Mohamed Ismail

Immunoregulatory effects of freeze injured whole tumour cells on human dendritic cells using an in vitro cryotherapy model.

Tumour cryotherapy has been described as both immunostimulatory and immunoinhibitory in previous studies. However, previous studies have not accurately reproduced the precise conditions of current clinical cryotherapy. The objective of this study is to assess the immunological effects of cryotreated whole tumour cells on dendritic cells (DC) maturation and function using an in vitro model. Prostate cancer cells were cooled using Endocare cryo-system to mimic temperatures achieved during clinical cryotherapy. Human DC were prepared from cluster of differentiation (CD) 14 monocytes and matured with lipopolysaccharide (LPS). Cryotreated cancer cells were added to DC on day 3. On day 7, DC were harvested and phenotyped. Cytokine gene expression was assessed using real time quantitative polymerase chain reaction (RT-PCR). Functional activity of DC was assessed in allogenic mixed lymphocyte reaction (MLR) and the molecular changes using gene microarray technology. There was statistically significant upregulation of costimulatory molecules and maturation markers (CD86, CD83, CD80 and CL II) in DC loaded with cryotreated whole tumour cells compared to both control DC and DC matured with LPS (P < 0.001). There was a significant increase in stimulatory cytokines gene expression (IL-2, IL-12, IL-15, IL-18 and IFN-γ). However, IL-10 and TGF-β expression reduced significantly. The effect of different freezing temperature was equal. cDNA microarray analysis showed upregulation of interleukin 1 (IL-1) and cycline dependent kinase inhibitor 1A (CDKN1A (p21) and downregulation of Caspase 8 and BCL2. Overall, our findings suggest that the effect of cryotherapy is generally stimulatory to DC which may enhance anti-tumour effects. Therefore, the combination of cryotherapy and DC vaccine may represent a novel method to increase the efficacy of cryotherapy especially at the peripheral zones of the prostate where cells are exposed to sub-lethal temperature.

Enhancing prostate cancer cryotherapy using tumour necrosis factor related apoptosis-inducing ligand (TRAIL) sensitisation in an in vitro cryotherapy model

Cryotherapy is a minimally invasive treatment for prostate cancer. Complete ablation of cancer tissue some times fails and results in disease recurrence. In this study we investigate the effect of TRAIL as a sensitising agent to enhance the effects of cryotherapy on prostate cancer cells. Prostate cancer cells were cooled using Endocare cryo-system to mimic temperatures achieved during clinical cryotherapy. The effects of TRAIL, cryotherapy or combination of both treatment on DU-145 and PC-3 were evaluated. Viability and mode of cell death was assessed following treatment. Cryotherapy did not result in complete cell death at temperature -40 degrees C. Cells died by both necrosis and apoptosis. Cells which survived freeze-thaw cycle became more sensitive to a second freezing injury. TRAIL resulted in minimal cell death. Concomitant treatment of the tumour cells with TRAIL and cryotherapy resulted in complete loss of viability at -10 and -20 degrees C. Cell death was mainly due to marked increase in necrosis. Our finding demonstrates that combined treatment of TRAIL and cryotherapy represent a novel approach to increase the sensitivity to cryotherapy. This combined approach may be feasible for locally advanced prostate cancer.

Salvage cryotherapy for recurrent prostate cancer after radiation failure: current status and future perspectives

In the last decade, cryotherapy has emerged as a minimally invasive alternative for the treatment of localized or locally advanced prostate cancer. With better understanding of the pathophysiology of cryogenic injury and the introduction of the gas-driven systems, the procedure has been optimized to improve patient survival and reduce complication. The results of salvage cryotherapy are becoming more promising. Modifying standard cryotherapy technique by the use of a urethral warming catheter and thermocouples has resulted in the reduction in serious complications and improved quality of life following the procedure. Focal nerve-sparing cryotherapy represents a novel approach to treat prostate cancer and preserve potency. Cryoimmunotherapy and cryochemotherapy are new concepts in adjuvant therapy. Early in vitro studies revealed the feasibility of such an approach. Further clinical trials are essential before using these models as standard treatment.

Renal cryoablation: Multidisciplinary, collaborative and perspective approach

Renal cryoablation is becoming an established treatment option for small renal masses. It allows preservation of renal function without compromising cancer control. The technique has evolved considerably since it was first reported using liquid nitrogen over 20 years ago. We describe the modern technique for both laparoscopic and image guided renal cryoablation. Renal cryoablation is performed either laparoscopically or percutaneously depending on tumour characteristics. Common features include biopsy of the mass, protection of adjacent organs, and the use of compressed argon gas for freezing and helium for thawing. Dynamic monitoring is used to ensure adequate treatment. The shape of the iceball can be modified by adding extra needles or changing their positions. A double freeze/thaw is necessary for confident ablation of all cancer cells. The laparoscopic approach includes exposure of the tumour and may involve extensive mobilisation of the kidney. Laparoscopic ultrasound is essential for correct localisation of the tumour, needle placement, and monitoring the treatment. A Temperature probe is placed at the edge of the tumour to record treatment temperature. The percutaneous approach is typically performed with CT guidance. Adjacent organs can be protected by injecting saline or carbon dioxide. Early imaging is helpful to detect or rule out incomplete treatment. Post-operative follow-up is structured at specific intervals (e.g. 3, 6, 12 months then annually) and perhaps tailored or modified based on the degree of suspicion of inadequate treatment.

Laparoscopic vs Percutaneous Cryotherapy for Renal Tumors: A Systematic Review and Meta-Analysis.

BACKGROUND Cryoablation has emerged as an alternative to the more invasive partial nephrectomy for small renal masses. The approach can be carried out by two techniques, either laparoscopic cryoablation (LCA) or percutaneous cryoablation, (PCA) with CT guidance. We aimed to compare between the two procedures. MATERIALS AND METHODS A systematic review and meta-analysis was conducted, including studies comparing the two techniques. Outcomes included incomplete ablation, late local recurrence, cancer-specific survival, procedure time, transfusion rates, hospital stay, and complications. RESULTS A total of 1475 patients were included, 788 patients in the laparoscopic group and 687 patients in the percutaneous group. There was statistical difference favoring the laparoscopic group with regard to having less incomplete ablation (p = 0.0008) and higher cancer-specific survival patients (p = 0.04). However, there was longer hospital stays in the LCA group (p < 0.00001) and was found to be more costly than the PCA group. There was significantly more Clavien-I complications in the PCA group (p = 0.001) and more Clavien-III complications in the LCA group (p = 0.001). Otherwise, there were no differences in any other outcome parameter. CONCLUSION LCA was found to have less incomplete tumor ablation rates and higher cancer-specific survival rates, however, higher hospitalization time, more major complications (Clavien III), and was costlier compared with PCA.

Laparoscopic versus percutaneous cryotherapy for renal tumours: a systematic review and meta-analysis

BACKGROUND Cryoablation has emerged as an alternative to the more invasive partial nephrectomy for small renal masses. The approach can be carried out by two techniques, either laparoscopic cryoablation (LCA) or percutaneous cryoablation, (PCA) with CT guidance. We aimed to compare between the two procedures. MATERIALS AND METHODS A systematic review and meta-analysis was conducted, including studies comparing the two techniques. Outcomes included incomplete ablation, late local recurrence, cancer-specific survival, procedure time, transfusion rates, hospital stay, and complications. RESULTS A total of 1475 patients were included, 788 patients in the laparoscopic group and 687 patients in the percutaneous group. There was statistical difference favoring the laparoscopic group with regard to having less incomplete ablation (p = 0.0008) and higher cancer-specific survival patients (p = 0.04). However, there was longer hospital stays in the LCA group (p < 0.00001) and was found to be more costly than the PCA group. There was significantly more Clavien-I complications in the PCA group (p = 0.001) and more Clavien-III complications in the LCA group (p = 0.001). Otherwise, there were no differences in any other outcome parameter. CONCLUSION LCA was found to have less incomplete tumor ablation rates and higher cancer-specific survival rates, however, higher hospitalization time, more major complications (Clavien III), and was costlier compared with PCA.

Cryosurgical Ablation for Prostate Cancer

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