1.American Ar-He knife – the latest achievement in tumor cold and heat ablation technology In October 1998, the American company Endocare successfully developed a new ultra-low temperature interventional cold and heat ablation argon-helium targeted tumor treatment equipment: Endocare CryocareTM Surgical System ( American Ar-He knife ), and through the U.S. FDA approval, IEC, EMC and EU CE certification, and used in hospitals around the world. The Endocare CryocareTM Surgical System ( US Ar-He knife ) is FDA approved, IEC, EMC and CE certified and is used in hospitals worldwide. Its invention is the latest achievement in the development of cryotherapeutic technology, which not only inherits and develops the basic and clinical research results of ultra-low temperature therapy, but also introduces a new concept of minimally invasive tumor treatment – argon-helium targeted tumor treatment technology. The development of the Ar-He knife minimally invasive targeted surgery system in the United States combines aerospace, biosensing, electronic computer, fit monitoring and targeted therapy technologies, which organically combines ultra-low temperature targeted cryotherapy and interventional thermotherapy, bringing a breakthrough in the development of tumor cold and heat ablation treatment technology. Zhujiang Hospital of Southern Medical University in Guangzhou was the first in Asia to introduce this technology in 1999, bringing a boon to the treatment of patients with mid- to late-stage tumors. The American Ar-He knife minimally invasive surgery operating system is the latest high-tech equipment system for minimally invasive cancer treatment with full monitoring and precise positioning. There are four to eight thermally insulated superconducting knives that can be individually controlled. The superconducting knives are 2, 3, 5, and 8 mm diameter hollow tubular knives that can deliver either ambient argon gas (cold medium) or high pressure ambient helium gas (hot medium). The temperature differential coupling is mounted directly on the tip of the knife, allowing continuous monitoring of the tip temperature. The argon helium tip is inserted percutaneously into the center of the tumor under the guidance of CT or B-ultrasound, and the argon ultra-low temperature cooling technology can reduce the tumor tissue to below -100°C within seconds by the rapid adiabatic cooling effect of argon gas at the tip of the knife. The helium gas can also be used to rapidly thaw the ice ball and rapidly raise the temperature to 50 ℃. Thus, ice crystals are formed in the cancer cells during freezing, and the rapid warming causes the ice crystals to burst, which completely destroys the cancer cells. The speed, time and temperature difference between cooling and heating of the Ar-He knife, as well as the size and shape of the ice ball, can be fully controlled and precisely set, resulting in precise efficacy in the target area. Because Ar-He knife cooling or heating is limited to the superconducting tip, the blade has excellent thermal insulation and does not cause major damage to the tissue in the puncture path. The US Ar-He knife is the only advanced technology that can be used for percutaneous cold and heat ablation treatment. 2.The status of Ar-He knife in tumor treatment Tumor is a century-old problem faced by human beings, more than 80% of tumor patients have lost the opportunity of surgical treatment when they come to the hospital. 95% of tumor patients fail in treatment because the local primary tumor is not controlled, recurrence or systemic metastasis. Over the past half century, tumor treatment in China has been based on surgical resection, radiotherapy, chemotherapy, traditional Chinese medicine and immunobiotherapy. The clinical cure of surgery, radiotherapy and chemotherapy is only 22%, 18% and 5%. The treatment of inoperable patients is a clinical challenge. Therefore, the differences between disciplines, the influence of market economy, the specificity of specialized technology, medical management and many other issues that need to be explored have caused many difficulties in the selection of comprehensive treatment measures, which affects the efficacy of treatment. The birth of the Ar-He knife in the United States has provided a powerful treatment tool for many patients that were previously untreatable. The clinical use of Ar-He knife has proved that minimally invasive ablative treatment should be preferred for tumors that cannot be radically resected by conventional surgery, and that minimally invasive ablation can rapidly reduce the tumor load, reduce the patient’s pain, improve the quality of survival, and ensure the efficacy of comprehensive treatment, which is irreplaceable by radiotherapy. Among the minimally invasive ablation techniques, the Ar-He knife is less invasive and more effective than 90%, and has become an indispensable tool for many clinicians in surgical treatment. According to the statistical data of domestic multi-center clinical collaboration, argon helium knife combined with interventional chemotherapy for liver cancer and lung cancer; argon helium knife combined with radiotherapy for lung cancer; combined with Chinese medicine for lung cancer and liver cancer; compared with radiotherapy, chemotherapy and interventional embolization alone, the survival rate of 1 year and 2 years have been significantly improved, and the clinical efficacy is encouraging. This shows that the Ar-He knife will become an important tool in the treatment of clinical solid tumors, especially in the treatment of liver cancer and lung cancer. At present, few hospitals have introduced argon-helium targeted tumor treatment technology, and it is not commonly carried out in clinical practice. With the widespread use of this new technology, it will definitely promote the clinical progress of minimally invasive tumor treatment. Argon-helium knife can be used intraoperatively with doctors, and at the same time, it can be widely used in the clinical treatment of various solid tumors under the guidance of CT, B-ultrasound and other positioning systems and lumpectomy. Currently, Ar-He knife has been used to treat lung cancer, liver cancer, pancreatic cancer, glioma, neurofibroma, nerve sheath tumor, breast cancer, soft tissue tumor, bone tumor, kidney cancer, prostate cancer, rectal cancer, ovarian cancer, cervical cancer, skin cancer, nasopharyngeal cancer, throat tumor, teratoma, retroperitoneal tumor, pleural peritoneal mesothelioma, maxillary sinus tumor, tongue cancer, parotid cancer, and other solid tumors, and it is also widely used for It is also widely used in the treatment of benign lesions such as prostate hyperplasia, uterine fibroids and hemangioma. 3.Ar-He knife promotes the development of minimally invasive tumor treatment technology in China Because of the unique technical advantages of the American Ar-He knife, it has greatly promoted the development of minimally invasive tumor ablation treatment. 1999 Professors Zhang Jiren, Wang Senming and Zhang Shizhong of Zhujiang Hospital in Guangzhou were the first in the world to carry out and establish the minimally invasive surgical techniques of CT and B-ultrasound guided percutaneous Ar-He targeted treatment for liver cancer and stereotactic Ar-He targeted treatment for brain tumor; Shanghai Director Wu Qing was the first in China to carry out CT-guided percutaneous argon helium targeting for lung cancer; academician Wu Mengchao and Dr. Qian Guojun of Shanghai Oriental Hepatobiliary Surgery Hospital were the first to carry out argon helium knife combined surgery for refractory advanced liver cancer; Professor Li Jian of Peking University First Hospital was the first in the world to carry out thoracoscopy-guided argon helium knife targeting for middle and advanced lung cancer; Professor Hu Kaiwen of Beijing University of Traditional Chinese Medicine and Dr. Bai Guangde of Guangxi Prof. Hu Kaiwen of Beijing University of Traditional Chinese Medicine and Prof. Bai Guangde of Guangxi College of Traditional Chinese Medicine were the first in China to combine argon helium knife and laparoscopic technology, and created the laparoscopic guided argon helium targeted ablation for abdominal and pelvic tumors, and combined with Chinese medicine treatment to propose a new concept of ‘green treatment’ for tumors; Prof. Wang Hongwu and Prof. Feng Huasong of Beijing Naval General Hospital were the first in the world to report the development of argon helium targeted ablation for lung cancer. Professors Wang Hongwu and Feng Huasong of Beijing Naval General Hospital reported the clinical experience of argon-helium targeted ablation in the treatment of middle and advanced lung cancer [9]; Professor Guo Zhi of Tianjin Cancer Hospital reported the clinical experience of argon-helium knife sequential intervention in the treatment of refractory liver cancer; Professor An Yonghui of Shijiazhuang First People’s Hospital, Professor Song Huazhi of Wuhan Military Region General Hospital, and Dr. Niu Lizhi of Guangzhou Fuda Cancer Hospital have achieved rich clinical experience in the use of argon-helium knife in the treatment of various solid tumors and the combination with radiotherapy and other comprehensive treatments. They have gained rich clinical experience in treating various solid tumors with Ar-He knife and combining it with radiotherapy and chemotherapy. Thanks to the efforts of the China Ar-He Targeted Therapy Collaborative Group, the clinical progress of Ar-He targeted therapy in China has attracted the attention of international colleagues. Professor Peter Littrup, Professor Daniel Rukstalis, Hahnemann University, Philadelphia, Professor Rudolf Hanka and Professor Mila Hanka, University of Cambridge Medical School, Cambridge, UK; Professor John Rewcastle, University of Calgary, Canada; Professor Dennis Peterson, Endo2care Clinical Research, Endo2care, USA Prof. John Rewcastle from University of Calgary, Canada, Prof. Dennis Peterson and Dr. Suzy Chosy from Endo2care Clinical Research, USA, Prof. Go Wakadayash and Prof. Winoruanabe from Keio Uniersity Hos2pital, Tokyo, Japan, etc. have come to China for many times for lectures, training, surgical instruction and academic exchanges. Academician Wu Mengchao, Director Qian Guojun, Professor Zhang Jiren, Professor Wang Senming, Professor Zhang Shizhong and Professor Xu Kecheng have been invited to the United States for academic exchanges. Prof. Duan Yun-uran and Prof. Wang Hongwu were invited to Europe for lectures and exchanges. They have all contributed to the extensive cooperation of international clinical argon-helium targeted therapy technology and the development of argon-helium targeted therapy technology in China. The clinical success of argon-helium targeted therapy technology has promoted the progress of minimally invasive tumor treatment technology in China. The scientific standard has laid the foundation for the clinical application of argon helium knife. The International Committee of Argon Helium Targeted Therapy Technology, the Chinese Society of Biomedical Engineering Tumor Targeted Therapy Technology and the Chinese Argon Helium Targeted Therapy Collaborative Group have held international and Chinese seminars on new technologies of argon helium targeted therapy in the United States, Canada, Guangzhou, Dalian, Shanghai and Beijing, etc. since 2000, and organized seminars on new technologies of argon helium targeted therapy in China. The members of the collaborative group had a thorough exchange on the treatment principles, treatment methods, clinical indications and contraindications, surgical procedures, intraoperative monitoring, postoperative reactions and complications, and clinical precautions, etc.; they also had a thorough discussion on the design of clinical treatment plans, the selection of comprehensive treatment measures, the direction of basic and clinical research, how to reduce the residual rate and improve the long-term efficacy, etc. The issues such as the design of clinical treatment protocols, the selection of comprehensive treatment measures, the direction of basic and clinical research, and how to reduce residual rates and improve long-term efficacy were fully discussed. The experience of lung cancer treatment by Prof. Peter Littrup from USA, Prof. Wu Qing, Prof. Wang Hongwu, Prof. Feng Huasong, Prof. An Yonghui, Prof. Song Huazhi from Wuhan, Prof. Gregory Graes from USA, Prof. Go Wakadayash from Japan, Prof. Qian Guojun from Shanghai, Prof. Wang Senming and Dr. Niu Lizhi from Guangdong, Prof. Guo Zhi from Tianjin, Prof. Zhang Shizhong’s experience of brain tumor treatment, Prof. Dan Dan Wakadayash from USA, Prof. Zhang Shizhong’s experience of brain tumor treatment, and Prof. Zhang Shizhong’s experience of liver cancer treatment. Professor Zhang Shizhong’s experience in brain tumor treatment, Professor Daniel Rukstalis from USA, Professor Winoruanabe from Japan, Professor Li Jian from China, Professor Bai Guangde’s experience in lumpectomy-guided argon helium knife treatment. He published the world’s first monograph, which laid the foundation for the standardization and scientific use of international argon-helium-targeted tumor treatment technology. Thanks to the unremitting efforts of the Chinese Ar-He Targeted Therapy Collaborative Group, the clinical experience of Chinese doctors has been recognized by their foreign counterparts; CT and B-ultrasound-guided percutaneous Ar-He targeted ablation for liver cancer, lung cancer, kidney tumors and bone sarcoma; stereotactic-guided transcranial treatment for brain tumors; lumpectomy-guided Ar-He knife for thoracic and abdominal tumors; percutaneous puncture Ar-He knife for prostate tumors; volume cryoablation such as Ar-He knife; and combined surgical resection. Combined surgical resection and other techniques have been widely used. With the combination of Ar-He knife therapy with surgery, navigation therapy, endoscopic therapy, radiation therapy, interventional therapy, Chinese medicine therapy and immunotherapy, it will help Ar-He targeted therapy become an important tool for clinical treatment of solid tumors. 5.Argon helium knife targeted ablation therapy for tumors has remarkable clinical efficacy. Argon helium knife targeted therapy is a local physical therapy technology that directly destroys tumor tissues. Unlike conventional surgery, radiotherapy and chemotherapy, argon helium knife treatment does not remove the ablated tumor tissue, but the tumor tissue has been completely destroyed by argon helium ablation treatment. The target area of treatment is the area where the tumor is ablated and inactivated. However, the absorption of ablated necrotic tissue cells is a slow process in most tumor patients. The pathological follow-up results confirm that the necrotic tumor tissue after ablation therapy shows a gradual absorption and fibrosis process, which generally takes 3-5 months. Therefore, it is not scientific to judge the recent local efficacy of Ar-He knife based on the clear boundary of the tumor target area and the exact ablation, as well as the change of tumor size and morphology before and after treatment, which cannot truly reflect the recent clinical effect of Ar-He knife treatment. The discussion of the Ar-He Targeted Therapy Collaborative Group suggested that: Ar-He knife therapy is different from other local therapeutic techniques, the target area of cold and heat ablation has been proved by CT, MRI, PET, vascular scan and pathological examination before and after treatment: the tumor cells in the target area of Ar-He ablation have completely died, so the clinical evaluation of the recent clinical efficacy can be made according to the scope of the target area and the size of the tumor ablated during Ar-He knife surgery. The ablation rates of liver cancer and lung cancer tumors below 3 cm in diameter can reach 100%, and the ablation rates of tumors between 3 and 6 cm in diameter can reach more than 90% with the Ar-He knife. The recent efficacy of Ar-He knife is very significant. The Ar-He knife has achieved satisfactory clinical efficacy in the treatment of solid tumors in the United States. The combination of local ablation with radiotherapy, chemotherapy, biologic therapy and interventional therapy has been shown to be more effective than single therapy, with a significantly higher survival rate of 1 to 2 years. The long-term efficacy of tumor depends on the choice of comprehensive treatment measures. Rapid ablation, tumor load reduction, and tumor cell destruction are the preferred treatment modalities for solid tumors. The widespread implementation of Ar-He knife targeted therapy in oncology clinics has the potential to change the protocol and course of traditional radiotherapy and chemotherapy. At present, a multicenter collaborative study has been conducted to understand and evaluate the long-term efficacy of argon helium targeted therapy in tumor clinical treatment, how to design adjuvant radiotherapy and chemotherapy regimens after argon helium targeted therapy, how to understand the regulation of cellular immune function of patients by argon helium freezing and its molecular biological mechanisms, how to design the best surgical procedures and protocols for argon helium targeted therapy for different tumors, and the changes of tumors after argon helium targeted ablation therapy. In the future, we still need to expand the cases, multi-center collaboration, strict clinical research design, scientific statistical analysis, and strengthen the long-term follow-up. 6. 6.1 Precise planning, accurate positioning and guidance are the guarantee of efficacy. The distinctive feature of argon helium knife targeted ablation therapy is that it can inactivate tumor cells and eliminate tumor load rapidly and accurately. Due to the different size and shape of the tumor, whether it is a single treatment or a fractionated ablation treatment, the ice ball should cover the tumor as much as possible according to the condition, and most doctors believe that it should exceed the tumor imaging edge by more than 1 cm to ensure the complete inactivation of the tumor tissue. This is the key to prevent local residual, prevent recurrence and improve the efficacy. At present, intraoperative direct vision and multi-angle monitoring by ultrasound and CT can achieve conformal treatment, but when choosing percutaneous puncture treatment, due to the limitation of multidimensional monitoring conditions and the different proficiency and experience of doctors, conformal planning and accurate guidance positioning are the keys to radical argon helium targeted ablation treatment. Before surgery, the size and shape of the tumor at different CT levels should be carefully analyzed, and the angle, direction, depth and level of access of the Ar-He knife should be measured. It is important to determine the entry diameter of the Ar-He knife and to simulate the extent of the target area formed by the Ar-He knife in the body ice ball and its relationship with the surrounding anatomical structures. He also determines the location of the thermometric probe and the focus of monitoring, and is skilled in diagnostic imaging and image monitoring. The design of the ablation target area for multiple knife combination should be evaluated accurately. B-ultrasound guidance and monitoring are simple, but percutaneous surgical treatment requires the operator to have three-dimensional anatomical concepts and experience in conformal treatment. The B-ultrasound guidance and monitoring are simple, but percutaneous treatment requires the operator to have experience in three-dimensional anatomy and conformal therapy to detect the process of ice ball formation from different directions and to assess the extent of the ablation target area. Intraoperative B-ultrasound monitoring and guidance during lumpectomy and small incisions are more accurate than percutaneous treatment, while CT-guided localization is more accurate, but attention should be paid to the formation of target areas at different CT levels during surgery. For sites that are not easily monitored, irregular tumors, and especially when multiple Ar-He knives are used to treat large tumors. Intraoperative timely monitoring of ablation target areas should pay attention to the level of fusion between the ice spheres and minimize damage to normal tissues. At present, the clinical monitoring means mainly rely on the information provided by imaging, except for B-ultrasound, the timely monitoring of CT and MRI in China is still difficult, and the correct use of the thermometric probe can provide timely target area definition information for surgery. Especially for the treatment of tumors near important tissues and organs, timely monitoring and accurate temperature measurement is an effective method for effective treatment and residual prevention. 6.3 Combination of Ar-He knife ablation and comprehensive treatment After decades of traditional tumor treatment mode, minimally invasive tumor technology has promoted the clinical progress of tumor, and now surgical resection, minimally invasive ablation, radiotherapy, chemotherapy, Chinese medicine, and biological therapy have become the new choice mode of treatment for solid tumors. Ar-He knife ablation has become an important technology for minimally invasive treatment. Clinical experience shows that minimally invasive ablation should be the first choice of treatment for patients who cannot be surgically removed in a comprehensive tumor treatment model. Ar-He knife can rapidly reduce the tumor load to the greatest extent possible, and can provide efficacy for radiotherapy, chemotherapy, Chinese medicine and biological therapy. Ar-He knife therapy can target and inactivate solid tumors on imaging, rapidly reducing patient pain and improving quality of life. However, as with other local physiotherapies, the same problems are faced. The treatment of subclinical lesions and potential residual cancer cells throughout the body after argon helium cryotherapy must be accompanied by appropriate systemic therapy. Different integrated treatment protocols have been proposed and recognized by foreign colleagues. For example, argon-helium targeted therapy combined with interventional embolization chemotherapy for mid-stage liver cancer; argon-helium targeted ablation combined with radiotherapy and chemotherapy for mid-stage tumors; argon-helium targeted ablation combined with Chinese medicine and immunotherapy for mid-stage tumors have been widely used. For tumors close to the mediastinum, hepatic hilum, bile duct, spinal cord, etc., complete local ablation with Ar-He knife is difficult, and Ar-He knife treatment can be combined with other local treatments. Combining with radiotherapy can greatly reduce the radiation dose; combining with drug implantation and radioactive particle implantation can improve the efficacy and reduce the dose of implanted particles. The effective combination with other local and systemic treatment techniques can change the current concept of comprehensive treatment and improve the long-term treatment effect. The effect of argon cooling on the formation of intracellular ice crystals leading to cell death is closely related to the rate of intracellular ice crystal formation. The rate of increase in cell death is closely related to the rate of intracellular ice crystal formation. Ar-He knife is based on the Joule-Thomson law, which states that the rate of freezing leading to cell death is influenced by the pressure, resistance, conduction and recovery method of argon gas flow. When the FDA approves a device, the working pressure of argon and helium that is required to cause cell death is set. The technical parameters of the FDA-approved argon and helium knives vary widely, as do the size of the ablation target area, due to the different patents and designs of the knives. For example, the Cryocare argon-helium knife (2,3,5 mm) manufactured by Endocare has an argon working pressure of 2500 PSI and a helium working pressure of 1000 Psi. The FDA and the State Food and Drug Administration of China have approved the Cryohit argon-helium knife (2.4, 3.2, 3.4mm) made by Galimed, Israel, with argon and helium working pressure of 4000Psi. Currently, the argon pressure in China is 5500 to 6000 PSI and the helium pressure is 1800 to 2000 Psi. Therefore, the effective working pressure range for clinical use of the American Ar-He knife is 6000-2500 PSI for argon and 1800-1000 psi for helium, and should be discontinued when the argon pressure is below 2500 psi and the helium pressure is below 1000 psi. The effective gas working pressure range of the Israeli argon and helium knife is 6000~4000Psi, and should be stopped when argon and helium are lower than 4000Psi. Otherwise, although the ice ball is formed, it is difficult to obtain therapeutic effect, and the patient’s interests are harmed. Animal experiments show that when the hot and cold temperatures of cells reach a certain range, the degree of cell damage is positively correlated with the duration of hot and cold. The duration of argon ultra-low temperature treatment should be 15 min, and the pathological examination 24-72 h after surgical treatment can indicate irreversible cell damage and necrosis process. Due to the different water content of different tissues and the difference of cell biological properties, the optimal time for cryotherapy of tumors in different organs is somewhat different, but in principle, the time and number of argon treatment cannot be shortened arbitrarily. The key temperature for cell necrosis in the US argon helium knife double freezing tissue is – 38 ℃. Therefore, when developing a clinical argon helium-targeted treatment plan, the imaging observation of ice ball formation should extend beyond the tumor margin. The target area should be contained within the range of – 38 °C to below – 100 °C. In clinical treatment, some doctors found that the treatment effect of the edge of the ice sphere is not good, and it is easy to have residual or recurrence, one of the reasons is that the edge of the ice sphere does not exceed the edge of the tumor target area during the treatment. Clinically, it is recommended that the edge of the puck should exceed the tumor target area by 1 cm. When the ablation target area of one Ar-He knife probe does not completely cover the tumor tissue, two or three Ar-He knife probes can be used in a conformal combination depending on the size and shape of the tumor. One of the distinctive features of Ar-He knife targeted therapy in the United States is the thoroughness of freezing to destroy tissue cells. In argon helium targeted therapy, it is necessary to understand the access of argon helium knife and the anatomical structure and pathophysiological characteristics of the frozen target area before and during the operation, and to take active preventive, monitoring and treatment measures for the possible damage. Since argon-helium cryopreservation is not selective in destroying cells, the target area must be selected accurately to avoid freezing damage to normal tissue structures caused by incorrect operation. For example, the urethral insulation system should be used appropriately during argon helium knife surgery for prostate cancer; the skin should be protected when treating subcutaneous and soft tissue tumors on the face; the heart should be protected when treating central lung cancer, especially tumors near the mediastinum, and the edge of the target area should be accurately monitored with a thermometric probe. The impact of ultra-low temperature treatment and the necrosis process of tissue cells on tissues and organs and the pathophysiological reactions caused by them should be handled well. In the clinical experience accumulation, the members of the Chinese Ar-He Targeted Therapy Collaborative Group have made important contributions and provided more than 20,000 cases of clinical treatment experience for the international Ar-He Targeted Therapy technology. In the minimally invasive treatment of tumors, we have explored a new model for the treatment of solid tumors. The treatment effect of solid tumors has been improved. At the same time of local ablation therapy, combined with traditional surgery, radiotherapy, chemotherapy, interventional embolization therapy, Chinese medicine therapy, immunotherapy, gene therapy and other means, we will continue to carry out clinical and basic research, develop and improve argon helium knife targeted therapy technology in the future clinical treatment, so that argon helium knife therapy can play a more effective role in the treatment of solid tumors and further improve the long-term efficacy of tumor treatment. This is the clinical research direction of the China Ar-He Knife Targeted Therapy Collaborative Group in the future.