Endogenous histamine has been shown to effect growth mechanisms in experimental mammary carcinomas via H2 membrane receptors (Cricco et al, 1994). Both H1 and H2 binding sites are present in human mammary glands but only 75% malignant carcinomas express H2 receptors (Lemos et al, 1995). The presence of mast cells around tumour tissue raises questions concerning the source of histamine in breast tumour tissue. While cimetidine, an H2 antagonist, has been shown to influence the presence of tumour infiltrating lymphocytes (TIL) in colorectal cancer (Adams and Morris, 1994, 1997) that was not found to be the case in breast cancer (Ng et al, 1995). In recent studies tumour cell proliferation, as measured by Ki-67 antibody labelling, has been seen as an additional prognostic indicator in breast cancer (Railo et al, 1993, 1997; Ferno, 1998; Schauer et al, 1998). We investigated the possibility that cimetidine may influence tumour proliferation by blocking the growth-promoting effects of histamine. No relationship between preoperative cimetidine administration and tumour cell proliferation was seen overall. A weak correlation was seen between tissue histamine content and mast cell count which was not influenced by cimetidine. Tumour cell proliferation correlated well with other prognostic indicators such as grade and differentiation. © 2000 Cancer Research Campaign

Although morbidity following cryotherapy is usually minor, a syndrome of multiorgan failure and disseminated intravascular coagulation (DIC) has been described and referred to as the cryoshock phenomenon. We hypothesized that mediators similar to those in septic shock may be involved in this syndrome. In this study we aimed to assess the plasma concentrations of the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) following hepatic cryotherapy and to relate them to the duration and volume of freezing and to hepatocellular injury. Between April and December 1997 blood samples were taken preoperatively and at different times postoperatively from patients undergoing hepatic artery catheter-insertion (HAC) (n = 15), cryotherapy (n = 5), liver resection (n = 9), liver resection and edge cryotherapy (n = 7), or liver resection and cryotherapy of additional lesions (n = 9). They were analyzed for serum aspartate transaminase (AST) and plasma TNF-alpha and IL-6 levels. There was a significant association (Pearson correlation) of serum AST levels 1 hour postoperatively with plasma TNF-alpha and IL-6 levels at the end of the procedure. In patients undergoing cryotherapy or resection with cryotherapy of additional lesions (n = 14), the volume and duration of hepatic freezing were significantly associated with postoperative serum AST and plasma TNF-alpha and IL-6 levels at various postoperative times. Hepatic cryotherapy is followed by cytokine release, with postoperative plasma TNF-alpha and IL-6 levels associated with the degree of hepatic cryotrauma. These mediators may be involved in the occurrence of cryoshock following large-volume hepatic freezing.

These findings suggest that the vitamin D3 analog, EB1089, is a potent antiproliferative agent for some human colon cancers.

Although cryotherapy of liver tumors is generally considered a safe procedure, a syndrome of coagulopathy and fatal multiorgan failure has been observed in some patients and is called the cryoshock phenomenon. Our aim was to establish an animal model of this phenomenon and examine the effects of the basic parameters of freezing or cryotherapy on it. A group of 75 female Sprague-Dawley rats were allocated randomly to five groups: (1) sham laparotomy (n = 15); (2) small (25% liver volume) single freeze (n = 15); (3) small (25% liver volume) double freeze (n = 15); (4) large (50% liver volume) single freeze (n = 15); (5) large (50% liver volume) double freeze (n = 15). Blood samples were collected at different postoperative times, and organs were harvested for histopathology. There was a significant release of tumor necrosis factor-a (TNFa) and interleukin 6 (IL-6) following hepatic freezing, which was greatest in group 5. Postoperative serum cytokine levels were significantly associated with hepatocellular injury, as measured by postoperative serum aspartate transaminase (AST) concentrations. Severe hemoglobinuria and renal injury, as demonstrated by the serum creatinine level and the glomerular neutrophil count, were observed and were greatest in group 5. Hepatic cryosurgery is associated with release of IL-6 and TNFa and renal injury in a rat model. It is likely that the cryoshock phenomenon is another form of the systemic inflammatory response syndrome. Based on the results of this study, it is possibly mediated by cytokines released from the frozen liver tissue. We therefore caution against cryotherapy of large tumor volumes.