I. Tumor Thermotherapy Tumor thermotherapy (Hyperthermia) is the treatment of tumor by heating. Traditional tumor thermotherapy, also known as hyperthermia, is to heat the whole body or local area of human body to raise the temperature of tumor tissues to the effective treatment temperature (about 42℃) and maintain it for a certain period of time, so as to achieve the treatment purpose of inactivating tumor cells and leaving the surrounding normal tissues intact. In 1866, German doctor Busch reported a case of histologically confirmed pediatric facial tumor, which disappeared completely after the hyperthermia caused by tumor poisoning. . Robdendury summarized 166 cases of tumors that resolved on their own, 72 of which had received heat therapy or had hyperthermia. Such reports led to the recognition of the possibility of heat as a means of treating tumors, and a large number of scholars attempted to treat tumors by various means of inducing hyperthermia or heating the body, and studied in depth the biological effects of heating tumor tissues. Although the physical heating devices used at that time were rudimentary, the monitoring methods were crude and the technical means were limited, almost all of them came to one conclusion: tumor tissues are less heat-resistant than normal tissues, i.e. tumors are afraid of heat. This has given birth to modern tumor thermotherapy. 1.Tumor thermal therapy mechanism: Most tumor tissues and tumor cells cannot tolerate high temperature from 41.5℃ to 43℃, while the limit temperature tolerated by normal tissues is 45℃, so about 42℃ is the key temperature of tumor thermal therapy. (1) Selective cancer treatment effect of high temperature: tumor tissues have poorly developed vascular network, disorganized structure and lack of innervation, thus there are more blood sinuses in tumor but lack of complete arteriovenous system, and the blood flow in tumor is only about 10% of normal tissue. The temperature difference can make the tumor in effective killing temperature, while the surrounding tissues are not damaged. (2) The effect of heat on oxygen-depleted cells: solid tumor tissues contain 20% to 50% oxygen-depleted cells, which is the main reason for the failure of radiotherapy and chemotherapy for most tumors. A large number of studies have shown that hypoxic cells are sensitive to high heat, and high heat can also lower the pH value in the tumor microenvironment, which further increases the killing effect of heat on tumor. It is inferred and experimentally confirmed that heat therapy has a sensitizing effect on radiotherapy. (3) Heat can cause changes in nucleolus and membrane structure, destabilize biological macromolecules DNA, RNA and protein, and prevent cancer cells from entering the division phase. In addition, high temperature can induce apoptosis of tumor cells and can enhance the anti-tumor immune function of the body through the release of tumor antigens. 2.Heating method: According to the area to be heated, there are systemic heating and local heating (1) Systemic heating: to kill cancer cells in the blood stream or metastasized and spread by increasing systemic body temperature ① Extracorporeal circulation systemic thermal perfusion method (TEMETtm1000, FDA approved): under general anesthesia, bilateral femoral veins are punctured to draw blood out of the body, and then heated and injected back into the body to increase systemic body temperature. The warming process to rectal temperature to reflect the central temperature of the human body; ② infrared heating: the patient is placed in the heating chamber, infrared wavelength of 700 ~ 1400 nm uniform heating subcutaneous capillaries, through the blood circulation to control the body temperature at 40 ℃ ~ 41.8 ℃. (2) Local heat transmission: Tumor tissues heat up faster than surrounding normal tissues due to the above-mentioned characteristics, and thermal damage is obvious. (1) Electromagnetic wave heating: microwave and radio frequency have strong penetration and have been applied to deep tumor heating, but both of them have different degrees of fat overheating phenomenon; (2) Planar ultrasonic heating: ultrasonic wave also has strong penetration and is a completely green treatment method, but its clinical application is limited because it cannot pass through gas-containing tissues and bone. Local transthermal heat is a safe, simple and nearly nondestructive thermal therapy method, but its efficacy is limited by the lack of effective nondestructive thermometry, i.e., the true temperature of each part of the tumor cannot be clarified; invasive thermometry (insertion of thermometry needle) is also difficult to be widely accepted due to pain, infection, bleeding and possible needle tract metastasis. (3) Body cavity perfusion thermotherapy: chemotherapeutic drugs and saline are heated to 45℃ outside the body, introduced into the body cavity with an extracorporeal circulation pump, and continuously circulated to monitor the temperature of the outlet and inlet and the body cavity to ensure that the water temperature in the body cavity is 42℃～43℃ and maintained for a period of time. This method can be used during surgery, and can also be used to enhance the killing effect of implantation lesions by continuous flushing irrigation after surgery. (4) Inter-tissue thermotherapy: The needle-like heating device is inserted into the tumor and emits radiofrequency or microwave to produce a high thermal field around it for a short period of time, locally up to 100℃, which causes necrosis of the tumor tissue within that range. This heating method is also called tumor ablation, and its mechanism of cancer treatment is different from the traditional heat therapy, but closer to the “knife-like effect” of surgery, so it is also called RF knife or microwave knife. Strictly speaking, inter-tissue heating does not belong to the category of traditional thermal therapy. 3.Clinical application: Although the cancer-killing effect of high temperature has been recognized, but in terms of the current thermal therapy means and devices, thermal therapy is ranked after surgery, chemotherapy, mostly as chemotherapy, radiotherapy sensitization aids, and less applied alone. For local thermotherapy, the lack of intuitive, nondestructive and accurate temperature measurement technology is still the main reason that hinders its clinical promotion. High intensity focused ultrasound therapy for tumors Since ultrasound has both penetrating and directional properties, as early as in the 1940s, some foreign scholars envisioned that ultrasound would pass through human body and focus on deep tumor tissues to kill tumors by high temperature, which is high intensity focused ultrasound (HIF). This is the concept of high intensity focused ultrasound (also known as HIFU). With the rapid development of computer technology and high-definition imaging technology in recent years, this concept has been realized. In the mid-1990s, China’s Chongqing, Shanghai and Beijing developed successful HIFU treatment devices and started clinical treatment in 1997, which was the first in the world to systematically elaborate the effectiveness and feasibility of HIFU treatment for tumors, and rapidly accumulated a large number of successful cases, which attracted high attention from international counterparts. At present, China is in the forefront of the world in the clinical application of HIFU. 1.Mechanism Heat can kill tumor, but the time required for irreversible cell damage caused by different temperatures is different: 15 hours at 45℃, 180 seconds at 50%, 3 seconds at 60℃, and only 0.25 seconds at 70℃, so the best way to improve the efficacy is to increase the temperature significantly. HIFU system can focus the ultrasonic waves on the tumor in the body, forming an ellipsoidal high energy density area of 3mm in diameter and 8mm in length, in which the area can reach 3000W/cm2, which is 30 to 50,000 times of the diagnostic ultrasound, causing the tumor tissue to reach over 70℃ in a short time, resulting in instant coagulation necrosis, while the normal tissues around the tumor are intact because they are far from the focus. 3*3*8mm The 3*3*8mm focal area is only a treatment “pixel”, which is arranged by superposition of dots and dots to form a line, and superposition of lines and lines to form a plane, and finally arranged by multiple planes to form a three-dimensional shape, covering the whole tumor. This treatment method of scanning the whole tumor tissue by the superposition of dots makes the heating of each part of the tumor very uniform and can completely follow the three-dimensional shape of the tumor, which is the real conformal treatment. HIFU treatment has advantages that cannot be compared with other treatments. The HIFUNIT9000 machine developed by Shanghai Aishen Technology Co., Ltd. is used as an example to illustrate: (1) complete in vitro treatment, no obvious pain to the patient, no bleeding and no anesthesia; (2) no ionizing radiation damage, good safety, almost non-invasive and repeatable; (3) real-time monitoring and conformal treatment: during the treatment process, the The operator can monitor the treatment process synchronously through the built-in ultrasound probe, and can judge the immediate efficacy through grayscale changes; (4) high temperature closes the small blood vessels and lymphatic vessels around the tumor, blocking the metastatic pathway of the tumor. 2.Clinical application At present, HIFU has been widely used in the treatment of abdominal and pelvic solid tumors, such as pancreatic cancer, liver cancer, kidney cancer, retroperitoneal tumors, uterine fibroids, ovarian cancer, prostate cancer and metastatic tumors in the abdominal and pelvic cavities, especially for pancreatic cancer and retroperitoneal tumors, HIFU treatment is not restricted by the complex anatomical structure of the retroperitoneum such as blood vessels, which shows its advantages in treatment. In addition, HIFU has been used for breast-conserving treatment of breast cancer and limb-conserving treatment of osteosarcoma, and successful cases have been reported. Because ultrasound cannot penetrate gas-containing tissue and bone tissue, HIFU cannot treat lung and intracranial tumors; another part of right lobe liver tumors cannot be treated with HIFU because of rib blockage; tumors within 1 cm from the skin will inevitably damage the skin when treated with HIFU; cavernous organs may be perforated during treatment because of thin walls and gas content, so intestinal cancer is not considered as its indication; sometimes patients with abdominal Sometimes the patient’s abdomen is obviously distended and the tumor tissue is difficult to be clearly displayed by ultrasound, and also the ultrasound beam will have obvious loss when passing through the gas-containing tissue, which will also affect the efficacy. As a safe and conformal tumor hyperthermic ablation treatment, HIFU can be applied alone. However, HIFU has been in clinical use for less than a decade, and although its safety and local effects have been demonstrated, there is a lack of long-term follow-up data from large samples, especially from randomized comparisons with existing conventional treatments, so the clinical use of HIFU is currently limited to (1) advanced tumors that cannot be surgically resected; (2) tumors that cannot tolerate surgery due to advanced age, frailty, or comorbidities; (3) tumors that cannot tolerate surgery; and (4) tumors that cannot be treated with HIFU. (2) tumors that cannot tolerate surgery because of the patient’s advanced age, frailty or comorbidities; (3) tumors that are recurrent or metastatic after surgery and should not be operated again; (4) patients who firmly refuse surgery. 3. Outlook The lack of effective nondestructive temperature measurement methods is also a major factor affecting the efficacy of HIFU. Unlike radiation, ultrasound has refraction and reflection when passing through different tissues, and will be heavily attenuated when encountering gas-containing tissues, and the final dose to the target area is difficult to be accurately measured. Ultrasonography, color Doppler, enhanced CT, MRI, and even PET-CT can objectively reflect the inactivation of tumor tissue after treatment, but only real-time temperature measurement during treatment can truly guide the treatment and thus ensure the efficacy. HIFU devices have been applied abroad for MRI localization and temperature measurement [5], which are expensive and have been FDA-approved for the treatment of uterine fibroids, but have not been introduced in China yet. Shanghai Aishen is working with Fudan, Jiaotong University, East China Normal University and other universities to develop a MRI-HIFU device with low magnetic field and real-time temperature measurement. Compared with the existing HIFU devices guided by ultrasound, MRI-guided HIFU can fundamentally ensure the effectiveness and safety of HIFU treatment, which will be one of the most exciting revolutions in the field of local tumor treatment in the 21st century.