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.     

Current progress in cryosurgery

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.     

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.     

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.     

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.     

An investigation on the use of cryosurgery for treatment of bone spavin, splint, and fractured splint bone injuries in standardbred horses

Bone spavin, splint, and fractured splint bone injuries have been treated with varying methodologies at Wheatley Hall Farm Equine Clinic. Cryosurgery is the most successful. With cryosurgery the small, pain-producing afferent C fibers are destroyed, and painful neuromas do not return. Injured sites were cryosurgically treated with liquid nitrogen for a double freeze-thaw period of 45 sec. 5 sec, 45 sec. Before and after treatment comparisons were conducted on study standardbreds. In all three injury groups, results showed that the standardbreds tended to race as well or with improved times and classes after treatment. With cryosurgery, the horse undergoes a relatively short layoff period and does not experience any of the problems associated with other surgical procedures. Unlike denerving, a horse is still aware of outside stimulus to the treated area. Based upon personal observation and this preliminary investigation, cryosurgery provides a successful treatment alternative which is safe and humane to the horse, requiring a very short layoff or recovery time.     

Cryosurgery and rhTNF-α play synergistic effects on a rat cortex C6 glioma model

Glioma, a type of brain tumor originating from glioma cells, varies widely in aggressiveness and causes serious symptoms, but the treatments are limited. Studies have shown that cryosurgery has multiple effects on tumor treatments, and administration of human tumor necrosis factor-alpha (rhTNF-α) arguments the anti-tumor effect of cryotherapy in breast and prostate cancers. To test the hypothesis that cryosurgery and rhTNF-α play synergistic effects against brain tumors, we established a brain glioma model on rat cortex regions following different treatments: the G1 group was sham-operated; the G2 group was treated with cryosurgery; the G3 group was treated with rhTNF-α; and G4 group received combined treatment with cryosurgery and rhTNF-α. Tumor sizes were measured by magnetic resonance imaging; DNA fragmentation was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL assay); P21(WAF1/CIP1) and proliferating cell nuclear antigen (PCNA) expression levels were scored using immunohistochemical staining. G2 and G4 rats had significantly longer survival time than did G1 rats. Tumor sizes in each group were significantly decreased as compared with those in G1 rats. PCNA-positive cells were significantly decreased in G2, G3 and G4 rats as compared with G1 rats. In contrast, DNA fragmentation and P21(WAF1/CIP1)-positive cells were significantly increased in each treatment group. Importantly, a combined treatment enhanced the effects of cryosurgery. Combined treatment with cryosurgery and rhTNF-α may have a synergistic effect on glioma tumor therapy, enhancing the inhibition of proliferation and the induction of apoptosis.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Key issues in bioheat transfer simulations for the application of cryosurgery planning

The bioheat transfer simulation is undoubtedly the foundation for developing computerized tools for cryosurgery planning and analysis. While a large variety of techniques for bioheat transfer simulations are available in the literature of the past several decades, it is only their integration with clinical criteria and constraints which can make computerized planning a practical reality. This brief communication outlines (in the opinion of this author) the key issues that must be addressed in the application of bioheat transfer to cryosurgery planning and analysis, while drawing attention to recent and relevant publications in other journals, with reference to the most recent publication on the topic in the Journal of Cryobiology [Z. Magalov, A. Shitzer, D. Degani, Isothermal volume contours generated in a freezing gel by embedded cryo-needles with applications to cryo-surgery, Cryobiology 55 (2) (2007) 127–137].     

Antitumor immunologic reactivity in the relatively early period after cryosurgery: Experimental studies in the rat

An experimental investigation was performed on antitumor immunity in the relatively early postoperative period after cryosurgery, using a metastasizing rat's mammary tumor, MRMT-1. Two weeks after its inoculation, surgical excision of the tumor, cryosurgery, surgical excision plus inoculation with freezing-thawing produced vaccine, or surgical excision plus fasting for 72 hr was performed, and postoperative follow-up was done on incidences of metastases, those of metastatic death, etc. Specific immunologic reactivity was examined in the surgical excision (SE) and cryosurgery (CR) groups.The FTV and fasting groups showed more metastatic deaths as compared with the SE group. The CR and SE groups did not differ significantly from each other in incidences of lung and lymph node metastases.Specific footpad reactivity at 2 and 3 weeks after treatment was lower in the CR group than in the SE group.Winn's neutralization assay showed an inhibition of tumor growth at 1 and 3 week(s) after treatment both in the SE and in the CR groups, the inhibitory effect tending to be lower in the latter.Inactivated serum obtained at 1 week after treatment showed a facilitation of tumor growth in the SE group and a tendency of tumor suppression in the CR group, showing a significant difference between them.A mild reduction in antitumor immunity seen in the relatively early postoperative period following cryosurgery probably was not due to a blocking effect by superfluous antigens. Rather it was considered to be due to activation of suppressor cells, consequent on cryosurgical stress, and/or slow and steady absorption of antigens.