Integrin involvement in freeze resistance of androgen-insensitive prostate cancer

Technol Cancer Res Treat

Robilotto

Snyder

et al. 2017

As the clinical use of cryoablation for the treatment of cancer has increased, so too has the need for knowledge on the dynamic environment within the frozen mass created by a cryoprobe. While a number of factors exist, an understanding of the iceball size, critical isotherm distribution/penetration, and the resultant lethal zone created by a cryoprobe are critical for clinical application. To this end, cryoprobe performance is typically characterized based on the iceball size and temperature penetration in phantom gel models. Although informative, these models do not provide information as to the impact of heat input from surrounding tissue nor give any information on the ablative zone created. As such, we evaluated the use of a tissue-engineered tumor model (TEM) to assess cryoprobe performance including iceball size, real-time thermal profile distribution, and resultant ablative zone. Studies were conducted using an Endocare V-probe cryoprobe, with a 10/5/10 double freeze–thaw protocol using prostate and renal cancer TEMs. The data demonstrate the generation of a 33- to 38-cm3 frozen mass with the V-Probe cryoprobe following the double freeze of which ∼12.7 and 6.5 cm3 was at or below −20°C and −40°C, respectively. Analysis of ablation zone using fluorescence microscopy 24 hours postthaw demonstrated that the internal ∼40% of the frozen mass was completely ablated, whereas in the periphery of the iceball (outer 1 cm region), a gradient of partial to minimal destruction was observed. These findings correlated well with clinical reports on renal and prostate cancer cryoablation. Overall, this study demonstrates that TEMs provide an effective model for a more complete characterization of cryoablation device performance. The data demonstrate that while the overall iceball size generated in the TEM was consistent with published reports from phantom models, the integration of an external heat load, circulation, and cellular components more closely reflect an in vivo setting and the impact of penetration of the critical (−20°C and −40°C) isotherms into the tissue. This is important as it is well appreciated in clinical practice that the heat load of a tissue, cryoprobe proximity to vasculature, and so on, can impact outcome. The TEM model provides a means of characterizing the impact on ablative dose delivery allowing for a better understanding of probe performance and potential impact on ablative outcome.

Section: Introductionmentioning

confidence: 99%

Assessment of Cryosurgical Device Performance Using a 3D Tissue-Engineered Cancer Model

Technol Cancer Res Treat

Robilotto

Snyder

et al. 2017

“…[25][26][27][28][29] For instance, in prostate cancer, the loss of androgen receptor expression (shift from hormone responsive to unresponsive cancer) or increase in integrin expression can result in increased tolerance to freezing, shifting the minimal lethal temperature from −25°C to −40°C. 26,30 As such, for prostate cancer, a minimal lethal temperature of −40°C is typically targeted to assure complete cancer ablation. 16,19,27 In vitro studies have identified −20°C as the minimal lethal temperature for colorectal cancer 31,32 ; −25°C for renal cancer, 29,33 pancreatic cancer, 34,35 and bladder cancer 36,37 ; and −35° for liver cancer.…”

mentioning

confidence: 99%

Breast Cancer Cryoablation: Assessment of the Impact of Fundamental Procedural Variables in an In Vitro Human Breast Cancer Model

Snyder

Buskirk

et al. 2020

Breast Cancer�(Auckl)

Introduction: Breast cancer is the most prominent form of cancer and the second leading cause of death in women behind lung cancer. The primary modes of treatment today include surgical excision (lumpectomy, mastectomy), radiation, chemoablation, anti-HER2/neu therapy, and/or hormone therapy. The severe side effects associated with these therapies suggest a minimally invasive therapy with fewer quality of life issues would be advantageous for treatment of this pervasive disease. Cryoablation has been used in the treatment of other cancers, including prostate, skin, and cervical, for decades and has been shown to be a successful minimally invasive therapeutic option. To this end, the use of cryotherapy for the treatment of breast cancer has increased over the last several years. Although successful, one of the challenges in cryoablation is management of cancer destruction in the periphery of the ice ball as the tissue within this outer margin may not experience ablative temperatures. In breast cancer, this is of concern due to the lobular nature of the tumors. As such, in this study, we investigated the level of cell death at various temperatures associated with the margin of a cryogenic lesion as well as the impact of repetitive freezing and thawing methods on overall efficacy. Methods: Human breast cancer cells, MCF-7, were exposed to temperatures of −5°C, −10°C, −15°C, −20°C, or −25°C for 5-minute freeze intervals in a single or repeat freeze-thaw cycle. Samples were thawed with either passive or active warming for 5 or 10 minutes. Samples were assessed at 1, 2, and 3 days post-freeze to assess cell survival and recovery. In addition, the modes of cell death associated with freezing were assessed over the initial 24-hour post-thaw recovery period. Results: Exposure of MCF-7 cells to −5°C and −10°C resulted in minimal cell death regardless of the freeze/thaw conditions. Freezing to a temperature of −25°C resulted in complete cell death 1 day post-thaw with no cell recovery in all freeze/thaw scenarios evaluated. Exposure to a single freeze event resulted in a gradual increase in cell death at −15°C and −20°C. Application of a repeat freeze-thaw cycle (dual 5-minute freeze) resulted in an increase in cell death with complete destruction at −20°C and near complete death at −15°C (day 1 survival: single −15°C freeze/thaw = 20%; repeated −15°C freeze/thaw = 4%). Analysis of thaw interval time (5 vs 10 minute) demonstrated that the shorter 5-minute thaw interval between freezes resulted in increased cell destruction. Furthermore, investigation of thaw rate (active vs passive thawing) demonstrated that active thawing resulted in increased cell survival thereby less effective ablation compared with passive thawing (eg, −15°C 5/10/5 procedure survival, passive thaw: 4% vs active thaw: 29%). Conclusions: In summary, these in vitro findings suggest that freezing to temperatures of 25°C results in a high degree of breast cancer cell destruction. Furthermore, the data demonstrate that the application of a repeat freeze procedure with a passive 5-minute or 10-minute thaw interval between freeze cycles increases the minimal lethal temperature to the −15°C to −20°C range. The data also demonstrate that the use of an active thawing procedure between freezes reduces ablation efficacy at temperatures associated with the iceball periphery. These findings may be important to improving future clinical applications of cryoablation for the treatment of breast cancer.

“…[33][34][35][36] For this purpose, cytotoxic drugs, antifreeze proteins, chemical agents, immunologic enhancing drugs, TNF alpha, and others have been used. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] Irradiation has also been utilized. The timing for use of these agents in relation to the cryoablative procedure is not well established, but all contribute to cell death by apoptosis.…”

Section: Increasing Tissue Destructionmentioning

confidence: 99%

“…20,21,32,35,36 While an ongoing area of research, several studies have shown promise in elevating the minimal lethal temperature for prostate cancer from -40°C to approaching -10°C in in vitro and murine models using calcitriol pre-treatment. [48][49][50][51][52] More recent studies have focused on the combination of immunotherapy and cryoablation to improve cancer destruction, both localized and metastatic disease. 44,[53][54][55] Regardless of the agent utilized, the goal of these efforts is to "make ice lethal at 0°C" while eliciting minimal side effects.…”

Section: Increasing Tissue Destructionmentioning

confidence: 99%

Cryoablation of Prostate- Improving Efficacy and Safety

Polascik

Buskirk

et al. 2020

MRAJ

Cryoablation has been shown to be an effective therapy for all stages of prostate cancer. Though judged efficacious, complications of treatment and persistent disease, although minimal, show the need for improvement. To this end, research has focused on new technology design for cryosurgical apparatus and imaging techniques. Adjunctive therapy, focusing on increasing cell death by apoptosis, also plays a role in this new direction with the intent of increasing cell death in the frozen tissue. Additionally, incorporating methods of protecting adjacent structures, including the urethra, bladder neck sphincter, urogenital diaphragm, neurovascular bundles, and rectum, are critical to achieving a successful outcome and continue to evolve. Several strategies to protect these structures are now commonplace as part of a cryosurgical procedure. These strategies include real-time temperature monitoring, visualization of ice growth during freezing, active heating and even the injection of protective media have emerged as methods to protect these structures. Another more recent procedural application is partial gland ablation or image-targeted focal therapy, developed to maintain cancer control yet minimize the risk of collateral damage to the various structures. Each of these methods has been shown in vitro, in vivo, and clinically to be beneficial. This article describes the directions that cryoablation has taken in an effort to improve procedural efficacy while reducing/eliminating associated co-morbidities.