The SSTARS (STeroids and Stents Against Re-Stenosis) Trial: Different stent alloys and the use of peri-procedural oral corticosteroids to prevent in-segment restenosis after percutaneous coronary intervention.

BACKGROUND: Stent design and technological modifications to allow for anti-proliferative drug elution influence restenosis rates following percutaneous coronary intervention (PCI). We aimed to investigate whether peri-procedural administration of corticosteroids or the use of thinner strut cobalt alloy stents would reduce rates of binary angiographic restenosis (BAR) after PCI. METHODS: This was a two centre, mixed single and double blinded, randomised controlled trial using a factorial design. We compared (a) the use of prednisolone to placebo, starting at least six hours pre-PCI and continued for 28days post-PCI, and (b) cobalt chromium (CoCr) to stainless steel (SS) alloy stents, in patients admitted for PCI. The primary end-point was BAR at six months. RESULTS: 315 patients (359 lesions) were randomly assigned to either placebo (n=145) or prednisolone (n=170) and SS (n=160) or CoCr (n=160). The majority (58%) presented with an ACS, 11% had diabetes and 287 (91%) completed angiographic follow up. BAR occurred in 26 cases in the placebo group (19.7%) versus 31 cases in the prednisolone group (20.0%) respectively, p=1.00. For the comparison between SS and CoCr stents, BAR occurred in 32 patients (21.6%) versus 25 patients (18.0%) respectively, p=0.46. CONCLUSION: Our study showed that treating patients with a moderately high dose of prednisolone for 28days following PCI with BMS did not reduce the incidence of BAR. In addition, we showed no significant reduction in 6month restenosis rates with stents composed of CoCr alloy compared to SS (http://www.isrctn.com/ISRCTN05886349).

Dissociation of phenotypic and functional endothelial progenitor cells in patients undergoing percutaneous coronary intervention.

OBJECTIVES: Endothelial progenitor cells (EPCs) are circulating mononuclear cells with the capacity to mature into endothelial cells and contribute to vascular repair. We assessed the effect of local vascular injury during percutaneous coronary intervention (PCI) on circulating EPCs in patients with coronary artery disease. DESIGN AND SETTING: Prospective case-control study in a university teaching hospital. PATIENTS: 54 patients undergoing elective coronary angiography. INTERVENTIONS AND MAIN OUTCOME MEASURES: EPCs were quantified by flow cytometry (CD34(+)KDR(+) phenotype) complemented by real-time polymerase chain reaction (PCR), and the colony forming unit (CFU-EC) functional assay, before and during the first 24 hours after diagnostic angiography (n = 27) or PCI (n = 27). RESULTS: Coronary intervention, but not diagnostic angiography, resulted in an increase in blood neutrophil count (p<0.001) and C-reactive protein concentrations (p = 0.001) in the absence of significant myocardial necrosis. Twenty-four hours after PCI, CFU-ECs increased threefold (median [IQR], 4.4 [1.3-13.8] vs 16.0 [2.1-35.0], p = 0.01), although circulating CD34(+)KDR(+) cells (0.019% (SEM 0.004%) vs 0.016% (0.003%) of leucocytes, p = 0.62) and leucocyte CD34 mRNA (relative quantity 2.3 (0.5) vs 2.1 (0.4), p = 0.21) did not. There was no correlation between CFU-ECs and CD34(+)KDR(+) cells. CONCLUSIONS: Local vascular injury following PCI results in a systemic inflammatory response and increases functional CFU-ECs. This increase was not associated with an early mobilisation of CD34(+)KDR(+) cells, suggesting these cells are not the primary source of EPCs involved in the immediate response to vascular injury.

Radiobiological studies of PC-3 and DU-145 human prostate cancer cells: x-ray sensitivity in vitro and hypoxic fractions of xenografted tumors in vivo.

PURPOSE: To determine the quantitative responses to x-irradiation of exponentially growing human prostatic cancer cell lines PC-3 and DU-145 in vitro, and to determine the hypoxic percentages of these two cell lines when grown in vivo as xenografted solid tumors in nude mice. METHODS AND MATERIALS: Radiation survival in vitro was quantitated using both single-hit, multitarget and linear-quadratic formalisms. Hypoxic fractions in vivo were determined from tumors of average sizes of about 750 mm3 using clonogenic excision assay. RESULTS: In vitro, the average single-hit, multitarget survival values for 7 replicate experiments for the DU-145 line were n = 1.92 (1.39-2.65), Dq(Gy) = 1.25, and Do(Gy) = 1.91 (1.88-1.94) (all values in parentheses indicate 95% confidence limits). For the PC-3 line (10 replicate experiments), these values were n = 2.84 (2.11-2.79), Dq(Gy) = 1.02, and Do(Gy) = 1.06 (0.87-1.25). For the linear-quadratic formalism, values of alpha(Gy-1 x 10(1) and beta(Gy-2 x 10(2) for the DU-145 and PC-3 lines were, respectively, 1.55 (0.42) and 5.21 (1.09); and 4.87 (1.11) and 5.50 (1.88). The mean percentage survival of the DU-145 and PC-3 lines at a dose of 2 Gy were, respectively, 59.8 (53.3-67.0) and 32.0 (25.8-38.2). In vivo, the hypoxic fractions for the DU-145 and PC-3 tumors were, respectively, 7.20 (4.30-11.5), and 52.3 (42.8-63.9). RESULTS: The data from the in vitro experiments show that the DU-145 cell line is significantly more radioresistant than the PC-3 cell line. In vivo, the DU-145 tumors exhibit a significantly lower hypoxic percentage than do PC-3 neoplasms. CONCLUSIONS: Results indicate that significantly variability exists within human prostate tumors in regard to both intrinsic radiosensitivity in vitro and levels of hypoxia in vivo. Because these data appear to be the first published information on the intrinsic radiosensitivity and intratumor hypoxia characteristics of human prostate cancer, additional studies are needed to define the distributional aspects of these clinically relevant endpoints.

Effects of partial hepatectomy on the growth characteristics and hypoxic fractions of xenografted DLD-2 human colon cancers.

A recent publication by Leith et al. (Cancer Res. 51, 4111-4113, 1991) showed that administration of epidermal growth factor (EGF) (0.25 mg/kg; q.i.d. x 7) to mice bearing xenografted A431 human epidermoid cancers produced increased tumor growth and a reduction of the percentage of hypoxic cells within neoplasms. In contrast, sialoadenectomy, which removes the majority of circulating EGF in the mouse, resulted in slower tumor growth and increased hypoxic percentages. To investigate such homeostatic mechanisms further, we investigated the growth characteristics and hypoxic fractions of xenografted DLD-2 human colon tumors when tumor-bearing mice received partial hepatectomy (about 65%), unilateral nephrectomy, or nonspecific surgical trauma (laparotomy). Surgical procedures were performed when tumor volumes were about 375 mm3, and hypoxic percentages within tumors were measured by clonogenic excision assay procedures 72 h later. We found that partial hepatectomy increased the growth rates of the transplanted DLD-2 cancers by about a factor of 2.4. This increased growth rate was accompanied by an increase in the mitotic index from about 1.5 to 3.0%. Also, hypoxic fractions were decreased from 0.561 in control tumors to 0.235 in tumors from mice receiving partial hepatectomies. Unilateral nephrectomy and nonspecific surgery manipulations did not alter tumor growth rates, mitotic indices, or hypoxic percentages. These results indicate that partial hepatectomy produces significant alterations in tumor physiology. Results are consistent with a growth factor-mediated mechanism.

Effect of preirradiation of transplantation site on growth characteristics and hypoxic fractions in human colon tumor xenografts.

The volumetric growth curves and hypoxic fractions of seven different human colon tumor lines (clone A, clone D, WiDR, SW480, SW620, DLD-2, and HCT-8) xenografted into the flank regions of either unirradiated nude mice or mice that had received 17.5 Gy of 250-kVp X-rays 1 day prior to implantation were biomathematically analyzed using the Verhulstian equation. Significant variation was found among tumors with respect to both initial growth rates (r, days-1) and theoretical final volumes (carrying capacities, K, mm3). In radiation-damaged normal tissue, tumors grew relatively well for about the first 2 wk postimplantation, attaining volumes of about 70 to 155 mm3. Then, tumor growth rates altered. This effect varied from relatively minor effects on growth rate (tumors of clones A and D) to inhibition of growth, with actual decreases in tumor volume (e.g., WiDr, SW480, SW620, HCT-8, and DLD-2). After this short-term transience in growth kinetics, neoplasms began to steadily regrow at about 3 wk postimplantation, albeit at a slower rate than that seen in controls. Tumor bed effect values were calculated using the ratio of times at which control tumors and tumors growing in the radiation-injured tissue reached a volume of 7.5% of the K values derived from the respective control growth curves. Values for clone D, clone A, and WiDR, SW480, SW620, DLD-2, and HCT-8 tumors were, respectively, 1.89, 2.41, 3.48, 3.62, 2.82, 3.66, and 3.65, indicating that tumor bed effect responses varied by almost 100%, even for cancers of the same neoplastic class. Also, the hypoxic fractions of all tumors growing in radiation-damaged sites were increased as compared with levels in controls.

Hypoxic fractions in xenografted human colon tumors.

We investigated the percentage of radiobiologically hypoxic cells within 11 different xenografted human colon tumors using an in vivo-in vitro excision assay technique. Tumors were excised at average volumes of 750 mm3, and it was found that hypoxic fractions varied from less than 1% (clone D) to over 80% (HCT-8). The geometric mean hypoxic percentage was 10.4% (95% confidence interval, 4.9 to 22.1%). Comparison of the percentage of hypoxia results from the xenografted human colon tumors to published data from xenografted melanomas suggests that transplanted colorectal tumors as a class contain significantly less hypoxia than do the melanomas.

Modification of the growth rates and hypoxic fractions of xenografted A431 tumors by sialoadenectomy or exogenously supplied epidermal growth factor.

We studied A431 epidermoid carcinomas xenografted into male nude mice either in the unperturbed state or after either surgical removal of the salivary glands or i.p. injection of exogenous epidermal growth factor (0.2 mg/kg daily for 7 days). The percentage of hypoxic cells in unperturbed tumors was 10.5% (95% confidence limits, 6.6-16.8%). In mice that received epidermal growth factor injections, hypoxic percentages decreased to 3.7% (1.7-7.8%), and tumor growth rates increased. In sialoadenectomized mice, hypoxic percentages increased to 35.2% (27.1-45.6%), and tumor growth rates decreased. These data indicate that the biology of solid tumors can be significantly modified by the host status.

Effects of feeder cells on the X-ray sensitivity of human colon cancer cells.

The survival responses to 250 kVp X-irradiation of 20 different exponentially growing human colon tumor lines have been described using the linear-quadratic equation of cell survival. Because some of these tumor lines (6/20) showed statistically significant increases in colony forming efficiency (CFE) when feeder cells (FCs) were added (10(5) FCs/60 mm dish), radiation survival parameters were determined for all 20 tumor lines with and without added feeder cells. In neither FC independent nor FC dependent lines did addition of FCs significantly affect any of the derived radiation survival parameters, including the alpha and beta inactivation constants, the mean inactivation dose (D, Gy), or the surviving fraction of cells at 2 Gy (S2). The average alpha, beta, and S2 values for these 20 human colon cancer cell lines with added feeder cells were: 0.281 Gy-1, 0.0711 Gy-2, and 0.443. A cumulative frequency distribution plot of the mean inactivation dose (D) which includes other published radiobiological data on human colon cancer cell lines (N = 26) indicates that the D50 value is 2.17 Gy.