Evaluation of the impedance technique for cryosurgery in a theoretical model of the head

Bioimpedance is a noninvasive technique that produces information on the electrical characteristics of tissue inside the body from currents injected and electrical potentials measured on the surface of the body. Because freezing causes a large increase in tissue electrical impedance we thought that it may also cause significant changes in the surface electrical potential making the bioimpedance technique suitable for noninvasive monitoring and imaging of cryosurgery. To evaluate the feasibility of the bioimpedance technique in cryosurgery we examined, as a case study, a theoretical model for the electrical potentials during brain cryosurgery. A three-dimensional spherical model was used to calculate the change in the electrical potential distribution in the head as a function of the current source location and the size of the frozen lesion in the brain. The numerical calculations were executed using the finite volume method and the iterative successive over relaxation method. The results demonstrate that, indeed, freezing inside the head produces measurable changes in the electrical potential on the outer surface-the scalp.     

Cyclophosphamide pretreatment in tumor cryotherapy: A murine model

Following the protocol of Turk and Lagrange for selective potentiation of cell-mediated immunity, a single high dose of cyclophosphamide was given to inbred mice bearing subcutaneous tumors 3 days before cryosurgery. Cyclophosphamide pretreatment caused a rise in the rate of total tumor ablation and local recurrence was delayed. The dose response to tumor size, cyclophosphamide, and freeze parameters indicated that these effects were the result of synergistic rather than additive processes. Instances of metastatic tumor growth and immunologically mediated complications of cryosurgery were also lower when the cryosurgery was accompanied by cyclophosphamide pretreatment.     

Hair follicle destruction and regeneration in guinea pig skin after cutaneous freeze injury

We have investigated the histological changes in hair follicles in guinea pig skin after standardized moderate and severe cryosurgery injuries. Hair follicles were permanently destroyed by cryosurgery, but more than one mechanism may be operative during follicle destruction and shedding. The mechanism depends upon the severity of the freeze. After a light freeze injury, the changes are predominantly within the hair follicle. The hair is shed at the surface and there is selective autolysis of follicular cells, but dermal connective tissue is preserved and there is little surrounding damage. However, after a severe cryoinjury as used in "tumor doses," there is destruction of dermal connective tissue and dermal scarring. The necrotic dermis is shed, taking with it the dead follicles and morphologically normal elastic tissue.     

Experimental cryosurgery on bone: A light and electron microscopical investigation

Three rabbits were treated with cryosurgery on the lateral surface of the mandible. Osteocytes with normal appearance were not detected in the cortex after 2 or 7 days following cryosurgery. In the marrow cavity, cells appeared more resistant and often showed a normal morphology as studied with both light and electron microscopy. The reason why cells survived in the marrow cavity is probably due to a combination of sheltering bone and the near proximity to an intact circulation due to a patent alveolar artery.The uncertain extension of the cold front beyond the cortex may indicate that cryosurgery alone is not suitable if a tumor has invaded the marrow cavity, while more superficially located tumors can be eradicated. However, tumor invasion itself destroys the cortex and thus the marrow cavity will be more readily exposed to the more extensive cryosurgical techniques used in clinical cryosurgery.     

Two-phase computerized planning of cryosurgery using bubble-packing and force-field analogy

BACKGROUND: Cryosurgery is the destruction of undesired tissues by freezing, as in prostate cryosurgery, for example. Minimally invasive cryosurgery is currently performed by means of an array of cryoprobes, each in the shape of a long hypodermic needle. The optimal arrangement of the cryoprobes, which is known to have a dramatic effect on the quality of the cryoprocedure, remains an art held by the cryosurgeon, based on the cryosurgeon's experience and "rules of thumb." An automated computerized technique for cryosurgery planning is the subject matter of the current paper, in an effort to improve the quality of cryosurgery. METHOD OF APPROACH: A two-phase optimization method is proposed for this purpose, based on two previous and independent developments by this research team. Phase I is based on a bubble-packing method, previously used as an efficient method for finite element meshing. Phase II is based on a force-field analogy method, which has proven to be robust at the expense of a typically long runtime. RESULTS: As a proof-of-concept, results are demonstrated on a two-dimensional case of a prostate cross section. The major contribution of this study is to affirm that in many instances cryosurgery planning can be performed without extremely expensive simulations of bioheat transfer, achieved in Phase I. CONCLUSIONS: This new method of planning has proven to reduce planning runtime from hours to minutes, making automated planning practical in a clinical time frame.     

Cryosurgery of pulmonary metastases.

Indications and results of 33 cryosurgical interventions for metastatic tumors in the lung are presented. Regression of local and metastatic pulmonary growth on the contralateral side was observed in four cases. Nine cases showed temporary halt of metastatic pulmonary tumor growth. The technique of cryosurgery for pulmonary metastases is reviewed. The procedure of cryosurgery of pulmonary metastases was found to be an innocuous method to attempt both tumor destruction and eventually specific immunologic stimulation. Preliminary observations with the lymphocytes and sera indicate that cryosurgery of pulmonary metastases induces an increase in specific cell mediated immune response without producing blocking serum factors and may give rise to specific, complement dependent cytotoxic antibodies. In one case both mechanisms were observed after cryotherapy. In three cases with progressive disease, lymphocyte mediated cytotoxicity alone was stimulated.     

Cryosurgery with pulsed electric fields

This study explores the hypothesis that combining the minimally invasive surgical techniques of cryosurgery and pulsed electric fields will eliminate some of the major disadvantages of these techniques while retaining their advantages. Cryosurgery, tissue ablation by freezing, is a well-established minimally invasive surgical technique. One disadvantage of cryosurgery concerns the mechanism of cell death; cells at high subzero temperature on the outer rim of the frozen lesion can survive. Pulsed electric fields (PEF) are another minimally invasive surgical technique in which high strength and very rapid electric pulses are delivered across cells to permeabilize the cell membrane for applications such as gene delivery, electrochemotherapy and irreversible electroporation. The very short time scale of the electric pulses is disadvantageous because it does not facilitate real time control over the procedure. We hypothesize that applying the electric pulses during the cryosurgical procedure in such a way that the electric field vector is parallel to the heat flux vector will have the effect of confining the electric fields to the frozen/cold region of tissue, thereby ablating the cells that survive freezing while facilitating controlled use of the PEF in the cold confined region. A finite element analysis of the electric field and heat conduction equations during simultaneous tissue treatment with cryosurgery and PEF (cryosurgery/PEF) was used to study the effect of tissue freezing on electric fields. The study yielded motivating results. Because of decreased electrical conductivity in the frozen/cooled tissue, it experienced temperature induced magnified electric fields in comparison to PEF delivered to the unfrozen tissue control. This suggests that freezing/cooling confines and magnifies the electric fields to those regions; a targeting capability unattainable in traditional PEF. This analysis shows how temperature induced magnified and focused PEFs could be used to ablate cells in the high subzero freezing region of a cryosurgical lesion.     

Numerical simulation of selective freezing of target biological tissues following injection of solutions with specific thermal properties

Recently, we proposed a method for controlling the extent of freezing during cryosurgery by percutaneously injecting some solutions with particular thermal properties into the target tissues. In order to better understand the mechanism of the enhancement of freezing by these injections, a new numerical algorithm was developed to simulate the corresponding heat transfer process that is involved. The three-dimensional phase change processes in biological tissues subjected to cryoprobe freezing, with or without injection, were compared numerically. Two specific cases were investigated to illustrate the selective freezing method: the injection of solutions with high thermal conductivity; the injection of solutions with low latent heat. It was found that the localized injection of such solutions could significantly enhance the freezing effect and decrease the lowest temperature in the target tissues. The result also suggests that the injection of these solutions may be a feasible and flexible way to control the size of the ice ball and its direction of growth during cryosurgery, which will help to optimize the treatment process.     

Analysis of thermal stress in cryosurgery of kidneys

In this study, the thermal stress distribution in cryosurgery of kidney was investigated using a multiphysics finite element model developed in ANSYS (V8.1). The thermal portion of the model was verified using experimental data and the mechanics portion of the model (elastic) was verified using classic analytical solutions. Temperature dependent thermal and mechanical properties were used in the model. Moreover, the model accounts for thermal expansion due to both thermal expansion in single phase and volumetric expansion associated with phase change of tissue water to ice. For a clinical cylindrical cryoprobe inserted into the renal cortex from the top-middle renal capsule, it was found that the thermal stress distributions along the radial position are very different at different depths from the top renal capsule. The thermal stress is much higher at both ends than in the middle of the cryoprobe surface. It was found that there might be more tissue next to the top renal capsule than other region undergoing microcrack formation or plastic deformation. Furthermore, it was found that macrocrack formation is more likely to occur in tissue adjacent to the cryoprobe surface (especially on the sharp point tip) and during the thawing phase of cryosurgery. It was further found that the volumetric expansion associated with phase change induced much higher thermal stress than thermal expansion in a single phase and might therefore be the main cause of the frequently observed crack formation shortly after initiation of thawing in cryosurgery. Because the thermal stress adjacent to the cryoprobe is much higher than the yield stress of frozen renal tissue, a plastic stress model is required for better modeling of the thermal stress distribution in cryosurgery of kidney in future. However the computational effort will then be drastically increased due to the strong nonlinear nature of the plastic model and more experimental studies are indispensable for better understanding of the mechanical behavior of frozen tissue in cryosurgery.     

Cryosurgical nitrogen apparatus and recent results of its application in the radical treatment of certain neoplasms

In recent years a rapid development of equipment for controlled local freezing of tissues for cryosurgery has occurred. Depending on the velocity of freezing and on the technical parameters of the apparatus, diverse spreading of the ice front and tissue destruction are observed. The Research Centre of Medical Technology in Warsaw designed and produced an apparatus for cryosurgery, which was used in the Institute of Oncology in Warsaw for the radical treatment of skin, mucous membranes, and lip neoplasms. In the years 1973 to 1975 this technique was applied in 221 cases. In 167 patients radical treatment was performed (Group A); in 31 patients the treatment was paliativc (Group B); and in 23 patients non-neoplastic growths of the skin were treated (Group C). The present work concerns the results observed in Group A, where the mean duration of follow-up observations was 11 months. For the analysis of recent results of cryosurgery a subgroup was chosen from the Group A patients, i.e., those for whom the follow-up lasted at least 24 months (32 cases). The observations demonstrated that the apparatus is useful and simple to handle. In the clinical groups T₁, T₂, N₀, and M₀ the recent results of cryosurgery were similar to those observed with other types of treatment. Cryosurgical treatment is painless, is without blood loss, and is easy to perform. The period of healing is not longer than 3 weeks, and the cosmetic effect is good. General debilitation and the patient's age do not serve as counterindications to the performance of such treatment.     

Temperature field reconstruction for minimally invasive cryosurgery with application to wireless implantable temperature sensors and/or medical imaging

There is an undisputed need for temperature-field reconstruction during minimally invasive cryosurgery. The current line of research focuses on developing miniature, wireless, implantable, temperature sensors to enable temperature-field reconstruction in real time. This project combines two parallel efforts: (i) to develop the hardware necessary for implantable sensors, and (ii) to develop mathematical techniques for temperature-field reconstruction in real time—the subject matter of the current study. In particular, this study proposes an approach for temperature-field reconstruction combining data obtained from medical imaging, cryoprobe-embedded sensors, and miniature, wireless, implantable sensors, the development of which is currently underway. This study discusses possible strategies for laying out implantable sensors and approaches for data integration. In particular, prostate cryosurgery is presented as a developmental model and a two-dimensional proof-of-concept is discussed. It is demonstrated that the lethal temperature can be predicted to a significant degree of certainty with implantable sensors and the technique proposed in the current study, a capability that is yet unavailable.     

Temperature field reconstruction for minimally invasive cryosurgery with application to wireless implantable temperature sensors and/or medical imaging

There is an undisputed need for temperature-field reconstruction during minimally invasive cryosurgery. The current line of research focuses on developing miniature, wireless, implantable, temperature sensors to enable temperature-field reconstruction in real time. This project combines two parallel efforts: (i) to develop the hardware necessary for implantable sensors, and (ii) to develop mathematical techniques for temperature-field reconstruction in real time—the subject matter of the current study. In particular, this study proposes an approach for temperature-field reconstruction combining data obtained from medical imaging, cryoprobe-embedded sensors, and miniature, wireless, implantable sensors, the development of which is currently underway. This study discusses possible strategies for laying out implantable sensors and approaches for data integration. In particular, prostate cryosurgery is presented as a developmental model and a two-dimensional proof-of-concept is discussed. It is demonstrated that the lethal temperature can be predicted to a significant degree of certainty with implantable sensors and the technique proposed in the current study, a capability that is yet unavailable.     

Pre-conditioning cryosurgery: cellular and molecular mechanisms and dynamics of TNF-α enhanced cryotherapy in an in vivo prostate cancer model system

Cryosurgery is increasingly being used to treat prostate cancer; however, a major limitation is local recurrence of disease within the previously frozen tissue. We have recently demonstrated that tumor necrosis factor alpha (TNF-α), given 4h prior to cryosurgery can yield complete destruction of prostate cancer within a cryosurgical iceball. The present work continues the investigation of the cellular and molecular mechanisms and dynamics of TNF-α enhancement on cryosurgery. In vivo prostate tumor (LNCaP Pro 5) was grown in a dorsal skin fold chamber (DSFC) on a male nude mouse. Intravital imaging, thermography, and post-sacrifice histology and immunohistochemistry were used to assess iceball location and the ensuing biological effects after cryosurgery with and without TNF-α pre-treatment. Destruction was specifically measured by vascular stasis and by the size of histologic zones of injury (i.e., inflammatory infiltrate and necrosis). TNF-α induced vascular pre-conditioning events that peaked at 4h and diminished over several days. Early events (4-24 h) include upregulation of inflammatory markers (nuclear factor-κB (NFκB) and vascular cell adhesion molecule-1 (VCAM)) and caspase activity in the tumor prior to cryosurgery. TNF-α pre-conditioning resulted in recruitment of an augmented inflammatory infiltrate at day 3 post treatment vs. cryosurgery alone. Finally, pre-conditioning yielded enhanced cryosurgical destruction up to the iceball edge at days 1 and 3 vs. cryosurgery alone. Thus, TNF-α pre-conditioning enhances cryosurgical lesions by vascular mechanisms that lead to tumor cell injury via promotion of inflammation and leukocyte (esp. neutrophil) recruitment.     

Cryoprotective therapy for huge hepatocellular carcinoma: A study of 14 patients with a single lesion

Percutaneous cryoablation is a potential cure for hepatocellular carcinoma (HCC). This study reviewed retrospectively clinical data from 14 patients who underwent cryoablation of huge HCC (long diameter >7 cm). The side effects of cryosurgeries and liver function reverse were recorded and compared everyday. All the patients survived cryosurgery and none died before leaving hospital 2 weeks later. Despite liver-protective treatment before cryosurgery, alanine transaminase (ALT) and aspartate transaminase (AST) levels were increased significantly, but returned to preoperative levels 2 weeks post-cryosurgery. Before cryosurgery, mean total bilirubin (T.BIL) and direct bilirubin (D.BIL) levels were normal; 8–10 days after cryosurgery, they increased more than two-fold, but returned to the preoperative level 2 weeks post-cryosurgery. Serum transaminase and bilirubin levels were compared between hepatitis B positive and negative patients. The hepatitis B negative group’s AST level increased significantly 1 day post-cryosurgery (mean, 186 U/L) and decreased to the preoperative level at day 14. In the hepatitis B positive group, means transaminase and bilirubin reached peak values at different days post-cryosurgery. Overall, ALT and AST are valuable indicators of liver function impairment following cryosurgery. In patients with hepatitis B virus, close attention to the serum bilirubin level should be paid 8–10 days after cryosurgery. Liver-protective treatment may alleviate liver function impairment caused by cryosurgery of huge HCC.     

Cryoelectrolysis; an acute case study in the pig liver

We report results from an acute, single case study in the pig liver on the effects of a tissue ablation protocol (we named cryoelectrolysis) in which 10 min of cryosurgery, with a commercial cryosurgical probe, are delivered after 10 min of electrolysis generated by a current of about 60 mA. The histological appearance of tissue treated with cryoelectrolysis is compared with the appearance of tissue treated with 10 min of cryosurgery alone and with 10 min of electrolysis alone. Histology done after 3 h survival shows that the mixed rim of live and dead cells found around the ablated lesion in both cryosurgery and electrolytic ablation is replaced by a sharp margin between life and dead cells in cryoelectrolysis. The appearance of the dead cells in each, cryoelectrolysis, cryosurgery and electrolytic ablation is different. Obviously, this is an acute study and the results are only relevant to the conditions of this study. There is no doubt that additional acute and chronic studies are needed to strengthen and expand the findings of this study.     

Computerized planning of prostate cryosurgery using variable cryoprobe insertion depth

The current study presents a computerized planning scheme for prostate cryosurgery using a variable insertion depth strategy. This study is a part of an ongoing effort to develop computerized tools for cryosurgery. Based on typical clinical practices, previous automated planning schemes have required that all cryoprobes be aligned at a single insertion depth. The current study investigates the benefit of removing this constraint, in comparison with results based on uniform insertion depth planning as well as the so-called “pullback procedure”. Planning is based on the so-called “bubble-packing method”, and its quality is evaluated with bioheat transfer simulations. This study is based on five 3D prostate models, reconstructed from ultrasound imaging, and cryoprobe active length in the range of 15-35 mm. The variable insertion depth technique is found to consistently provide superior results when compared to the other placement methods. Furthermore, it is shown that both the optimal active length and the optimal number of cryoprobes vary among prostate models, based on the size and shape of the target region. Due to its low computational cost, the new scheme can be used to determine the optimal cryoprobe layout for a given prostate model in real time.     

Basic studies of cryochemotherapy in a murine tumor system

The combined effect of cryosurgery and anticancer drugs (cryochemotherapy) was studied in an experimental B16 melanoma/BDF1 tumor system. Vascular volume and vascular permeability after cryosurgery of normal skin and the tumor were measured by using 51Cr-labeled red blood cells and 125I-labeled serum albumin. The vascular volume and vascular permeability of both the normal vessels and the tumor vessels greatly increased immediately after cryosurgery, and their vascular volume decreased to less than the normal level within a few hours. However, the tumor vessels showed less dilatation and increase in permeability than the vessels of normal tissue. There was a difference in functional characteristics in response to cryoinjury between the normal vessels and the tumor vessels. The anticancer drugs, peplomycin and adriamycin, were administered intraperitoneally in combination with cryosurgery. When peplomycin was administered 5 min, 1 hr, and 3 hr after cryosurgery, the drug concentration in the frozen tumor was higher than that in the untreated tumor. But when administered 1 hr before cryosurgery, peplomycin was not trapped in the tumor. Trapping of adriamycin was not observed after the same treatment. In cryochemotherapy, it is necessary to administer the appropriate drug at the appropriate time. However, the trapping of the anticancer drug results in a high concentration and lasts for a long time, so that cryochemotherapy is expected to be a new mode of cancer therapy, particularly as a multidisciplinary treatment for cancer.     

Pre-conditioning cryosurgery: Cellular and molecular mechanisms and dynamics of TNF-α enhanced cryotherapy in an in vivo prostate cancer model system

Cryosurgery is increasingly being used to treat prostate cancer; however, a major limitation is local recurrence of disease within the previously frozen tissue. We have recently demonstrated that tumor necrosis factor alpha (TNF-α), given 4 h prior to cryosurgery can yield complete destruction of prostate cancer within a cryosurgical iceball. The present work continues the investigation of the cellular and molecular mechanisms and dynamics of TNF-α enhancement on cryosurgery. In vivo prostate tumor (LNCaP Pro 5) was grown in a dorsal skin fold chamber (DSFC) on a male nude mouse. Intravital imaging, thermography, and post-sacrifice histology and immunohistochemistry were used to assess iceball location and the ensuing biological effects after cryosurgery with and without TNF-α pre-treatment. Destruction was specifically measured by vascular stasis and by the size of histologic zones of injury (i.e., inflammatory infiltrate and necrosis). TNF-α induced vascular pre-conditioning events that peaked at 4 h and diminished over several days. Early events (4–24 h) include upregulation of inflammatory markers (nuclear factor-κB (NFκB) and vascular cell adhesion molecule-1 (VCAM)) and caspase activity in the tumor prior to cryosurgery. TNF-α pre-conditioning resulted in recruitment of an augmented inflammatory infiltrate at day 3 post treatment vs. cryosurgery alone. Finally, pre-conditioning yielded enhanced cryosurgical destruction up to the iceball edge at days 1 and 3 vs. cryosurgery alone. Thus, TNF-α pre-conditioning enhances cryosurgical lesions by vascular mechanisms that lead to tumor cell injury via promotion of inflammation and leukocyte (esp. neutrophil) recruitment.     

Immunological aspects of cryosurgery in general surgery

Existence and verification of the cryoimmunologic reaction are established in basic experiments and clinical studies. However, the most effective condition in which to elicit cryoimmunologic reaction is still unknown. Evidence suggests the necessity to intensify cryoimmune reaction, if we intend to use this as one of the specific immunotherapies clinically. Establishment of criteria to select patients receiving cryosurgery is another pending question. It is important to assess the patient's immunity or immunological competence prior to cryosurgery, thereby preventing immunologically induced aggravation after cryosurgery.Twelve years of clinical experience in cryosurgery was presented and analyzed. Overall 3-year survival in the primary cancer patients was 33.3%, and 5-year survival was 17.7%. It is our aim to achieve the most beneficial effects of cryosurgery for the patients with malignancies which would otherwise be difficult to treat by conventional means.     

Tissue impedance and temperature measurements in relation to necrosis in experimental cryosurgery

Tissue temperature and impedance were measured in dog skin during freezing in situ. The previously frozen skin was removed by punch biopsies 3 days later to permit microscopic evaluation of the extent of necrosis. The histologic observations were related to the temperature and impedance measurements in an effort to determine the usefulness of the monitoring techniques in clinical cryosurgery. Tissue temperature and impedance have a definite relationship in tissue freezing, but the range of temperatures about any impedance values causes some concern. The tissue biopsies showed that an impedance value of at least 10 Mohms is not always associated with tissue death. In these experiments, there was the usual range of temperatures in relation to tissue death, but tissue temperatures of -30 degrees C and colder were always associated with complete necrosis. It is concluded that tissue temperatures are the more accurate and useful monitoring technique to supplement clinical judgment. However, impedance techniques may also be used to monitor therapy, especially if used primarily to monitor depth of therapy, and if controlled by clinical judgment wary of the inaccuracy of the technique.