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A Multicenter Study Using Cryoablation for the Palliation of Painful Bone Metastases

Overview

About this study

This study will evaluate the effectiveness of cryoablation for palliation of painful metastases in patients with metastatic lesions involving bone who have failed, are not candidates for, or are not experiencing adequate pain relief from current pain therapies (e.g. radiation, analgesics).

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria

  • 18 years of age or older 
  • Metastatic disease involving bone with metastatic disease previously confirmed by prior biopsy
  • Metastatic disease involving bone previously confirmed on imaging (e.g. CT or MRI) with known (biopsied) primary disease (primary bone cancer is excluded) 
  • Current analgesic therapies have failed, the subject is not a candidate for, OR the subject is not experiencing adequate pain relief from current pain therapies (e.g. radiation, analgesics)
  • The 'worst pain' in the last 24 hours must be reported to be 4 or above on a scale of 0 (no pain) to 10 (pain as bad as subject can imagine) 
  • Pain must be from one painful metastatic lesion involving the bone that is amenable to cryoablation with CT (additional less painful metastatic sites may be present) 
  • Cryoablation should be performed within 14 days of screening visit 
  • If taking hormonal therapy, use should be stable (no changes within 4 weeks prior to the cryoablation procedure) 
  • Karnofsky Performance Scale (KPS) score ≥ 60 
  • Life expectancy ≥ 6 months
  • No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment and follow-up 
  • Known coagulopathy or bleeding disorders are controlled

 

Exclusion Criteria

  • Primary cancer is leukemia, lymphoma, or myeloma 
  • Tumor involves a weight-bearing bone with the tumor causing > 50% loss of cortical bone 
  • Has undergone prior surgery at the tumor site or the index tumor has undergone previous surgery or ablation treatment 
  • Prior radiation therapy of the index tumor < 3 weeks prior to the screening visit 
  • Index tumor causing clinical or radiographic evidence of spinal cord or cauda equina compression/effacement
  • Anticipated treatment of the index tumor that would require iceball formation within 0.5 cm of the spinal cord, brain, other critical nerve structure, large abdominal vessel (possibly achieved with additional maneuvers such as hydrodissection) 
  • Index tumor involves the skull 
  • Currently pregnant, nursing, or wishing to become pregnant during the study 
  • Serious medical illness, including any of the following
    • Uncontrolled congestive heart failure
    • Uncontrolled angina
    • Myocardial infarction
    • Cerebrovascular event within 6 months prior to the screening visit 
  • Concurrent participation in other studies that could affect the primary endpoint

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

Rochester, Minn.

Mayo Clinic principal investigator

Anil Kurup, M.D.

Closed for enrollment

More information

Publications

  • This study sought to describe the results of a single-arm multicenter clinical trial using image-guided percutaneous cryoablation for the palliation of painful metastatic tumors involving bone. Read More on PubMed
  • Cryosurgery is the use of freezing temperatures to elicit an ablative response in a targeted tissue. This review provides a global overview of experimentation in vivo which has been the basis of advancement of this widely applied therapeutic option. The cellular and tissue-related events that underlie the mechanisms of destruction, including direct cell injury (cryolysis), vascular stasis, apoptosis and necrosis, are described and are related to the optimal methods of technique of freezing to achieve efficacious therapy. In vivo experiments with major organs, including wound healing, the putative immunological response following thawing, and the use of cryoadjunctive strategies to enhance cancer cell sensitivity to freezing, are described. Read More on PubMed
  • In oncological patients, life quality can be greatly impaired by the presence of painful bone metastases, as standard forms of treatment often achieve inadequate palliation. The aim of our study was to evaluate the clinical efficacy of radiofrequency ablation (RFA) with respect to pain relief in patients with refractory bone metastases or who are ineligible to conventional treatments. Read More on PubMed
  • Pain palliation can be challenging in patients with metastases to the musculoskeletal system, and conventional therapy can be less than optimal for pain management. Recent advances in technology have allowed for the addition of image-guided ablation to the armamentarium for treating musculoskeletal metastases. This article focuses on one such technique, percutaneous cryoablation, and the experiences with this technique at the authors' institution. After a brief review of the history and theory behind cryoablation, the basic technique of percutaneous cryoablation of musculoskeletal metastases is described. This is followed by a review of the cases that have been performed at the authors' institution. A discussion on the many advantages and relatively few disadvantages of this exciting new technique is then put forth. Percutaneous cryoablation is beginning to emerge as a useful method of image-guided ablation of musculoskeletal metastases. As data continue to mount on this exciting application of new technology, image-guided cryoablation of musculoskeletal metastases appears to hold much promise in the treatment of pain related to these lesions. Read More on PubMed
  • Thermal ablation can be applied to treat any thoracic malignancy: primary lung cancers, recurrent primary lung cancers, metastatic disease, chest wall masses, and painful, bony metastases. Since the first reported use of thermal ablation for lung cancer in 2000 there has been an explosive use of the procedure, and by 2010 the number of procedures to treat thoracic malignancy is expected to exceed 150,000 per year. Presently, thermal ablation is best used for patients with early-stage lung cancers in patients who are not surgical candidates, patients with small and favorably located pulmonary metastases, and patients in whom palliation of tumor-related symptoms is the goal. Radiofrequency ablation, microwave ablation, and cryoablation are novel treatment modalities for lung cancer and can safely accomplish tumor destruction and even complete eradication of tumor in patients who are not candidates for surgical resection. In this article, we discuss technical considerations for each modality and the periprocedure and postprocedure management of patients with this disease. Read More on PubMed
  • Painful skeletal metastases are a common problem in cancer patients. Although external beam radiation therapy is the current standard of care for cancer patients who present with localized bone pain, 20 to 30% of patients treated with this modality do not experience pain relief and few further options exist for these patients. For many patients with painful metastatic skeletal disease, analgesics remain the only alternative treatment option. Recently, image-guided percutaneous methods of tumor destruction have proven effective for treatment of this difficult problem. Patient selection, treatment methods, and results of treatment are described for the use of percutaneous radiofrequency ablation and cryoablation for patients with painful metastatic disease. Read More on PubMed
  • To prospectively determine the safety and effectiveness of percutaneous cryoablation for the reduction of pain, improvement in the activities of daily life, and reduction in the use of analgesic medications for patients with painful metastatic lesions involving bone. Read More on PubMed
  • Pain is prevalent for large numbers of patients with metastatic cancer, and this pain is often due to bone metastases. Despite the availability of effective pain treatments and various pain management guidelines, multiple studies document the undertreatment of pain in patients with cancer. The most frequently identified barriers to appropriate pain management are physician underestimation of the patient's pain, inadequate pain assessment, and patient reluctance to report pain. A first step toward reducing inadequate pain control in clinical practice is adequate assessment of cancer pain using validated pain measurement instruments. Using treatment for bone pain as an example, we discuss how patient satisfaction measures and self-report measures of pain and other symptoms, symptom interference with patient function, and related adverse effects can be combined with appropriate trial design to provide the information needed to choose the best possible treatment for bone pain. Symptom assessment needs to be done via standardized questionnaires, administered at appropriate times during the trial. The Brief Pain Inventory uses 11-point numerical rating scales to measure both pain severity and the resulting functional interference caused by pain. These severity and interference ratings can be further categorized as mild, moderate, or severe, as required to implement most pain management guidelines and define outcome expectations for clinical trials. Consistent pain measurement and standardized recording of analgesic use across clinical trials would enhance comparability and increase the chances that treatment decisions for management of bone pain could be evidence based. These and other considerations in the design of clinical trials are discussed. Read More on PubMed
  • Many percutaneous image-guided ablative techniques have been utilized in the treatment of bone cancers. These techniques are fast becoming a focus in the treatment of patients with both benign and malignant forms of bone cancer. This article will review the principles of radiofrequency ablation including its use in combination with other therapies, cryoablation, and microwave ablation in the treatment of osteoid osteomas and bone metastases. Read More on PubMed
  • Few options are available for pain relief in patients with bone metastases who fail standard treatments. We sought to determine the benefit of radiofrequency ablation (RFA) in providing pain relief for patients with refractory pain secondary to metastases involving bone. Read More on PubMed
  • Cryosurgery is the in situ ablation of a target tissue by application of extreme cold temperature. The ability of cryosurgery to ablate tissue is unquestioned. It is the controlled application of a cryoinjury in a manner to minimize morbidity that is problematic. Prostate cryosurgery is complicated by the proximity of the prostate to adjacent structures that are sensitive to a freeze injury, namely the urethra, rectal wall, and neurovascular bundles. Several recent technological advances have led to the development of an effective treatment protocol with acceptable morbidity. These include the advent of real-time transrectal ultrasound, cryomachines with almost instant freeze-thaw control through the use of the Joule-Thompson effect, and warming catheters to effectively preserve the integrity of the urethra and external sphincter. Further, temperature monitoring at the posterior margin of the prostate sometimes combined with an injection of saline solution into Denonvilliers fascia has reduced the occurrence of urethrorectal fistula formation to 0% to 0.5% in modern series. We review the key innovations of prostate cryosurgery that differentiate this state-of-the-art procedure from that used by early investigators to even that of the early 1990s. Potential future innovations, specifically related to image guidance of the procedure, are also addressed. Read More on PubMed
  • To determine the safety and efficacy of radio-frequency (RF) ablation for pain reduction, quality of life improvement, and analgesics use reduction in patients with skeletal metastases. Read More on PubMed
  • Radiotherapy is used commonly to provide pain relief for painful bone metastases, and there is a perception that of the three-quarters of patients who achieve pain relief, half of these stay free from pain. However, the precise contribution from radiotherapy may be unclear because of difficulties in assessing the numbers of people achieving relief, the extent of relief and its duration, and the influence of other contemporaneous interventions, such as analgesics. Read More on PubMed
  • Metastatic bone disease develops as a result of the many interactions between tumor cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signaling mechanisms involved in cancer-induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and its use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases. Read More on PubMed
  • Cryosurgical treatment of unresectable hepatic malignancies has proven beneficial in adults. Concerns regarding its use in children include the effect on growth and the risk of injury to adjacent structures. To test the effect of cryoablation on adjacent vascular structures in a growing animal, liquid nitrogen cryoablation was performed on a juvenile murine model. Sprague Dawley rats underwent double freeze-thaw cryoablation of the abdominal aorta with interposed liver tissue. Serial sacrifices were performed over 120 days. Comparisons were made with sham-operated controls. Overall, animal growth paralleled that of sham controls through all time points. Gross examination of aortic diameter also showed similar growth in vessel size between the groups. Histologic analysis demonstrated injury after cryoablation with smooth muscle cell vacuolization, followed by cell death. Aortic media layer collapse resulted from cellular loss, however, elastin fiber composition was maintained. Aortic patency was preserved despite evidence of cellular injury and aortic wall remodeling. An associated thermal sink effect on the opposing wall was identified. After cryoablation adjacent to the abdominal aorta in adolescent rats, vascular patency is maintained and animal growth and structural function is preserved, despite cellular injury and wall compression. These observations suggest that cryoablation may be a useful treatment adjunct in young subjects. Read More on PubMed
  • Advances in the technology of cryomachines in the last 10 years have led to the development of both liquid nitrogen and argon-based Joule-Thompson cryomachines. Theoretical and practical evaluation of the CMS Accuprobe and the ENDOcare CRYOcare was performed as respective examples of these technologies. Read More on PubMed
  • Carcinoma of the lung is the commonest cause of death from malignant disease in humans. At diagnosis, about 85% of patients are in an advanced stage of the disease and approximately 30% present with a tumour blocking a large bronchial lumen, causing distressing and life threatening symptoms. Early reopening and treatment of the blocked airways is required to improve symptoms and quality of life. There are a number of methods available to achieve this aim including cryotherapy, the controlled application of extreme cold. Read More on PubMed
  • During liver cryosurgical procedures, the authors observed seriously inconsistent rates of iceball growth implying inconsistent probe cooling rates. This inconsistency can lead to several problems, most importantly, loss of precision and reliability in freezing the chosen volume of tissue. The observation led to investigation of the performance of the cryosurgery machine. Read More on PubMed
  • To evaluate the experiences of women who underwent laparoscopic leiomyoma coagulation (myolysis) alone and those who had myolysis in conjunction with transcervical endomyometrial resection (TEMR), transcervical electrosurgical resection of submucous leiomyomas (TSR), or both. Read More on PubMed
  • This study was designed to evaluate the safety and efficacy of renal cryotherapy as a possible treatment of renal malignancy with preservation of renal parenchyma. Read More on PubMed
  • A new liquid-nitrogen-based apparatus for minimally invasive cryosurgery is presented. The cryoprobe was designed for application to breast tumors; however, it can be used for the treatment of other tumors. The cryoprobe has three major components, a cryoneedle, a thermal insulation shell, and a protective tube, which may be assembled as part of the operation. This special assembly keeps destruction to surrounding tissues due to cryoprobe penetration minimal, and allows accurate localization of the cryoprobe tip by means of stereotactic or needle-localization techniques. An alternative cryoprobe consists of a cryoneedle and a thermal insulation shell, which are rigidly connected. The liquid nitrogen supply system has two major components, an air-pressure source and a liquid nitrogen container, which are physically separated. This special configuration allows placement of the liquid nitrogen container adjacent to the cryotreated tissue and decreases the length of the cryoprobe feeding tube. In turn, heat losses to the surroundings are reduced, and therefore coolant consumption is reduced. The short feeding tube allows safe operation at low pressures. The small size of the apparatus makes it attractive for cryosurgical operations. It has been evaluated in gelatin solutions and in porcine skeletal muscle and liver. In-vivo results do not differ significantly from those obtained in gelatin solutions with regard to the dimensions of frozen regions. Using a three cryoprobe configuration, a frozen region with an average diameter of 50 mm and a length of 75 mm was obtained within 11 minutes. The thermal efficiency of that procedure was found to be 43%. Read More on PubMed
  • A new cryosurgical device was developed in this study to facilitate examination of factors affecting the outcome of cryotreatment. Special emphasis was placed on the control of the cooling rate at the freezing front. In the new computer-controlled cryosurgical device, the controlling variable is the cryoprobe temperature, which is calculated to ensure prespecified cooling rates at the freezing front. Details of the new cryodevice, results of a validation test, and the system characteristics are presented in Part I of this study. In this part of the study initial results of 13 in vivo experimental cryotreatments, including histological observations, are presented. The in vivo pilot investigations include the normal, healthy skin and the underlying skeletal muscle of the thighs in rabbits. Using low cooling rate-controlled freezing, the new cryosurgical device is demonstrated here as an effective surgical tool. An in vivo temperature measurement technique is employed based on miniature thermocouples and X-ray images. Thermal analysis of the heat transfer in the cryotreated tissue is presented, based on the temperature measurements and on numerical heat transfer simulations. Cryotreated tissue was extracted either immediately or 4 or 7 days following the procedure. The histological observations on the skeletal muscle of the 4- and 7-day postcryoinjury were not substantially different. The effective penetration depth of the cryolesion was in the range of 5-15 mm, possibly extending up to 25 mm, depending on the specific area treated and operating parameters. The cryotreatment resulted in complete destruction of cells in the skin followed by rapid replacement by epithelial cells. Histological responses to cryotreatment of skeletal muscle were similar to those resulting from a range of traumatic episodes, e.g., crush damage. It was also found that most of the blood vessels in the cryotreated region remained intact without histological evidence of extravasation of erythrocytes. Read More on PubMed
  • Cryotherapy is the therapeutic application of extreme cold for local destruction of living tissue. This technique has been shown to be effective and safe in treating endobronchial lesions, particularly in patients with endobronchial carcinoma and airway obstruction. This article describes cryotherapy and its use in treating tracheobronchial disorders. Read More on PubMed
  • For specification of the requirements for efficient cell cryodestruction in tumors, we tested a N2O-driven cryoprobe on experimental models. The cryoprobe was a 3-mm-diameter type for operation via fiber optic bronchoscopes in respiratory medicine. The freezing process, namely the "ice-ball" formation around the cryoprobe tip, was monitored with an impedancemeter. Physical characteristics and formation kinetics of the ice-ball formation (volume, diameter, freezing rate) were studied under defined experimental conditions in various biological liquids, including saline, serum, whole blood, and tumor cell suspensions (rat ascitic hepatoma), either plain or supplemented with gelling agents to approximate solid tumor consistency. Cell destruction (i.e., cryotoxicity to cells) within the ice ball produced in rat ascitic hepatoma was assessed in two ways: the cells, collected after ice-ball thawing, were (1) seeded and cultured according to methods currently in use, or (2) injected into a rat to check for possible development of ascites. Both tests showed that cryotoxicity correlated with freezing rate within the ice ball, cell mortality was total next to the cryoprobe tip (i.e., site of highest freezing rate), while it was absent within the ice-ball periphery. In the area in between, mortality varied gradually. Together our experimental results show that cryotoxicity to cells may be improved by increasing the freezing rate (e.g., by brief precooling of the cryoprobe). Furthermore, for tumor cryosurgery, since cell mortality is maximal next to the cryoprobe, we point out that higher efficacy might be achieved by several overlapping short freezing spots in tumoral tissue, instead of one single prolonged freeze. Read More on PubMed
  • A hand-held fully electrically powered and programmable cryoprobe for general-purpose cryosurgery and cryotherapy has been developed. By combining the technologies of thermoelectric cooling and heat pipes, the temperature at the tip of the probe can easily reach -50 to -60 degrees C. It can hold below -40 degrees C when it cools a load of 10 W at the tip. Previous efforts developing cryoprobes made of thermoelectric modules have been hindered by the inherent characteristics of commercially available thermoelectric coolers: low efficiency, size and inflexible shape and very sensitive to heat intensity and thermal insulation. Matching thermoelectrics with heat pipes uses the advantages of both technologies. In the cryoprobe the heat pipe is used to focus and transport the cooling power of multi-thermoelectric modules. The heat flux for the thermoelectric modules is reduced and their efficiencies are increased. The transport of heat by a heat pipe also allows flexible access to treated spots of patients. Read More on PubMed
  • The Nd:YAG laser dispersion effect, 2-5 mm in diameter, is utilized in a new laparoscopic procedure to coagulate and reduce symptomatic serosal and intramural myomas of moderate size (less than or equal to 10 cm). Depot leuprolide pretreatment for 2-6 months resulted in 40-60% shrinkage. Seventy-five patients 35-50 years old with symptomatic myomas, pain and pressure then underwent Nd:YAG laser coagulation for thorough devascularization of uterine myomas. Postoperative transvaginal ultrasound one, three and six months later showed the myomas reduced an average of 50-70% beyond the effect attributable to leuprolide. In two groups of patients whose myomas measured 5-10 cm and 3-5 cm after leuprolide pretreatment, laser coagulation subsequently reduced the myomas an average of 50%. In patients with postleuprolide myomas of 2-3 cm, virtually no myomas were identified postoperatively. The patients were followed up to 14 months. This laparoscopic procedure can be used in patients approaching menopause who wish to avoid abdominal myomectomy or hysterectomy. Read More on PubMed
  • The Workshop on Cryosurgery at the 28th Annual Meeting of the Society for Cryobiology contained a diversity of papers which fairly represented the present state of cryosurgery in medical practice and which identified directions for future research. Emphasis was clearly on the development of visceral cryosurgery, which appears likely to become of increased clinical importance as a result of combination with ultrasound imaging techniques. This report reviews in brief the important new developments in cryosurgery and focuses on those presentations which were of special interest from the viewpoint of research in cryosurgery. Read More on PubMed
  • The 4-day sessions of the Eighth Annual Meeting of the American College of Cryosurgery in New Orleans, February 18-21, 1988, provided an intense overview of the position of cryosurgery in modern day medical practice. The variety of speakers demonstrated that interest in the therapeutic technique of cryosurgery remains high and that usage is greater, more diversified, and more selective than in past years. Emphasis at the meeting was placed on the selective use of cryosurgery, that is, defining the terms under which the physician would choose between diverse methods of local therapy, such as excision, electrosurgery, laser surgery, and cryosurgery. Most of the presentations were oriented clinically with emphasis on the results of cryosurgery. This brief report is intended to mention the important new developments in cryosurgery and to focus on some of the issues and needs that affect the future of the technique. Read More on PubMed
  • The effects of cryosurgical procedures and surgical excision in preventing the local recurrence of mammary adenocarcinoma were studied in BALB/cfC3H mice carrying syngeneic, virus-induced mammary adenocarcinomas transplanted into the fourth mammary fat pad. In this report we present evidence demonstrating that cryosurgical procedures involving multiple freeze-thaw cycles followed by tumor excision markedly reduce the local recurrence rate of mouse mammary cancer. Surgical resection without cryotreatment resulted in an 80% local recurrence rate; in contrast, cryotreatment consisting of three freeze-thaw cycles before excision prevented local tumor recurrence in 70% of the animals. The use of cryotherapy and local excision (cryolumpectomy) in the treatment of human breast cancer is discussed. Read More on PubMed
  • Six different freezing/thawing programs, which varied freezing rate, duration of freezing, and thawing rates, were used to investigate the effect of these factors on cell destruction in dog skin. The range of tissue temperatures produced was from -15 to -50 degrees C. The extent of destruction was evaluated by skin biopsies 3 days after cold injury. In single, short freezing/thawing cycles, the temperature reached in the tissue was the prime factor in cell death. Longer freezing time and slow thawing were also important lethal factors which increased destruction of cells. Cooling rate, whether slow or fast, made little difference in the outcome. The experiments suggested that present-day, commonly employed cryosurgical techniques, which feature fast cooling, slow thawing, and repetition of the freeze/thaw cycle, should be modified by the use of maintenance of the tissue in the frozen state for several minutes and slow thawing. Thawing should be complete before freezing is repeated. These modifications in technique will maximize tissue destruction, an important consideration in cancer cryosurgery. Read More on PubMed
  • Bronchoscopic cryotherapy of localized endobronchial tumors can be applied in selected patients who are not candidate for other traditional therapy. Twenty-eight patients were treated on 60 occasions with a closed liquid nitrogen system and a long insulated probe that was specifically designed to be used through an open ventilating bronchoscope. The conditions of 15 patients (54%) was improved, as judged by local tumor control, decreased bleeding, or improved airway patency. Fatal complications that could be ascribed to cryotherapy occurred in 2 of the 60 treatments (3%). Two patients have experienced complete control of squamous cell cancers four years and five years nine months after cryotherapy. Read More on PubMed
  • Human red cells were equilibrated for 30 min at 20degreesC in buffered saline containing 2 M glycerol and then frozen to --196degreesC at 0.27, 1.7, 59, 180, 480, 600, and 1300degreesC/min and warmed at 0.47, 1, 26, 160, and 550degreesC/min. Cells frozen at 600 and 1300degreesC/min responded in the classical fashion for cells containing intracellular ice; i.e., survivals were low when warming was slow (less than 10%), but increased progressively with increasing warming rate. The sensitivity to slow warming presumably reflects the recrystallization of intracellular ice. Cells frozen at 59 and 180degreesC/min yielded high survivals at all warming rates. This response is also consistent with the findings for other cells cooled just slowly enough to preclude intracellular ice. Cells frozen very slowly at 0.27 and 1.7degreesC/min, however, responded differently; survivals were considerably higher when warming was slow (0.47 or 1degreesC/min) than when it was 26, 160, or 550degreesC/min. This response is analogous to that observed recently by others in mouse embryos and in higher plant tissue-culture cells and to that observed for many years in higher plants. It also confirms previous observations of Meryman in human red cells. It may reflect osmotic shock from rapid dilution but, if so, the basis of the osmotic shock is uncertain. Read More on PubMed

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