherapy brachytherapy or sealed source radiation therapy or systemic radioisotope therapy or unsealed source radiotherapy.
  • the radiation therapy may be performed before (e.g. 1 week before or 1, 2, 3, 4, 5, 6, or 7 day(s) before) or after (e.g. 1 week after or 1, 2, 3, 4, 5, 6, or 7 day(s) after) the administration of the extracorporeal blood above normal body temperature to the patient.
  • the radiation therapy may be performed simultaneously or nearly simultaneous with the administration of the extracorporeal blood above normal body temperature to the patient.
  • the administration of the extracorporeal blood above normal body temperature, the administration of the chemotherapeutic agent and the application of radiation therapy may take place simultaneously or nearly simultaneous
  • the administration of the chemotherapeutic agent and the application of radiation therapy may take place before or after the administration of extracorporeal blood above normal body temperature
  • the administration of the chemotherapeutic agent may take place before the administration of extracorporeal blood above normal body temperature and the radiation therapy may be applied after the administration of extracorporeal blood above normal body temperature, or
  • the radiation therapy may be applied before the administration of extracorporeal blood above normal body temperature and the chemotherapeutic agent may be applied after the administration of extracorporeal blood above normal body temperature.
  • cancer surgery may be applied in order to remove the cancer and nearby tissue and/or cancer metastases from the body in an operation.
  • Cancer surgery may also be applied as an alternative to radiation therapy and/or chemotherapy.
  • cancer surgery is performed before administering to a patient in need thereof extracorporeal blood above normal body temperature. More preferably, cancer surgery is performed before administering to a patient in need thereof extracorporeal blood above normal body temperature and before conducting radiation therapy and/or chemotherapy.
  • the patient to whom extracorporeal blood above normal body temperature is administered has already received a cancer and/or cancer metastases surgery. This therapy has been applied before heat treatment.
  • the present invention relates to a method for treating cancer in a patient comprising the step of:
  • the patient suffers from cancer.
  • the extracorporeal blood is from the patient suffering from cancer.
  • the blood is obtained/isolated from said patient and subsequently heated above the patient’s normal body temperature. Afterwards, the blood heated above the patient’s normal body temperature is administered to the same patient.
  • the extracorporeal/isolated blood is from another subject, a blood donor.
  • the blood is obtained/isolated from said donor and subsequently heated above the donor’s normal body temperature. Afterwards, the blood heated above the donor’s normal body temperature is administered to the patient.
  • the donor does not suffer from cancer.
  • the normal body temperature of the donor is preferably comparable with the normal body temperature of the patient or higher than the normal body temperature of the patient.
  • the blood of the donor is heated above the normal body temperature of the patient.
  • the normal body temperature refers to the typical temperature found in an individual.
  • the normal human body temperature range for example, is typically stated as being between 36.1 °C and 37.5 °C, e.g. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0 37.1, 37.2, 37.3, 37.4, or 37.5 °C.
  • the extracorporeal blood has a temperature of between 39°C and 44°C, preferably of between 40°C and 44°C, and more preferably of between 40°C and 42.5°C, e.g. of between 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, or 44 °C.
  • the extracorporeal blood is oxygenated before administration.
  • the extracorporeal blood is preferably oxygenated by external means, e.g. using an oxygenator.
  • the oxygenator enhances oxygen within the blood.
  • Extracorporeal blood purification is a treatment in which a patient’s/donor’s blood is passed through a device (e.g. membrane, sorbent) in which solute (e.g. waste products, toxins) and possibly also water are removed. When fluid is removed, replacement fluid is usually added. It is preferred that purified blood does not comprise inflammatory, toxic molecules and/or other harmful molecules anymore or comprises a reduced amount of said molecules compared to unpurified blood.
  • Extracorporeal therapies designed to remove or filter substances from the circulation in order to purify blood include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies and combinations of any of the above.
  • the purified blood is filtered blood. More preferably, the purified blood is dialyzed blood. Blood dialysis removes waste, salt, toxins, extra water to prevent them from building up in the body, keeps a safe level of certain chemicals in the blood such as potassium, sodium, and bicarbonate, and helps to control blood pressure. It is particularly preferred that the blood, e.g. the purified, filtered, or dialyzed blood, is free of inflammatory or other harmful molecules.
  • the technique of warming/heating of extracorporeal blood above normal body temperature is also designated as haemo/hemo-hyperthermia.
  • the technique of purification of blood is also designated as haemoperfusion/hemoperfusion.
  • this technique is also designated as hyperoxygenated haemoperfusion/hemoperfusion.
  • the combination of warming of extracorporeal blood above normal body temperature, filtering of extracorporeal blood and oxygenation of extracorporeal blood is also designated as Extracorporeal Hyperthermia Perfusion (EHP) therapy.
  • EHP Extracorporeal Hyperthermia Perfusion
  • the cancer is selected from the group consisting of skin cancer, nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squamous cell cancer, laryngeal cancer, retina cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bone cancer, lymphoma, and leukemia.
  • skin cancer nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squam
  • the amount of radiation used in photon radiation therapy is measured in grays (Gy), and varies depending on the type and stage of cancer being treated.
  • the typical dose for a solid epithelial tumor ranges from 60 to 80 Gy, while lymphomas are treated with 20 to 40 Gy for curative cases.
  • the radiation therapy may be an external beam radiation therapy (EBRT or XRT) or teletherapy, brachytherapy or sealed source radiation therapy or systemic radioisotope therapy or unsealed source radiotherapy.
  • EBRT external beam radiation therapy
  • XRT XRT
  • teletherapy brachytherapy or sealed source radiation therapy or systemic radioisotope therapy or unsealed source radiotherapy.
  • the radiation therapy may be performed before (e.g. 1 week before or 1, 2, 3, 4, 5, 6, or 7 day(s) before) or after (e.g. 1 week after or 1, 2, 3, 4, 5, 6, or 7 day(s) after) the administration of the extracorporeal blood above normal body temperature to the patient.
  • the radiation therapy may be performed simultaneously or nearly simultaneous with the administration of the extracorporeal blood above normal body temperature to the patient.
  • the method further comprises the step of administering a chemotherapeutic agent to the patient.
  • the chemotherapeutic agent is preferably administered such that said agent becomes widely distributed in the body of a patient in significant amounts and develops a biological effect (systemic administration).
  • systemic routes of administration include administration by introducing the chemotherapeutic agent directly into the vascular system or oral, pulmonary, or intramuscular administration wherein the chemotherapeutic agent enters the vascular system and is carried to one or more desired site(s) of action via the blood.
  • the systemic administration may be by parenteral administration.
  • the chemotherapeutic agent is administered such that said agent does not pass the intestine (parenteral administration).
  • parenteral administration includes intravenous administration, subcutaneous administration, intradermal administration, or intraarterial administration, but is not limited thereto.
  • the chemotherapeutic agent is preferably administered in an amount of 0.1 to 10 mg/kg body weight, preferably 0.2 to 8 mg/kg body weight, more preferably 0.3 to 6 mg/kg body weight, more preferably 0.4 to 5 mg/kg body weight, more preferably 0.5 to 4 mg/kg body weight.
  • the chemotherapeutic agent is administered to the patient before the administration of the extracorporeal blood above normal body temperature to the patient, e.g. within one week or 1, 2, 3, 4, 5, 6, or 7 day(s) before the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent is administered to the patient after, in particular immediately after, the administration of the extracorporeal blood above normal body temperature to the patient, e.g. within one week or 1, 2, 3, 4, 5, 6, or 7 day(s) after the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent is administered to the patient during the administration of the extracorporeal blood above normal body temperature to the patient or at the same time as the administration of the extracorporeal blood above normal body temperature to the patient.
  • the chemotherapeutic agent can be administered to the patient either during the administration of the extracorporeal blood above normal body temperature to the patient (e.g. simultaneously or nearly simultaneous, for instance, within the time period of administration of the blood) or separately (e.g. administered at different times, typically more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or more hours apart).
  • the chemotherapeutic agent may be administered up to 6 or 12 hours before or after the blood is administered.
  • the administration of the extracorporeal blood above normal body temperature, the administration of the chemotherapeutic agent and the application of radiation therapy may take place simultaneously or nearly simultaneous
  • the administration of the chemotherapeutic agent and the application of radiation therapy may take place before or after the administration of extracorporeal blood above normal body temperature
  • the administration of the chemotherapeutic agent may take place before the administration of extracorporeal blood above normal body temperature and the radiation therapy may be applied after the administration of extracorporeal blood above normal body temperature, or
  • the radiation therapy may be applied before the administration of extracorporeal blood above normal body temperature and the chemotherapeutic agent may be applied after the administration of extracorporeal blood above normal body temperature.
  • cancer surgery may be applied in order to remove the cancer and nearby tissue and/or cancer metastases from the body in an operation. Cancer surgery may also be applied as an alternative to radiation therapy and/or chemotherapy. Preferably, cancer surgery is performed before administering to a patient in need thereof extracorporeal blood above normal body temperature. More preferably, cancer surgery is performed before administering to a patient in need thereof extracorporeal blood above normal body temperature and before conducting radiation therapy and/or chemotherapy.
  • the patient to whom extracorporeal blood above normal body temperature is administered has already received a cancer and/or cancer metastases surgery. This therapy has been applied before heat treatment.
  • the present invention relates to a method for treating a disease in a patient comprising the steps of:
  • the disease is selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the blood is obtained from the patient’s blood circulation before heating.
  • the patient suffers from a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease., an inflammatory disease, and sepsis.
  • a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease., an inflammatory disease, and sepsis.
  • the extracorporeal blood is from the patient suffering from a disease selected from the group consisting of cancer, an autoimmune disease, an infectious disease, an inflammatory disease, and sepsis.
  • the extracorporeal blood obtained from the patient’s blood circulation has a temperature of between 36.1 °C and 37.5 °C, e.g. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0 37.1, 37.2, 37.3, 37.4, or 37.5 °C.
  • the extracorporeal blood is heated to a temperature of between 39°C and 44°C, preferably of between 40°C and 44°C, and more preferably of between 40°C and 42.5°C, e.g. of between 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, or 44 °C.
  • the extracorporeal blood is preferably heated with a heat transfer device.
  • the heat transfer device preferably comprises a heat exchanger or an electric heater.
  • the heat transfer device is preferably a device as described in the context of the first aspect of the present invention. Said heat transfer device preferably functions as described in the context of the first aspect of the present invention.
  • the extracorporeal blood is preferably oxygenated.
  • the extracorporeal blood is preferably oxygenated by external means, e.g. using an oxygenator.
  • the oxygenator enhances oxygen within blood.
  • the oxygenator is preferably a device as described in the context of the first aspect of the present invention. Said oxygenator preferably functions as described in the context of the first aspect of the present invention.
  • Extracorporeal blood purification is a treatment in which a patient’s/donor’s blood is passed through a device (e.g. membrane, sorbent) in which solute (e.g. waste products, toxins) and possibly also water are removed. When fluid is removed, replacement fluid is usually added. It is preferred that the purified blood does not comprise inflammatory, toxic molecules and/or other harmful molecules anymore or comprises a reduced amount of said molecules compared to unpurified blood.
  • Extracorporeal therapies designed to remove or filter substances from the circulation in order to purify blood include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies and combinations of any of the above.
  • the purified blood is filtered blood. More preferably, the purified blood is dialyzed blood. Blood dialysis removes waste, salt, toxins, extra water to prevent them from building up in the body, keeps a safe level of certain chemicals in the blood such as potassium, sodium, and bicarbonate, and helps to control blood pressure. It is particularly preferred that the blood, e.g. the purified, filtered, or dialyzed blood, is free of inflammatory or other harmful molecules.
  • the adsorber in particular filter, is preferably a device as described in the context of the first aspect of the present invention.
  • Said adsorber, in particular filter preferably functions as described in the context of the first aspect of the present invention.
  • the blood is purified/filtered/dialyzed during the heating process, parallel to the heating process, or after the heating process and before returning the heated blood to the patient’s blood circulation. It is alternatively or additionally further preferred that the blood is enriched with oxygen during the heating process, parallel to the heating process, or after the heating process and before returning the heated blood to the patient’s blood circulation.
  • the technique of warming/heating of extracorporeal blood above normal body temperature is also designated as haemo/hemo-hyperthermia.
  • the technique of purification of blood is also designated as haemoperfusion/hemoperfusion.
  • this technique is also designated as hyperoxygenated haemoperfusion/hemoperfusion.
  • the combination of warming of extracorporeal blood above normal body temperature, filtering of extracorporeal blood and oxygenation of extracorporeal blood is also designated as Extracorporeal Hyperthermia Perfusion (EHP) therapy.
  • EHP Extracorporeal Hyperthermia Perfusion
  • the cancer is selected from the group consisting of skin cancer, nasopharyngeal cancer, neuroendrocrine cancer, lung cancer, colon cancer, urothelial cancer, bladder cancer, liver cancer, ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, stomach cancer, esophageal cancer, breast cancer, renal cancer, head and neck cancer, brain cancer, lymphatic cancer, blood cancer, squamous cell cancer, laryngeal cancer, retina cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bone cancer, lymphoma, and leukemia,
  • the autoimmune disease is selected from the group consisting of rheumatism/rheumatic disease, e.g. rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (lupus), Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, Myasthenia gravis, Vasculitis, Pernicious anemia, and Celiac disease,
  • rheumatism/rheumatic disease e.g. rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (lupus), Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, Myasthenia gravis, Vasculitis, Pernicious anemia, and Celiac disease
  • the infectious disease is selected from the group consisting of viral infection, preferably chronic or persistent viral infection, bacterial infection, parasitic infection, or
  • the inflammatory disease is selected from the group consisting of atherosclerosis, an autoimmune disease, allergy, asthma, a coeliac disease, glomerulonephritis, hepatitis, and an inflammatory bowel disease.
  • the viral infection is selected from the group consisting of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), rhinovirus (common cold), herpes simplex virus (HSV), and respiratory syncytial virus (RSV) infection,
  • HAV human immunodeficiency virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • RV rhinovirus
  • RSV respiratory syncytial virus
  • the bacterial infection is selected from the group consisting of Borrelia burgdorferi (Borreliose), Helicobacter pylori, Mycobacterium tuberculosis, Mycobacterium leprae, and Chlamydia trachomatis infection, or
  • the parasitic infection is selected from the group consisting of a Schistosoma mansoni, Taenia crassiceps, or Leishmania mexicana infection.
  • the rheumatism/rheumatic disease caused by autoimmunity is selected from the group consisting of ankylosing spondylitis, relapsing polychondritis, system lupus erythematosus, rheumatoid arthritis (RA), gout, inflammatory arthritis, pseudogout, juvenile arthritis, Sjogren syndrome, scleroderma, polymyositis, dermatomyositis, Behcet’s disease, and psoriatic arthritis.
  • RA rheumatoid arthritis
  • the above mentioned method may be combined with chemotherapy, radiation therapy, and cancer surgery.
  • the warming blood therapy may supplement chemotherapy, radiation therapy, and/or cancer surgery.
  • the patient from whom extracorporeal blood at normal body temperature is removed and to whom extracorporeal blood above normal body temperature is returned has already received a cancer and/or cancer metastases surgery. This therapy has been applied before heat treatment.
  • the method according to the fourth to seventh aspect is a method which supplements chemotherapy, radiation therapy, and/or cancer surgery.
  • it is a combination therapy whereby the effects of chemotherapy, radiation therapy, and/or cancer surgery can be further improved.
  • the proposed method and its embodiments may not be used for treatment of the human or animal body by surgery or therapy and may not be a diagnostic method practiced on the human or animal body.
  • the proposed method and its embodiments may be used for treatment of the human or animal body by surgery or therapy and may be a diagnostic method practiced on the human or animal body.
  • Figure 1 a system for warming up or heating blood
  • FIG. 2 the system for warming up blood in more detail
  • Figure 3 a first alternative of the system
  • Figure 4 a second alternative of the system.
  • Figure 1 illustrates a system 10 for warming up blood.
  • System 10 may be configured according to a first alternative 10a that is shown in Figure 3 or according to a second alternative 10b that is shown in Figure 4. Other configurations are, of course, possible as well.
  • System 10 may comprise:
  • All tubes of system 10 may be flexible tubes made of plastics, preferably also the inlet tube 12 and the outlet tube 14.
  • Inlet I and outlet O are connected to a subject 20, for instance to a patient suffering from cancer.
  • Subject 20 may lay on a surface 22, for instance the surface 20 of a bed, of a patient bench/couch or of a patient table.
  • Surface 20 may be declined, for instance with an angle of 5 to 20 degrees with regard to a horizontal surface.
  • surface 20 may also be a horizontal surface 20. It is also possible that the subject 20 sits during the performance of the method that uses system 10.
  • femoral location 24 for inlet I and for outlet O.
  • a jugular location 26 may be used. Combinations of femoral location 24 and jugular location 26 are possible as well. It is also possible to use other locations of the blood vessels of subject 20 for the placement of inlet I and outlet O. Furthermore, it is possible to use more than one inlet I and/or to use more than one output O.
  • Figure 1 illustrates also the heart 28 of subject 20 schematically.
  • a body temperature Tempi of subject 20 may be measured during the performance of the method that is described in this application. It is possible to determine body temperature Tempi using a first temperature sensor that is placed for instance on the hand of subject 20 or at a location near to inlet I within system 10. Alternatively, body temperature Tempi may be measured on the arm, in the armpit or elsewhere on subject 20. Furthermore, blood pressure of subject 20 may also be determined using an appropriate sensor. EKG or ECG (electrocardiogram) sensors or electrodes may be used as well on subject 20 but are not shown in Figure 1.
  • FIG. 2 illustrates parts of system 10 for warming blood in more detail but still on a more abstract level. Detailed connections are not shown in Figure 2 but are explained with regard to Figures 3 and 4 below.
  • System 10 may further comprise: - a tube system 200 that also comprises inlet tube 12 and outlet tube 14 as well as further tubes that are not shown in detail in Figure 2 because there may be several possibilities for the connection of the parts of system 10,
  • tube system 200 for instance a peristaltic pump or a membrane pump or another kind of pump, for instance a centrifugal pump,
  • a heat transfer device 202 that is connected to tube system 200, for instance a heat exchanger or an electrical heater.
  • the heat transfer device 202 may be replaced by an oxygenator that may also be used for heat transfer of heat from a heat source to blood. This is described in more detail below.
  • auxiliary fluid 204 e.g. water
  • heat transfer device 202 if for instance a heat exchanger is used
  • control unit 206 an optional control unit 206, alternatively it is possible to use manual control.
  • a further temperature sensor may be used to determine or to measure the blood temperature Temp2 of the heated blood. It is for instance possible to place the further temperature sensor within heat transfer device 202.
  • Control unit 206 may comprise a microprocessor, a microcontroller or another device that allows the execution of commands or instructions of a software program that is stored within a digital memory, for instance within a RAM (Random Access Memory) or within a ROM (Read only Memory).
  • a control unit 206 that does not comprise a processor that performs a software program that is stored in a digital memory but that comprises electronic circuitry without a processor. It is possible to build a digital state machine using a processor or without using a processer. States of the state machine may be changed depending on special inputs, time conditions, etc. Depending on the states it is possible to create appropriate output signals.
  • the state machine may be realized using an ASIC (Application Specific Integrated Circuit) or an FPGA (Field programmable Gate Array) that may comprise programmable connections of parts of circuits.
  • ASIC Application Specific Integrated Circuit
  • FPGA Field programmable Gate Array
  • Control unit 206 may have one of, a combination of or all of the following inputs:
  • Control unit 206 may realize an automated control for the control of the body temperature Tempi and/or for blood temperature Temp2. Open loop control or more sophisticated closed loop control may be used.
  • control unit 206 It is possible to control further parameters automatically using control unit 206, for instance flow rate FR based on target flow rate TFR.
  • a cardio technician may supervise the operation of control unit 206 during the performance of the method that is performed using system 10.
  • Control unit 206 may not be necessary in this case.
  • System 10 may further comprise:
  • Reservoir R1 may be filled with sodium chloride, Ringer lactate or other appropriate solutions. Furthermore, a substance that extends the ACT (Activated Clotting Time) may be added in reservoir Rl. Reservoir R2 may at first be empty and may then be filled by fluid that comes from reservoir Rl, for instance Heparin ® . This will be explained in more detail below. Both reservoirs Rl and R2 may be connected.
  • ACT Activated Clotting Time
  • one or more adsorber units Al, A2 each may comprise an adsorber, for instance an adsorber that is individually prepared depending on the needs of subject 20.
  • Control unit 206 may have the following outputs:
  • Figure 3 illustrates a first alternative 10a of system 10.
  • First alternative 10a may comprise an oxygenator device OXY and an optional first adsorber unit Al.
  • the shown connections are exemplary. Other connections are possible as well.
  • Oxygenator device OXY may comprise a flange 300.
  • a dual chamber reservoir may be connected to flange 300.
  • a single chamber reservoir may be connected to flange 300.
  • Adsorber unit Al may comprise an adsorber that is individualized for subject 20.
  • auxiliary fluid for instance water
  • This tube T5 may be an outlet for carbon dioxide and/or for waste oxygen tube T5 may be connected to reservoir Rla to collect the oxygen that is not usable at the moment.
  • Tube T6 may be transparent and marked with a longitudinal green line.
  • Pump PI is preferably a centrifugal pump. Alternatively, other kinds of pumps may be used for pump PI .
  • Tube T10 may be marked with red tape rings
  • Tube 14 may be marked with blue tape rings, and/or
  • Tube Ti l may be named as a bridge tube, see also Figure 4, tube T34.
  • the tube Ti l may be mostly hold closed by a clamping device.
  • Oxygenator device OXY may comprise a temperature sensor for measuring temperature Temp2 of the warmed blood.
  • Tubes T3 and T4 may be connected to a further pump for pumping the auxiliary fluid, for instance to a water pump.
  • a heated reservoir for the auxiliary fluid e.g. water may be used.
  • a first node N2 may be used to connect tube T12 to an outlet of a reservoir Rla.
  • a further node N3 may be used to connect tube T12 to an outlet of a further reservoir Rib.
  • a node N4 may be used to have a junction of a tube T16 and tube T12. Tube T16 is connected to the output of adsorber unit Al.
  • An adsorber within adsorber unit A1 may be individualized for the patient or subject 20.
  • a further node N5 may be used to connect tube T8 with the input side of adsorber unit Al using a branch.
  • the input side of the adsorber unit Al may be marked by using a red end cap.
  • the output side of adsorber unit Al may be marked by using a blue end cap.
  • Inlet I and outlet O are connected directly, i.e. without a connection at the subject 20.
  • inlet I and outlet O are connected directly before system 10/altemative 10a of system 10 is connected to the subject 20.
  • air is within the tubes of tube system 200.
  • a clamping device is clamped on clamping position K1 of tube T12, i.e. between nodes
  • Reservoir Rla contains or is filled with Ringer lactate, for instance, and preferably also with a substance that extends the ACT time, for instance Heparin ® .
  • Pump PI is switched on and generates a suction that transports fluid from reservoir Rla through reservoir R2a, the right portion of tube T12, then through the inlet I, the outlet O, through tube T10, through the oxygenator device OXY, through pump PI, at node N2 back to reservoir R2a.
  • Both reservoirs Rla and R2a may be connected by a connection tube T19.
  • Both reservoirs Rla and R2a and their connection tube T19 may form a filling system.
  • the flow of air and of Ringer lactate may be opposite to the arrows that are shown in Figure 3 and that are valid for blood flow that is initiated later as described below.
  • Fluid is also pumped through tube T18, adsorber unit A1 and tube T16 back to tube T12 according to the direction that is indicated by the arrows shown in Figure 3 on tubes T16 and T18 because adsorber unit A1 may have a kind of one way valve inside.
  • the pump PI may be stopped or switched off if all air is removed from tube system 200, i.e. tubes T8 to T18. Thereafter, at the same time or before this, two clamping devices, for instance medical forceps, may be used to close tube T10 at the outlet O and tube T12 at the inlet I. The clamping device at clamping position K1 may also be disconnected.
  • ACT is measured. Care is taken that the ACT is for instance over 300 seconds. This may be reached by injection of Heparin ® , for instance through one of the catheters on subject 20.
  • Inlet I is connected to one catheter device.
  • Outlet O is connected to the other catheter device.
  • the pump PI may be switched on again and the clamping devices on tubes T10 and T12 may be removed or opened. Pump PI may be pump in the other direction if compared with step D mentioned above.
  • the arrows on tubes T12, T14 indicate the direction of blood transport.
  • the reservoirs Rla and Rib may be disconnected from the tube system 200. However, if for instance the heart rate of subject 20 raises Ringer lactate or another appropriate solution may be added to the blood using reservoir Rla and R2a again.
  • the blood of subject 20 is heated and using the water in tubes T3 and T4. Furthermore, the blood of subject 20 is preferably also oxygenated using oxygenator device OXY.
  • the method is stopped at the end of the treatment time that is for instance between 2 and 6 hours.
  • M) The method may be repeated several times for the same subject, for instance several times within a week.
  • a chemotherapeutic agent may be added during warming of the blood of the subject 20 in system 10, 10a, 10b.
  • a centrifugal pump may be advantageous if an oxygenator device OXY is used because higher pressures may be necessary compared to alternative 10b that uses a heat transfer device without using an oxygenator device OXY. It is possible to use more than one blood pump within system 10, 10a or 10b. Furthermore, it is possible to use more than one adsorber unit Al, A2, within a single system 10, 10a or 10b.
  • FIG. 4 illustrates a second alternative 10b of the system 10.
  • Second alternative 10b may comprise the heat transfer device 202, i.e. a heat exchanger in the example shown.
  • second part 10b may comprise a filter A2 that is individualized for subject 20.
  • Heat transfer device 202 i.e. the heat exchanger in the example shown, may comprise:
  • an inlet 400 for an auxiliary fluid for instance water.
  • a corresponding pump and a corresponding heating device for the auxiliary fluid are used but not shown in Figure 4.
  • auxiliary fluid for instance water
  • - sensor lines 404 which come from a temperature sensor within heat transfer device 202 and which are electrically conductively connected with control unit 206 or with another appropriate unit.
  • the temperature sensor within heat transfer device 202 may measure the blood temperature Temp2.
  • a tube T20 may be connected to purge port PURGE, - a tube T22 may be connected to input port IN and to a node N6,
  • a tube T24 may be arranged between an outlet of a heating device for auxiliary fluid 204 and inlet 400,
  • a tube T26 may be arranged between the outlet 404 and an inlet of the heating device for auxiliary fluid 204,
  • a tube T30 may be arranged between the outlet of an optional adsorber unit A2 and node N6,
  • a tube T32 may be arranged between inlet I and node N6,
  • an optional tube T34 may be arranged between a node N9 and a node N10. This bridge tube may be used to remove air bubbles from the tube system but is normally closed.
  • a tube T40 may be arranged between perfusion port PERFUSION of heat transfer device 202 and node N10 and may further extend to outlet O.
  • Node N9 is a branch from tube T32 to tube T34.
  • Node N10 is a junction of tubes T34 and T40. Medical forceps or other clamping devices may be used to open or close the ways from inlet I and the way to outlet O if it is necessary during the performance of the method.
  • a tube pump or a peristaltic pump may be used in alternative 10b for pump P2.
  • the pumping part of pump P2 may be located on tube T22 between node N6 and a further node N 12.
  • Two or more roller devices on tube T22 may be used to transport the blood from inlet I to outlet O.
  • a tube T42 may be connected with node N12 and with an inlet of adsorber unit A2. Again, the inlet of adsorber unit A2 may be marked using a red end cap.
  • a clamping position K1 corresponds to clamping position K2.
  • alternative 10b of the system 10 may be the same as the operation of alternative 10a as described above. Reference is made to the description given above in order to avoid unnecessary repetitions.
  • EHP extracorporeal hyperthermia perfusion
  • Patient I 55 years old, colorectal cancer, metastases in the liver and in the lung.
  • the patient is 1.72 m (meter) tall but has a weight of only 45 kg (kilogram).
  • She is extremely thin but the abdomen is hard, thickly swollen and big as a hand ball, primarily caused by the metastasis in the liver.
  • Conventional methods had not shown results or only small results.
  • Her state is good according to her own assessment and considering her circumstances. However, she has pain in the abdomen.
  • Both patients are prepared, i.e. electrocardiography (ECG or EKG) etc. Then they are taken to the treatment room lying on treatment beds. They are wearing the clothing of the hospital. They are connected to the monitoring devices that monitor pulse, blood pressure, etc. Furthermore, the ACT-value (Activated Clotting Time) is also measured.
  • the ACT is measured by a measuring device and it is a clotting or coagulation parameter to check the intrinsic path of secondary hemostasis measured close to the patient.
  • the blood is synthetically restrained in its agglutination characteristics according to these parameters, for instance using Heparin ® . Electrocardiography and measurement of pulse and blood pressure is taking place continuously during the whole treatment using devices that are available on the market.
  • Both patients are covered with sterilized cloth or fabric.
  • a local anesthetics is injected through a cloth having a hole into the femoral of both legs. Thereafter, a catheter is inserted into the femoral vein of each leg respectively. Both catheters are for a single use only and were delivered sterilized in their packages.
  • the tube with the inlet I and the tube with the outlet O are connected to the catheters of system 10, i.e. of the hyperthermy-hemoperfusion device.
  • the tubes are filled with sodium chloride solution first in order to prevent a flow including voids, i.e. comprising air, oxygen, etc.
  • the whole system 10 may be mounted to a carrier frame.
  • the carrier frame may have wheels, for instance four wheels that allow practical handling of the system within the treatment room.
  • the preparation of the patients is finished therewith. It is, of course, possible to treat only one patient at the same time or to treat more than two patients. However, each patient has their own system (10).
  • the method is performed using manual control of a medical practitioner and/or of a cardio technician. More automated control is possible as well for other examples of the method.
  • the blood is flowing now with a flow rate of 1.2 liter per minute out of the vein, into the inlet I, through an adsorber unit Al.
  • the adsorber unit A1 may be a single use device that is individually prepared for each patient.
  • Adsorbers within the adsorber unit Al clean the blood and remove inflammatory particles or molecules as cytokines and chemokines.
  • Small balls of macro porous resin may be used additionally within the adsorber of adsorber unit Al (and also within the adsorber of adsorber unit A2). These small balls may allow an effective removal of toxic elements from the blood of the patient.
  • the centrifugal pump CF may have a rotation speed in the range of 2000 to 5000 revolutions per minute (rpm) or in the range of 3000 to 4000 rpm, preferably about 3600 rpm or exactly 3600 rpm.
  • the blood may be enhanced with oxygen within the centrifugal pump CF. This oxygen may be produced by the oxygenator device OXY or it may be delivered from another source, for instance from an oxygen bottle or from the oxygen tube system of a hospital.
  • Inflammatory and/or chronic disease may always involve a shortage of oxygen within the blood of the patient.
  • the oxygen value of the blood may be enhanced considerably by the addition of oxygen to the blood of the patient.
  • the normal or enhanced oxygen value may allow the organism of the patient to keep down the inflammatory states, i.e. to strengthen the self-healing forces of the body of person 20.
  • Water or another auxiliary fluid 204 may be heated within a heater device to 45 °C for instance during the filtering of the blood in adsorber unit Al.
  • the heater device may be for instance a device from the company Elmeditec that is usually used for other methods of oncology.
  • the heating system for the auxiliary fluid may comprise auxiliary fluid in the range from 20 liters to 70 liters.
  • the flow rate may be within the range from 2 liters per minute to 20 liters per minute.
  • the heated auxiliary fluid 204 is guided to the heat transfer device 202 and the blood is heated continuously within the adjacent chamber of the heat transfer device 202.
  • the warmed or heated blood is guided back from the heat transfer device 202 via the tube system 200 to the outlet O and through the second vein channel into the body/organism of person 20 again.
  • Body temperature T1 (or abbreviated BT) is 37.2 ° C before the start of the method.
  • the blood flow is continuously monitored.
  • the method has been lasting now for about two hours.
  • the patient has covered herself with a blanket. She is drinking. Her face and her throat are strongly reddened. A humid fabric is cooling her forehead. The method is exhausting but the patient is responsive. She is talking to the staff and with the inventor of the method that is described here. She feels weak and worn out, naturally - even so as if she had very high fever.
  • the perfusion is finished and the whole blood is successively guided back into the organism of the patient or person 20.
  • the synthetical blood dilution, for instance with Protamin ® is finished. All devices of system 10 that have been used for the EHP are switched off.
  • the flexible tubes are removed from the catheter.
  • the catheters are released and the wounds from the insertion are closed for instance for about 20 minutes by a bandage, for instance using a “gold bandage”, i.e. plastic discs that are tightened.
  • the patient is shivering and is again covered by the blanket.
  • the state is good and she is drinking a lot.
  • the bandage for instance the gold bandage, is removed.
  • the blood in the bandage is clotted.
  • Compression bandages are applied that have to be carried for about 24 hours.
  • the compression bandages may be removed at home by the patient.
  • the patient stands up on her own, goes to the ladies room and puts on her street clothes. She can go home with someone’s company after a final medical consultation.
  • Patient I 55 years old, colorectal cancer, metastases in the liver and in the lung.
  • the patient received cancer surgery to remove the colorectal cancer.
  • the patient further received chemotherapy with the aim to shrink the metastases in the liver and in the lung and to kill all remaining tumor cells.
  • the chemotherapy was not completely successful.
  • the chemotherapy was not well tolerated by the patient. With the warming blood therapy all remaining tumor cells, especially in the blood, could be removed/killed and the shrinkage of the metastases could be achieved.
  • Patient II 62 years old, ovarian carcinoma.
  • the patient received cancer surgery to remove the ovarian carcinoma and the uterus.
  • the patient further received chemotherapy with the aim to kill all remaining cancer cells, especially in the blood.
  • the chemotherapy was not completely successful.
  • the chemotherapy was not well tolerated by the patient. With the warming blood therapy all remaining tumor cells, especially in the blood, could be removed/killed.
  • Patient III 62 years old, metastatic ovarian carcinoma. The patient had never been seriously ill before, but in June 2018 she suddenly experiences abdominal pain, feels weak and simply“ill”. A metastatic ovarian carcinoma was diagnosed and she was operated. Her ovaries, spleen, gall bladder, part of the intestine and peritoneum were removed. Four chemotherapies followed, which caused severe side effects in the patient. She was tired, exhausted, and discouraged. She also developed a massive depression and a generalized anxiety disorder. She is thin, her skin parchment-like and pale, her hair has fallen out.
  • 9.00 h Preparation of the therapy. After blood analysis, the patient is connected to the monitoring devices (blood pressure, pulse, etc.). The ACT value is measured. The blood is heparinized by the nephrologist according to this parameter.
  • 10.10 h The patient is covered sterile. After administration of a local anaesthetic, the catheters are placed in the femoral veins of both legs. The supply and discharge tubes of the hemo- perfusion device are connected. In this way, effective blood purification of toxic elements, e.g. after chemotherapy, is achieved.
  • the blood flows with approx. 1.2 1/min. out of the vein and is led through the adsorber (one-time usable and individually prepared).
  • the purified blood is passed through a centrifuge where it is enriched with oxygen (inflammatory and chronic diseases are often accompanied by a lack of oxygen).
  • the blood is warmed up and fed back to the body through the second venous catheter at a constant temperature.
  • the treatment usually lasts about four hours.
  • the EHP therapy is slowly terminated and all the blood is returned to the organism.
  • the artificial blood thinning is stopped with Protamin.
  • CHOL standard value 110 to 220 mg/dl
  • CHOL standard value 110 to 220 mg/dl
  • Thymidine kinase (THYK) standard value ⁇ 7.0 U/l Table 5: Patient VIII
  • LDH isoenzyme standard value 0 to 250 U/l
  • M2PK standard value 0 to 15 E/ml
  • EHP is also effective in the therapy of inflammatory diseases such as autoimmune diseases.
  • autoimmune diseases With EHP it is possible for the first time to maintain a temperature of up to 42.5°C in the bloodstream for more than 3 hours. This makes it possible to treat the above-mentioned indications - and many more - highly effective with low stress for the patient.
  • connection port O2 oxygen reservoir 400 inlet for auxiliary fluid (water) 402 outlet for auxiliary fluid (water) 404 sensor lines

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Abstract

La présente invention concerne un système de chauffage du sang, en particulier pour réaliser une thérapie par perfusion sous hyperthermie extracorporelle (EHP). En outre, la présente invention concerne le sang extracorporel au-dessus de la température corporelle normale destiné à être utilisé dans le traitement d'une maladie choisie dans le groupe constitué par le cancer, une maladie auto-immune, une maladie infectieuse, une maladie inflammatoire et la sepsie. En outre, la présente invention concerne une combinaison de sang extracorporel au-dessus de la température corporelle normale et d'un agent chimiothérapeutique destiné à être utilisé dans le traitement du cancer.
EP19745181.8A 2019-01-24 2019-08-01 Système et méthodes pour une thérapie par perfusion sous hyperthermie extracorporelle (ehp) Pending EP3914312A1 (fr)

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WO2022040376A2 (fr) * 2020-08-21 2022-02-24 Verthermia Acquisition, Inc. Méthode et système améliorés d'hyperthermie régulée

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AU777801B2 (en) * 1999-05-25 2004-10-28 Viacirq, Inc. Hyperthermia method and apparatus
US11344662B2 (en) * 2014-02-17 2022-05-31 Humanity Life Extension Llc Systems and methods for treating blood
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