Andrew A. Gage

The molecular basis of cryosurgery.

generally defined as arising from two major mechanisms. These are the direct injury to cells caused by ice crystal formation and the microcirculatory failure which occurs in the thawing period [2]. The relative importance of these two mechanisms has long been debated, but both are clearly major effects. Ice-crystal formation removes water from the biological system, which produces a host of deleterious effects. Intracellular ice is particularly lethal for cells. Cells closely packed in a tissue may sustain damage from ice crystals by purely mechanical means, as from the shearing forces of the crystals. The vascular effect, i.e. the microcirculatory failure that follows thawing, is evident in any experiments in vivo . The loss of blood supply deprives the cells of any chance of survival. The importance of this mechanism of injury, featuring vascular stasis in the thawed tissue, has long been stressed, including in recent investigations [3]. Nevertheless, from the molecular perspective, the most important advance in basic research related to cryosurgery is the recognition that apoptosis is a mechanism of cell death after cold injury [4].

Effect of varying freezing and thawing rates in experimental cryosurgery

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.

Experimental cryosurgery investigations in vivo

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.

The five-year cure rate achieved by cryosurgery for skin cancer

Cryosurgery was used to treat 3540 new basal cell and squamous cell carcinomas of the skin from 1971 to 1989; a cure rate of 98.4% was achieved. To determine the 5-year cure rate in more recent years, the results of treatment of 684 nonmelanotic skin cancers from 1980 to 1984 were reviewed. In the group of 628 basal cell carcinomas, the 5-year cure rate was 99.0%. In the group of 52 squamous cell carcinomas, the 5-year cure rate was 96.1%. In the series were also four patients with basosquamous cell carcinomas, all of whom were recurrence free for 5 years or more. The overall 5-year cure rate in the 684 cases was 98.8%. On the basis of these data and our cosmetic results, we conclude that cryosurgery is an effective treatment that compares favorably with other established methods of therapy.

Cryosurgery for oral and pharyngeal carcinoma

Abstract Freezing with liquid nitrogen was used for the treatment of oral and pharyngeal carcinoma in eighty-three patients. Some were treated only for palliation of incurable disease, but emphasis was placed on the use of cryosurgery to achieve cure. The reasons for the choice of therapy included the desire to avoid disabling sacrifice of the mandible or palate, location of cancer in an area difficult to excise, the presence of severe cardiopulmonary disease or persistence of cancer after conventional methods of treatment had been used. In terms of survival, the results appeared comparable to those achieved by excision. However, the survivors did not have the disabilities that often follow surgical excision. Although the results so far have been acceptable, longer observation is needed to determine if survival will justify continued use of cryosurgery for oral and pharyngeal cancer.

Time course of esophageal lesions after catheter ablation with cryothermal and radiofrequency ablation: implication for atrio-esophageal fistula formation after catheter ablation for atrial fibrillation.

Background: Atrio‐esophageal fistulas have been described as a consequence of radiofrequency (RF) ablation for the treatment of atrial fibrillation (AF). However, whether cryoablation can avoid this potential fatal complication remains unclear.

Cryotherapy for cancer of the lip and oral cavity

Cryotherapy with modern apparatus utilizing liquid nitrogen was used to control malignant and benign lesions of the lip and oral cavity in 5 patients. The reasons for the choice of therapy included resistance to radiotherapy, lesions in areas not amenable to excision without disabling bone sacrifice (palate, mandible) and severe cardiac disease which made the risk of operation prohibitive. Usually local anesthesia was used. One patient died of acute myocardial infarction 4 months after treatment and at autopsy no residual tumor was found in the treated area. The other patients are free of local recurrence at this time and none have palpable regional lymph nodes. Additional clinical evaluation is required but the results suggest that cryotherapy merits more extensive trial in selected patients in whom the customary methods of treatment have failed or cannot be used without great risk.

Critical temperature for skin necrosis in experimental cryosurgery

Abstract To investigate the minimal lethal freezing temperature required to produce skin necrosis in dogs, multiple skin sites were frozen with cryosurgical equipment. Tissue temperatures were recorded from thermocouple sites placed at diverse distances, usually 5 mm from the edge of the freezing probe. In single freezing cycles of about 3 min duration, tissue temperatures in the range of 0 to −60 °C were produced. Punch biopsies of the skin at the thermocouple sites 3 days after freezing injury provided tissues for estimation of viability by histologic examination. The histologic findings permitted classification of the biopsy tissue into three groups, that is, viable, borderline, or necrotic. When classified as borderline, the division between the necrotic and viable tissue was evident on the histologic slide. The viable specimens were scattered through the 0 to −35 °C range. All specimens frozen to −10 °C or warmer were viable. In biopsies classified as borderline, the range of viability extended from −11 ° to −50 °C. The necrotic biopsies covered a range of −14 ° to −50 °C. Cell death was certain at temperatures colder than −50 °C. The data showed cryosurgical freezing conditions produced a range of temperatures in which viability or death of tissue may occur and that the ranges of viability and necrosis overlapped to a great extent. The wide range of temperatures at which cells were viable shows the need to achieve tissue temperatures in the range of −50 °C in the cryosurgical treatment of cancer.

Cryosurgery for lentigo maligna

BACKGROUND The need for treatment of lentigo maligna is related to the cosmetic benefits and to the potential for malignant change. The usual treatment is excision, but often lesional size or location preclude this. OBJECTIVE Our purpose was to show that cryosurgery is an effective alternative treatment modality for lentigo maligna. METHODS Thirty white patients were treated with cryosurgery. The lesions ranged from 1.3 to 4.5 cm in diameter. Treatment consisted of freezing with liquid nitrogen delivered by open spray. RESULTS The lesion recurred in two patients, yielding a recurrence rate of 6.6% during the average follow-up period of 3 years. The two recurrent lesions were successfully re-treated with cryosurgery. Eleven patients observed for more than 5 years showed no recurrence. CONCLUSION Cryosurgery provides excellent cosmetic and curative results. These results are favorably comparable to excisional surgery.

Progress toward optimization of cryosurgery.

Cryosurgery for diverse neoplastic and non-neoplastic diseases has expanded in applicability in recent years, especially since intraoperative ultrasound became available as a method of monitoring the process of tissue freezing. However, persistence of disease after presumably adequate cryosurgical treatment has disclosed deficiencies in the technique, perhaps due to faulty application of the freeze-thaw cycles or due to shortcomings in the imaging method. Clearly cryosurgical technique is less than optimal. The optimal dosimetry for tissue freezing, the recent improvements in imaging techniques, and the need for adjunctive therapy are defined in this review, which assesses the progress toward improving the efficacy of cryosurgery.