Flemming Moesgaard

Preoperative plasma plasminogen activator inhibitor type-1 and serum C-reactive protein levels in patients with colorectal cancer

Background: Preoperative plasma plasminogen activator inhibitor-1 (PAI-1) is a prognostic variable in patients with colorectal cancer. It has been suggested, however, that plasma PAI-1 is a nonspecific prognostic parameter similar to the acute-phase reactant C-reactive protein (CRP). In the present study we analyzed the association between plasma PAI-1 and serum CRP in patients scheduled for elective resection of colorectal cancer. In addition, the prognostic value of PAI-1 and CRP was studied in this patient cohort. Methods: PAI-1 and CRP were analyzed in citrated plasma and serum, respectively, obtained preoperatively from 594 patients. Patients who required preoperative blood transfusion received SAGM blood, in which soluble PAI-1 is not present. None of the patients received pre- or postoperative adjuvant chemotherapy, and all were followed in the outpatient clinic for at least 5 years or until death. The association of PAI-1 and CRP, respectively, with survival was tested using the median value of PAI-1 and the upper normal limit for CRP. Analyses were performed by inclusion of all patients, and in the subgroup of patients, who underwent curative resection. Results: The median follow-up period was 6.8 (5.4–7.9) years. The median value of plasma PAI-1 was 35.8 ng/ml, and values greater than 94 nmol/L identified patients with increased CRP levels. Comparison of the molecules showed that PAI-1 was weakly correlated with CRP (r=.26;P<.0001). Both molecules showed a Dukes independent distribution. In univariate survival analyses high levels of PAI-1 were found associated with poor prognosis and low levels with good prognosis (P=.02, HR: 1.3). Similarly, high levels of CRP were found associated with poor prognosis and low levels with good prognosis (P<.0001, HR: 1.9). In a multivariate statistical analysis including Dukes classification, gender, age, tumor location, perioperative blood transfusion, PAI-1 and CRP, plasma PAI-1 was a dependent prognostic variable, while serum CRP (P<.0001; HR: 1.4; 95% CI: 1.3–1.5) was found to be a Dukes independent prognostic variable. Similar analyses, excluding patients with Dukes’ D disease showed serum CRP to be an independent prognostic variable (P<.0001; HR: 1.3: 95% CI: 1.2–1.5). Conclusions: This study did not show a strong correlation between plasma PAI-1 and serum CRP in patients with colorectal cancer. Serum CRP was found to be a Dukes independent prognostic variable in this patient cohort, and was found to identify a subgroup of curatively resected patients at risk for short survival.Background: Preoperative plasma plasminogen activator inhibitor-1 (PAI-1) is a prognostic variable in patients with colorectal cancer. It has been suggested, however, that plasma PAI-1 is a nonspecific prognostic parameter similar to the acute-phase reactant C-reactive protein (CRP). In the present study we analyzed the association between plasma PAI-1 and serum CRP in patients scheduled for elective resection of colorectal cancer. In addition, the prognostic value of PAI-1 and CRP was studied in this patient cohort.Methods: PAI-1 and CRP were analyzed in citrated plasma and serum, respectively, obtained preoperatively from 594 patients. Patients who required preoperative blood transfusion received SAGM blood, in which soluble PAI-1 is not present. None of the patients received pre- or postoperative adjuvant chemotherapy, and all were followed in the outpatient clinic for at least 5 years or until death. The association of PAI-1 and CRP, respectively, with survival was tested using the median value of PAI-1 and the upper normal limit for CRP. Analyses were performed by inclusion of all patients, and in the subgroup of patients, who underwent curative resection.Results: The median follow-up period was 6.8 (5.4–7.9) years. The median value of plasma PAI-1 was 35.8 ng/ml, and values greater than 94 nmol/L identified patients with increased CRP levels. Comparison of the molecules showed that PAI-1 was weakly correlated with CRP (r=.26;P<.0001). Both molecules showed a Dukes independent distribution. In univariate survival analyses high levels of PAI-1 were found associated with poor prognosis and low levels with good prognosis (P=.02, HR: 1.3). Similarly, high levels of CRP were found associated with poor prognosis and low levels with good prognosis (P<.0001, HR: 1.9). In a multivariate statistical analysis including Dukes classification, gender, age, tumor location, perioperative blood transfusion, PAI-1 and CRP, plasma PAI-1 was a dependent prognostic variable, while serum CRP (P<.0001; HR: 1.4; 95% CI: 1.3–1.5) was found to be a Dukes independent prognostic variable. Similar analyses, excluding patients with Dukes’ D disease showed serum CRP to be an independent prognostic variable (P<.0001; HR: 1.3: 95% CI: 1.2–1.5).Conclusions: This study did not show a strong correlation between plasma PAI-1 and serum CRP in patients with colorectal cancer. Serum CRP was found to be a Dukes independent prognostic variable in this patient cohort, and was found to identify a subgroup of curatively resected patients at risk for short survival.

Association between plasma concentrations of plasminogen activator inhibitor-1 and survival in patients with colorectal cancer

Editorial by Verspaget Invasion by cancer cells requires proteases such as the serine protease plasmin to degrade the cellular matrix. Plasmin is formed from its zymogen, plasminogen, a reaction catalysed by urokinase type plasminogen activator—which is implicated in invasion1—and partly regulated by plasminogen activator inhibitors. The active form of the inhibitor complexes with free and receptor bound active urokinase plasminogen activator and is bound by vitronectin in plasma and extracellular matrix.2 A high concentration of plasminogen activator inhibitor-1 in biopsy specimens from tumours is associated with a poor prognosis,3 and some patients with ovarian cancer have raised plasma concentrations of plasminogen activator inhibitor-1.4 We studied the prognostic importance of plasma concentrations of plasminogen activator inhibitor-1 in patients with colorectal …

Ranitidine for prevention of postoperative suppression of delayed hypersensitivity

Cell-mediated immunity was assessed by skin testing with seven delayed-type common antigens in 20 patients undergoing major abdominal surgery and in 20 nonoperative control subjects. The 20 surgical patients were randomized to perioperative ranitidine (50 mg every 6 hours for 72 hours) or no ranitidine. The 20 control subjects received either no ranitidine or ranitidine in the same dosage as the surgical patients. Skin tests were performed 2 days before and 1 day after operation with the same time schedule in the control subjects. Postoperatively, the diameter of the positive skin test area decreased in each of 10 patients without ranitidine (p less than 0.006) but increased in 9 and was unchanged in 1 of the ranitidine-treated patients (p less than 0.01). The skin test changes were similar during the two tests in ranitidine-treated surgical patients and the nonoperative control subjects. Ranitidine did not amplify the response in the nonoperated group. The potential role of histamine blockade in reversal of other aspects of postoperative immunosuppression and reduction in the risk of infection should be explored.

Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors.

Multiple myeloma (MM) is characterized by an increased susceptibility to infections and to other malignancies. Selected related immune functions were studied. Spontaneous and interleukin‐2‐stimulated natural killer (NK) cell activities were normal in 19 patients with MM compared with 62 controls. In contrast, interferon‐stimulated NK cells had a significantly lower increase in activity in MM than in controls. The normal improvement in lytic NK cell activity after addition of indomethacin to the mononuclear cell cultures (to inhibit prostaglandin‐mediated suppression) was not observed in cultures from MM patients. As reported for other lymphoproliferative disorders, the levels of soluble interleukin‐2 receptors in serum were significantly higher in MM (600 U/ml median value) compared with controls (317 U/ml median value), P < 0.0001, and the concentration of interleukin‐2 receptors was significantly correlated with the concentration of monoclonal immunoglobulin in serum. Blood monocyte chemotactic responsiveness was significantly lower in MM patients with both zymosan‐activated serum and f‐Met‐Leu‐Phe as cytotaxins, suggesting reduced ability to accumulate at inflammatory foci. In contrast, release of reactive oxygen radicals, believed to be associated with the killing ability of monocytes, was normal after in vitro stimulation.

Cell-mediated immunity assessed by skin testing (Multitest®)

The Multitest CMI system consists of a disposable multiple puncture device that simultaneously applies seven standardized recall antigens for assessment of cell‐mediated immunity (CMI). The seven antigens included were toxoid from Clostridium tetani and Corynebacterium diphthenae, tuberculin, plus antigens from streptococcus (group C), Candida albicans, Trichophyton mentagrophytes, and Proteus mirabilis. A population of 352 healthy Danish adults, aged between 17 and 90 years, was tested to determine the incidence and size of delayed‐type hypersensitivity (DTH) responses. All but six healthy adults (98%) responded to one or more antigens, the median number of positive responses being four in males and three in females. The incidence of positive responses ranged from 91 % for tuberculin to 11 % for trichophyton. The number of positive responses declined with age, being somewhat faster in females than males. Six of the seven antigen response rates were significantly lower in the over 65‐years‐olds, the only exception being trichophyton, and for four of the seven antigens significantly lower in females compared to males. When correlated to age and sex no major differences were found with regard to the size of response to the seven antigens except that the tuberculin response was larger in males. A scoring system based on both number and size of positive responses revealed significant age and sex related differences. The median “score” in 17‐65‐year‐old males and females were, respectively, 17 mm and 14 mm compared to 13 mm and 8 mm in those over 65 years old (P 0.001 for both comparisons).

Effect of ranitidine and low-dose interleukin-2 in vitro on NK-cell activity in peripheral blood from patients with liver metastases from colorectal cancer.

Peripheral venous blood from 12 patients with colorectal cancer and eight healthy volunteers was used to identify the lowest in vitro dose of human, recombinant interleukin-2 (rIL-2) with immunoactivity on NK-cell lysis of K562 tumour cells. Subsequently, this dosage of 200 units/ml rIL-2, which may respond to 10(6) units in vivo, was used alone or in combination with ranitidine (0.02 mg/ml, which may correspond to 100 mg in vivo) to improve in vitro NK-cell activity in peripheral blood from 25 patients with liver metastases from colorectal cancer. A standard 4-hour Cr51-release assay of K562 tumour cells was used for the analyses. Spontaneous NK-cell activity was 19.0% (6.5-33.2), while ranitidine-induced NK-cell activity was 23.6% (7.8-46.2), and without statistical difference from spontaneous activity. Recombinant IL-2-induced NK-cell activity was 37.1% (11.1-71.7) (P < 0.05 compared to spontaneous activity), and rIL-2 plus ranitidine-induced NK-cell activity was 52.7% (18.9-85.6) (P < 0.05 compared to spontaneous and to rIL-2-induced activity, respectively). These results suggest a synergistic increase of low-dose rIL-2-induced NK-cell activity by ranitidine. Therefore, the combination of low-dose rIL-2 and ranitidine may be beneficial to improve post-operative immune competence, and should be considered in future adjuvant treatment regimens of cancer patients.

Release of Gastric Inhibitory Polypeptide and Insulin in Response to Intrajejunal Glucose in Duodenal Ulcer Patients before and after Truncal Vagotomy

Six duodenal ulcer patients were investigated before and 3 months after truncal vagotomy and pyloroplasty. Plasma concentrations of gastric inhibitory polypeptide (GIP), insulin, and glucose were measured during intrajejunal infusion of 50 g of glucose. The GIP response was significantly diminished postoperatively; insulin and glucose concentrations, however, were unchanged. The reduction of GIP release was positively correlated with the reduction of the peak acid output. The results suggest that a reduced vagal innervation of the intestine is accompanied by reduced GIP release after intrajejunal glucose, depending on the degree of completeness of vagotomy.

The effect of ranitidine on cellular immunity in patients with multiple myeloma

SummaryMultiple myeloma is characterized by an increased susceptibility to infections and to other malignancies. In a double-blind, placebo-controlled study the potential impact of immunomodulation by ranitidine was studied in 20 patients with multiple myeloma. Three patients were untreated, while 17 after previous cytotoxic therapy were in a stable phase of their disease. All were without clinical signs of infections and at that time had not been treated with other immunomodulating agents. The patients were randomized to oral ranitidine 300 mg twice a day for 21 days or placebo, and several immunological parameters related to multiple myeloma were studied. The blood monocyte chemotactic response was improved in patients treated with ranitidine, and superoxide anion production increased from 2.02 nmol/min to 3.86 nmol/min (median values), while it was unchanged in patients given placebo (2.19–2.25 nmol/min) (P <0.005 between groups). Among ranitidine-treated patients spontaneous NK cell activity was unchanged, while in vitro interleukin-2- and interferon-α-stimulated NK cell activity decreased (P <0.03, respectively). As production of oxygen radicals constitutes an important mechanism of monocyte killing activity against microorganisms and probably against malignant cells, it is suggested that ranitidine may be of beneficial impact in the treatment of multiple myeloma.

Ulcer healing after treatment with sucralfate emulsion or ranitidine: randomized controlled study in peptic ulcer disease

A randomized trial with a blind observer compared the efficacy of an emulsion containing micronized sucralfate (1 g four times daily) and ranitidine (150 mg twice daily) in the short-term healing of peptic ulcer. Patients with a minimum ulcer size of 5 mm located in the duodenal bulb, the pyloric canal, or in the prepyloric area within a distance of 2 cm from the pylorus were included. A total of 97 patients were randomized and 85 completed the trial. The endoscopically proven healing rate at 2 weeks of 41% for both sucralfate and ranitidine improved to 76% for sucralfate and 73% for ranitidine at 4 weeks and to 95% and 96%, respectively, at 12 weeks. The difference between the two treatment groups was not statistically significant, and the 95% confidence interval for the difference in ulcer healing efficacy of sucralfate emulsion compared with ranitidine was -0.15 to +0.21 at 4 weeks and -0.10 to +0.08 at 12 weeks.