Cryoablation

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Cryoablation
Hepatic cryoablation.gif
Animated GIF showing cryoablation of mass in right liver lobe using two probes. Time elapsed is approximately 30 minutes.
ICD-9-CM 37.33, 37.34, 60.62
MeSH D003452

Cryoablation is a process that uses extreme cold to destroy tissue. Cryoablation is performed using hollow needles (cryoprobes) through which cooled, thermally conductive, fluids are circulated. Cryoprobes are positioned adjacent to the target in such a way that the freezing process will destroy the diseased tissue. Once the probes are in place, the attached cryogenic freezing unit removes heat from ("cools") the tip of the probe and by extension from the surrounding tissues.

Contents

Ablation occurs in tissue that has been frozen by at least three mechanisms:

  1. formation of ice crystals within cells thereby disrupting membranes, and interrupting cellular metabolism among other processes;
  2. coagulation of blood thereby interrupting bloodflow to the tissue in turn causing ischemia and cell death; and
  3. induction of apoptosis, the so-called programmed cell death cascade.

The most common application of cryoablation is to ablate solid tumors found in the lung, liver, breast, kidney and prostate. The use in prostate and renal cryoablation are the most common. Although sometimes applied in cryosurgery through laparoscopic or open surgical approaches, most often cryoablation is performed percutaneously (through the skin and into the target tissue containing the tumor) by a medical specialist, such as an interventional radiologist. The term is from cryo- + ablation .

Prostate

Prostate cryoablation is moderately effective but, as with any prostate removal process, also can result in impotence. Prostate cryoablation is used in three patient categories:

  1. as primary therapy in patients for whom sexual function is less important or who are poor candidates for radical retropubic prostatectomy (RRP, surgical removal of the prostate);
  2. as salvage therapy in patients who have failed brachytherapy (the use of implanted radioactive "seeds" placed within the prostate) or external beam radiation therapy (EBRT); and
  3. focal therapy for smaller, discrete tumors in younger patients.

Bone cancer

Cryoablation has been explored as an alternative to radiofrequency ablation in the treatment of moderate to severe pain in people with metastatic bone disease. The area of tissue destruction created by this technique can be monitored more effectively by CT than RFA, a potential advantage when treating tumors adjacent to critical structures. [1]

Renal

Cryoablation has similar outcomes to radiofrequency ablation when treating renal cell carcinoma. [2]

Breast cancer

Cryoablation for breast cancer is typically only possible for small tumors. [3] Often surgery is used following cryoablation. [3] As of 2014 more research is required before it can replace lumpectomy. [3]

Cardiac

Another type of cryoablation is used to restore normal electrical conduction by freezing tissue or heart pathways that interfere with the normal distribution of the heart’s electrical impulses. Cryoablation is used in two types of intervention for the treatment of arrhythmias: (1) catheter-based procedures and (2) surgical operations.

A catheter is a very thin tube that is inserted into a vein in the patient’s leg and threaded to the heart where it delivers energy to treat the patient’s arrhythmia. In surgical procedures, a flexible probe is used directly on an exposed heart to apply the energy that interrupts the arrhythmia. By cooling the tip of a cryoablation catheter (cardiology) or probe (heart surgery) to sub-zero temperatures, the cells in the heart responsible for conducting the arrhythmia are altered so that they no longer conduct electrical impulses.

Fibroadenoma

Cryoablation is also currently being used to treat fibroadenomas of the breast. Fibroadenomas are benign breast tumors that are found in approximately 10% of women (primarily ages 15–30). [4]

In this procedure which has been approved by the U.S. Food and Drug Administration (FDA), an ultrasound-guided probe is inserted into the fibroadenoma and extremely cold temperatures are then used to destroy the abnormal cells. [5] Over time the cells are reabsorbed into the body. The procedure can be performed in a doctor's office setting with local anesthesia and leaves very little scarring compared to open surgical procedures. [5]

Catheter-based procedures

Different catheter-based ablation techniques may be used and they generally fall into two categories: (1) cold-based procedures where tissue cooling is used to treat the arrhythmia, and (2) heat-based procedures where high temperature is used to alter the abnormal conductive tissue in the heart.

Cryoablation

Cold temperatures are used in cryoablation to chill or freeze cells that conduct abnormal heart rhythms. The catheter removes heat from the tissue to cool it to temperatures as low as -75 °C. This causes localized scarring, which cuts undesired conduction paths.

This is a much newer treatment for supraventricular tachycardia (SVT) involving the atrioventricular (AV) node directly. SVT involving the AV node is often a contraindication for using radiofrequency ablation because of the risk of injuring the AV node, forcing patients to receive a permanent pacemaker. With cryoablation, areas of tissue can be mapped by limited, reversible, freezing (e.g., to -10 C). If the result is undesirable, the tissue can be rewarmed without permanent damage. Otherwise, the tissue can be permanently ablated by freezing it to a lower temperature (e.g., -73 C).

This therapy has revolutionized AV nodal reentrant tachycardia (AVNRT) and other AV nodal tachyarrhythmias. It has allowed people who were otherwise not a candidate for radiofrequency ablation to have a chance at having their problem cured. This technology was developed at The Montreal Heart Institute in the late 1990s. The therapy was successfully adopted in Europe in 2001, and in the US in 2004 following the "Frosty Trial". [6]

In 2004, the technology was pioneered in the midwest United States at Miami Valley Hospital in Dayton, Ohio, by Mark Krebs, MD, FACC, Matthew Hoskins, RN, BSN and Ken Peterman, RN, BSN. These electrophysiology experts were successful in curing the first 12 candidates in their facility.[ citation needed ]

Cryoablation for AVNRT and other arrhythmias do have some drawbacks. A recent study [7] concluded that procedure times are slightly higher on average for cryoablation than for traditional radio-frequency (heat-based) ablations. Also, higher rate of equipment failures were recorded using this technique. Finally, even though short term success rate is equivalent to RF treatments, cryoablation appears to have a significantly higher long term recurrence rate.

Site testing

Cryotherapy is able to produce a temporary electrical block by cooling down the tissue believed to be conducting the arrhythmia. This allows the physician to make sure this is the right site before permanently disabling it. The ability to test a site in this way is referred to as site testing or cryomapping.

When ablating tissue near the AV node (a special conduction center that carries electrical impulses from the atria to the ventricles), there is a risk of producing heart block – that is, normal conduction from the atria cannot be transmitted to the ventricles. Freezing tissue near the AV node is less likely to provoke irreversible heart block than ablating it with heat.

Surgical procedures

As in catheter-based procedures, techniques using heating or cooling temperatures may be used to treat arrhythmias during heart surgery. Techniques also exist where incisions are used in the open heart to interrupt abnormal electrical conduction (Maze procedure). Cryosurgery involves the use of freezing techniques for the treatment of arrhythmias during surgery.

A physician may recommend cryosurgery being used during the course of heart surgery as a secondary procedure to treat any arrhythmia that was present or that may appear during the primary open-chest procedure. The most common heart operations in which cryosurgery may be used in this way are mitral valve repairs and coronary artery bypass grafting. During the procedure, a flexible cryoprobe is placed on or around the heart and delivers cold energy that disables tissue responsible for conducting the arrhythmia.

Vascular malformations

Cryoablation has recently been used to treat low-flow vascular malformations such as venous malformations (VM) and fibroadipose vascular anomalies (FAVA). Cryoablation has proved effective for treating these disorders both as primary treatment and after sclerotherapy. [8]

Cryoimmunotherapy

Cryoimmunotherapy is an oncological treatment for various cancers that combines cryoablation of tumor with immunotherapy treatment. [9] In-vivo cryoablation of a tumor alone can induce an immunostimulatory, systemic anti-tumor response, resulting in a cancer vaccine – the abscopal effect. [10] However, cryoablation alone may produce an insufficient immune response, depending on various factors, such as high freeze rate. Combining cryotherapy with immunotherapy enhances the immunostimulating response and has synergistic effects for cancer treatment. [11]

History

The use of cold for pain relief and as an anti-inflammatory has been known since the time of Hippocrates (460–377 BC). [12] Since then there have been numerous accounts of ice used for pain relief including from the Ancient Egyptians and Avicenna of Persia (AD 982–1070). [13] Since 1899, Dr. Campbell White used refrigerants for treating a variety of conditions, including: lupus erythematosus, herpes zoster, chancroid, naevi, warts, varicose leg ulcers, carbuncles, carcinomas and epitheliomas. De Quervain successfully used of carbonic snow to treat bladder papillomas and bladder cancers in 1917. Dr. Irving S. Cooper, in 1913, progressed the field of cryotherapy by designing a liquid nitrogen probe capable of achieving temperatures of -196 °C, and utilizing it to treat of Parkinson's disease and previously inoperable cancer. Cooper's cryoprobe advanced the practice of cryotherapy, which led to growing interest and practice of cryotherapy. In 1964, Dr. Cahan successfully used his liquid nitrogen probe invention to treat uterine fibroids and cervical cancer. Cryotherapy continued to advance with Dr. Amoils developing a liquid nitrogen probe capable of achieving cooling expansion, in 1967. [14] [15] [16]

With the technological cryoprobe advancements in the 1960s came wider acceptance and practice of cryotherapy. Since the 1960s, liver, prostate, breast, bone, and other cancers have been treated with cryoablation in many parts of the world. Japanese physician Dr. Tanaka began treating metastatic breast cancer with cryoablation in 1968. [17] For the next three decades, Dr. Tanaka successfully treated small and localized as well as advanced and unresectable breast cancer with minimally invasive cryoablation. All of Dr. Tanaka's breast cancer cases were considered incurable: advanced, unresectable, and resistant to radiotherapy, chemotherapy, and endocrine therapy. [17] At the same time, physicians, including Dr. Ablin and Dr. Gage, started utilizing cryoablation for the treatment of prostate and bone cancer. [18] [19] Dr. Paul J. Wang MD and Dr. Peter L. Friedman MD, PhD invented cryoablation for the heart and cardiac arrhythmia in 1988. Their patents were for the cryoablation catheter and cryogenic mapping (US Patents 5147355A and 5423807A).

The 1980s and 1990s saw dramatic advancement in apparatus and imaging techniques, with the introduction of CMS Cryoprobe, and Accuprobe. [20] CT-, MRI-, and ultrasound-guided cryoprobes became available and improved the capabilities of cryoprobes in treatment. Excited by the latest advancements in cryotherapy, China embraced cryotherapy in the 1990s to treat many oncological conditions. [21] With the benefits well-established, the FDA approved the treatment of prostate cancer with cryoablation in 1998. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Bone tumor</span> Medical condition

A bone tumor is an abnormal growth of tissue in bone, traditionally classified as noncancerous (benign) or cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body such as from lung, breast, thyroid, kidney and prostate. There may be a lump, pain, or neurological signs from pressure. A bone tumor might present with a pathologic fracture. Other symptoms may include fatigue, fever, weight loss, anemia and nausea. Sometimes there are no symptoms and the tumour is found when investigating another problem.

<span class="mw-page-title-main">Interventional radiology</span> Medical subspecialty

Interventional radiology (IR) is a medical specialty that performs various minimally-invasive procedures using medical imaging guidance, such as x-ray fluoroscopy, computed tomography, magnetic resonance imaging, or ultrasound. IR performs both diagnostic and therapeutic procedures through very small incisions or body orifices. Diagnostic IR procedures are those intended to help make a diagnosis or guide further medical treatment, and include image-guided biopsy of a tumor or injection of an imaging contrast agent into a hollow structure, such as a blood vessel or a duct. By contrast, therapeutic IR procedures provide direct treatment—they include catheter-based medicine delivery, medical device placement, and angioplasty of narrowed structures.

<span class="mw-page-title-main">Supraventricular tachycardia</span> Abnormally fast heart rhythm

Supraventricular tachycardia (SVT) is an umbrella term for fast heart rhythms arising from the upper part of the heart. This is in contrast to the other group of fast heart rhythms – ventricular tachycardia, which start within the lower chambers of the heart. There are four main types of SVT: atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), and Wolff–Parkinson–White syndrome. The symptoms of SVT include palpitations, feeling of faintness, sweating, shortness of breath, and/or chest pain.

<span class="mw-page-title-main">Cryosurgery</span> Cauterization by freezing tissue

Cryosurgery is the use of extreme cold in surgery to destroy abnormal or diseased tissue; thus, it is the surgical application of cryoablation. The term comes from the Greek words cryo (κρύο) and surgery meaning "hand work" or "handiwork". Cryosurgery has been historically used to treat a number of diseases and disorders, especially a variety of benign and malignant skin conditions.

<span class="mw-page-title-main">Fibroadenoma</span> Medical condition

Fibroadenomas are benign breast tumours characterized by an admixture of stromal and epithelial tissue. Breasts are made of lobules and ducts. These are surrounded by glandular, fibrous and fatty tissues. Fibroadenomas develop from the lobules. The glandular tissue and ducts grow over the lobule to form a solid lump.

<span class="mw-page-title-main">Catheter ablation</span> Removal or termination of an electrical pathway from parts of the heart

Catheter ablation is a procedure used to remove or terminate a faulty electrical pathway from sections of the heart of those who are prone to developing cardiac arrhythmias such as atrial fibrillation, atrial flutter and Wolff-Parkinson-White syndrome. If not controlled, such arrhythmias increase the risk of ventricular fibrillation and sudden cardiac arrest. The ablation procedure can be classified by energy source: radiofrequency ablation and cryoablation.

<span class="mw-page-title-main">Radiofrequency ablation</span> Surgical procedure

Radiofrequency ablation (RFA), also called fulguration, is a medical procedure in which part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from medium frequency alternating current. RFA is generally conducted in the outpatient setting, using either local anesthetics or twilight anesthesia. When it is delivered via catheter, it is called radiofrequency catheter ablation.

The mini-maze procedures are cardiac surgery procedures intended to cure atrial fibrillation (AF), a common disturbance of heart rhythm. They are procedures derived from the original maze procedure developed by James Cox, MD.

Transurethral needle ablation is a technique that uses low energy radio frequency delivered through two needles to ablate excess prostate tissue. A cystoscope/catheter deploys the needles toward the obstructing prostate tissue and is inserted into the urethra directly through the penis under local anesthetic before the procedure begins. The energy from the probe heats the abnormal prostate tissue without damaging the urethra. The resulting scar tissue later atrophies, reducing the size of the prostate which in turn reduces the constriction of the urethra. It can be done with a local anesthetic on an outpatient basis. It takes about an hour to perform the procedure. It takes about 30 days for the ablated prostate tissue to resorb.

Clinical cardiac electrophysiology, is a branch of the medical specialty of cardiology and is concerned with the study and treatment of rhythm disorders of the heart. Cardiologists with expertise in this area are usually referred to as electrophysiologists. Electrophysiologists are trained in the mechanism, function, and performance of the electrical activities of the heart. Electrophysiologists work closely with other cardiologists and cardiac surgeons to assist or guide therapy for heart rhythm disturbances (arrhythmias). They are trained to perform interventional and surgical procedures to treat cardiac arrhythmia.

Pulsed radiofrequency is the technique whereby radio frequency (RF) oscillations are gated at a rate of pulses (cycles) per second (one cycle per second is known as a hertz (Hz)). Radio frequency energies occupy 1.0×104 Hz to 3.0×1011 Hz of the electromagnetic spectrum. Radio frequency electromagnetic energy is routinely produced by RF electrical circuits connected to a transducer, usually an antenna.

Treatment for prostate cancer may involve active surveillance, surgery, radiation therapy – including brachytherapy and external-beam radiation therapy, proton therapy, high-intensity focused ultrasound (HIFU), cryosurgery, hormonal therapy, chemotherapy, or some combination. Treatments also extend to survivorship based interventions. These interventions are focused on five domains including: physical symptoms, psychological symptoms, surveillance, health promotion and care coordination. However, a published review has found only high levels of evidence for interventions that target physical and psychological symptom management and health promotion, with no reviews of interventions for either care coordination or surveillance. The favored treatment option depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors include the man's age, his general health, and his feelings about potential treatments and their possible side-effects. Because all treatments can have significant side-effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations.

<span class="mw-page-title-main">Breast mass</span> Localized swellings that feel different from the surrounding tissue

A breast mass, also known as a breast lump, is a localized swelling that feels different from the surrounding tissue. Breast pain, nipple discharge, or skin changes may be present. Concerning findings include masses that are hard, do not move easily, are of an irregular shape, or are firmly attached to surrounding tissue.

Cryoneurolysis, also referred to as cryoanalgesia, is a medical procedure that temporarily blocks nerve conduction along peripheral nerve pathways. The procedure, which inserts a small probe to freeze the target nerve, can facilitate complete regeneration of the structure and function of the affected nerve. Cryoneurolysis has been used to treat a variety of painful conditions.

Targeted radiofrequency ablation is a minimally invasive procedure to treat severe pain and discomfort caused from metastatic tumors in the vertebral body of the spine. This procedure uses radiofrequency energy to target and ablate a specific spinal tumor, causing it shrink and reduce the pressure on the surrounding nerves and tissues. The procedure minimizes damage to the vertebrae and surrounding tissues. It is used as a palliative therapy rather with the intention of treating the cancer itself.

Interventional oncology is a subspecialty field of interventional radiology that deals with the diagnosis and treatment of cancer and cancer-related problems using targeted minimally invasive procedures performed under image guidance. Interventional oncology has developed to a separate pillar of modern oncology and it employs X-ray, ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) to help guide miniaturized instruments to allow targeted and precise treatment of solid tumours located in various organs of the human body, including but not limited to the liver, kidneys, lungs, and bones. Interventional oncology treatments are routinely carried out by interventional radiologists in appropriate settings and facilities.

Cryoimmunotherapy, also referred to as cryoimmunology, is an oncological treatment for various cancers that combines cryoablation of tumor with immunotherapy treatment. In-vivo cryoablation of a tumor, alone, can induce an immunostimulatory, systemic anti-tumor response, resulting in a cancer vaccine—the abscopal effect. Thus, cryoablation of tumors is a way of achieving autologous, in-vivo tumor lysate vaccine and treat metastatic disease. However, cryoablation alone may produce an insufficient immune response, depending on various factors, such as high freeze rate. Combining cryotherapy with immunotherapy enhances the immunostimulating response and has synergistic effects for cancer treatment.

This is a historical timeline of the development and progress of cancer treatments, which includes time of discovery, progress, and approval of the treatments.

Combinatorial ablation and immunotherapy is an oncological treatment that combines various tumor-ablation techniques with immunotherapy treatment. Combining ablation therapy of tumors with immunotherapy enhances the immunostimulating response and has synergistic effects for curative metastatic cancer treatment. Various ablative techniques are utilized including cryoablation, radiofrequency ablation, laser ablation, photodynamic ablation, stereotactic radiation therapy, alpha-emitting radiation therapy, hyperthermia therapy, HIFU. Thus, combinatorial ablation of tumors and immunotherapy is a way of achieving an autologous, in-vivo tumor lysate vaccine and treating metastatic disease.

Damian E. Dupuy, M.D., F.A.C.R. is an Adjunct Professor of Diagnostic Imaging at Brown University's Warren Alpert Medical School and Director of Ablation services at Cape Cod Hospital. He is also a Member of Cape Cod preferred Physicians.

References

  1. ↑ Callstrom, Matthew R.; Dupuy, Damian E.; Solomon, Stephen B.; Beres, Robert A.; Littrup, Peter J.; Davis, Kirkland W.; Paz-Fumagalli, Ricardo; Hoffman, Cheryl; Atwell, Thomas D. (2013-03-01). "Percutaneous image-guided cryoablation of painful metastases involving bone". Cancer. 119 (5): 1033–41. doi:10.1002/cncr.27793. ISSN   1097-0142. PMC   5757505 . PMID   23065947.
  2. ↑ El Dib, R; Touma, NJ; Kapoor, A (August 2012). "Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-analysis of case series studies". BJU International. 110 (4): 510–16. doi: 10.1111/j.1464-410x.2011.10885.x . PMID   22304329.
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  4. ↑ "fibroadenoma" – via The Free Dictionary.
  5. 1 2 "Cryotherapy Shrinks Benign Breast Lumps". WebMD.
  6. ↑ "Neuigkeiten". Archived from the original on 2013-12-19. Retrieved 2013-12-18.
  7. ↑ Nov. 2010 German CYRANO study (Cryoablation Versus Radiofrequency Energy for the Ablation of Atrioventricular Nodal Reentrant Tachycardia)
  8. ↑ Guevara, Carlos J; Ramaswamy, Raja S; Tiwari, Tatulya; Darcy, Michael D; Kim, Seung K; Akinwande, Olaguoke; Dasgupta, Niloy (2019). "Cryoablation of low-flow vascular malformations". Diagnostic and Interventional Radiology. Aves Yayincilik Ltd. STI. 25 (3): 225–230. doi: 10.5152/dir.2019.18278 . PMC   6521903 . PMID   31063139.
  9. ↑ Sidana Abhinav (2014). "Cancer immunotherapy using tumor cryoablation". Immunotherapy. 6 (1): 85–93. doi:10.2217/imt.13.151. PMID   24341887.
  10. ↑ With improvements in breast imaging and image-guided interventions, there is interest in ablative techniques for breast cancer. Cryosurgery initiates inflammation and leaves tumor-specific antigens intact, which may induce an anti-tumor immune response.Tarkowski R, Rzaca M (2005). "Immunologic response to cryoablation of breast cancer". Gland Surg. 3 (2): 88–93. doi:10.3978/j.issn.2227-684X.2014.03.04. PMC   4115762 . PMID   25083502.
  11. ↑ Haen SP, Pereira PL, Salih HR, Rammensee HG, Gouttefangeas C (2011). "More Than Just Tumor Destruction: Immunomodulation by Thermal Ablation of Cancer". Clin Dev Immunol. 2011: 1–19. doi: 10.1155/2011/160250 . PMC   3254009 . PMID   22242035.
  12. ↑ Cooper (2001). "The History of Cryosurgery". J R Soc Med. 94 (4): 196–201. doi:10.1177/014107680109400416. PMC   1281398 . PMID   11317629.
  13. ↑ Trescott (2003). "Cryoanalgesia in Interventional Pain Management". Pain Physician. 6 (3): 345–60. doi: 10.36076/ppj.2003/6/345 . PMID   16880882.
  14. ↑ Gage AA (1998). "History of cryosurgery". Semin Surg Oncol. 14 (2): 99–109. doi:10.1002/(sici)1098-2388(199803)14:2<99::aid-ssu2>3.0.co;2-1. PMID   9492880.
  15. ↑ Freiman, Anatoli; Bsc, Nathaniel Bouganim (2005). "History of cryotherapy". Dermatology Online Journal. 11 (2): 9. PMID   16150217.
  16. ↑ Cooper SM, Dawber RP (2001). "The history of cryosurgery". J R Soc Med. 94 (4): 196–201. doi:10.1177/014107680109400416. PMC   1281398 . PMID   11317629.
  17. 1 2 Richard J. Ablin (1998). "The Use of Cryosurgery for Breast Cancer". Arch Surg. 133 (1): 106. doi:10.1001/archsurg.133.1.106. PMID   9438770.
  18. ↑ Marcove RC, Miller TR (1969). "The treatment of primary and metastatic localized bone tumors by cryosurgery". Surg Clin North Am. 49 (2): 421–30. doi:10.1016/s0039-6109(16)38799-0. PMID   5774987.
  19. ↑ R. J. Ablin; et al. (1971). "Prospects for Cryo-Immunotherapy in Cases of Metastasizing Carcinoma of the Prostate". Cryobiology. 8 (3): 271–79. doi:10.1016/0011-2240(71)90050-2. PMID   5570410.
  20. ↑ Geisler, Eliezer; Heller, Ori (2012). Management of Medical Technology: Theory, Practice and Cases. p. 281. ISBN   9781461555193.
  21. ↑ Tumor treatment through cryotherapy was first invented by Americans in the 1960s. Aimed at promoting the new technology, the ISC was founded in Austria in 1972. The technology matured with each passing day after over 30 years of development. In recent years, in particular, China, with its greater economic development and scientific and technological progress, has been playing a leading role in the world in terms of both theoretical research and clinical application of cryotherapy. As an efficient medical method for treating tumors, cryotherapy has been adopted by more and more medical institutions in China and has achieved remarkable cancer-treating effectiveness. "China: New Chair of the International Society of Cryosurgery (ISC)". 2015. Archived from the original on 2016-10-20. Retrieved 2016-10-23.
  22. ↑ "Center for Devices and Radiological Health U.S. Food and Drug Administration". Food and Drug Administration .
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