Lung cancer is associated with an increased incidence of thrombosis. An activation of coagulation is demonstrable in lung cancer patients by sensitive activation markers, as well as a stimulation of neutrophil granulocytes, which are known to interfere with hemostasis, e.g., by degrading inhibitory proteins. We assessed antigen level, amidolytic activity, and clotting activity of the plasma anticoagulant protein C and the activation markers thrombin-antithrobin complex (TAT) and neutrophil elastase-α1-antitrypsin complex (EAT) in 67 lung cancer patients before antineoplastic treatment was begun. The protein C clotting activity was lower (p = 0.010) in the patients with extensive than in those with limited disease. However, the median levels remained within the normal range in both groups (91 vs. 108% of normal). The median amidolytic activity levels (110 vs. 117% of normal ; NS) were higher than the protein C antigen levels (82 vs. 77% of normal; NS) in- both groups. There was no significant correlation of protein C measurements with TAT levels, but there were significant negative correlations between EAT and protein C clotting activity and antigen level. The data suggest that in patients with lung cancer, there may be an alteration of the protein C molecule, which reduces antigen level and impairs clotting activity without affecting amidolytic activity. The negative correlation with EAT levels might point to limited degradation of protein C by neutrophil enzymes, leading to partial loss of epitopes detected by the immunologic determination and of structures necessary for the biologic effect of protein C upon clotting time. Further studies should clarify whether such a modification of protein C could contribute to the increased incidence of thrombosis in lung cancer patients. Key Words: Lung cancer-Neutrophil elastase-Protein C.

Activation of coagulation and fibrinolysis within tumour tissues is thought to be associated with tumour growth, angiogenesis, and metastasis. The plasma levels of markers of thrombin and plasmin generation are sensitive tools for monitoring activation of coagulation and fibrinolysis. We studied 47 patients with histologically confirmed lung cancer, 15 with small cell (SCLC) and 32 with non-small cell lung cancer (NSCLC). The plasma levels of the following markers were assessed:thrombin-antithrombin III complex (TAT), prothrombin activation fragment F1 + 2, plasmin-alpha 2-antiplasmin complex (PAP) and the split product from cross-linked fibrin, D-dimer. The first sample was obtained before receiving any specific antineoplastic treatment. The patients were followed thereafter until treatment was terminated. There was no difference in activation markers between patients with SCLC and NSCLC. Comparing patients with limited disease to those with extensive disease, there were significant differences in TAT (median 3.0 (1.9-9.8) vs 5.3 (1.8-35.6) micrograms/l,P = 0.021) and D-dimer (569 (135-1948) vs 1288 (120-2221) micrograms/l, P = 0.014). According to the response to subsequent treatment, those who achieved complete or partial tumour remission had significantly lower baseline levels samples than non-responders (TAT 2.9 (1.9-4.0) vs 4.7 (1.8-35.6) micrograms/l,P = 0.0047;D-dimer 527 (135-1149) vs 1242 (120-2221) micrograms/l, P = 0.0013). Thus, the increase of TAT and D-dimer appears to be related to tumour spread. The results suggest that high levels of these markers might be a sign of unfavourable prognosis in patients with lung cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental evidence and preliminary clinical data suggest a responsiveness of pancreatic adenocarcinoma to sex hormones and LH-RH agonists. In this study, we investigated the effect of the antiestrogen tamoxifen and the anti-androgen cyproterone acetate in combination with the LH-RH agonist buserelin in 9 patients with unresectable pancreatic adenocarcinoma. In all patients the disease was progressive under this therapeutic regimen. In conclusion, complete androgen blockade and antiestrogens in combination with LH-RH agonist cannot be recommended in patients with widespread pancreatic adenocarcinoma.

In three consecutive pilot studies the effect of recombinant human granulocyte/macrophage-colony-stimulating factor (rhGM-CSF) on haematopoetic recovery after chemotherapy in patients with small-cell lung cancer was investigated. In study I, 20 patients received AIO chemotherapy (A, Adriamycin 25 mg/m2 on days 1+2; I, ifosfamide 2 g/m2 on days 1–5; O, vincristine 2 mg on day 1) at 4-week intervals either with or without rhGM-CSF (250 μg/m2 sc) from day 8 until recovery of leucocytes. Neither the degree nor the duration of myelosuppression was markedly influenced by rhGM-CSF. Suggesting that these disappointing results were caused by the late onset of GM-CSF application, in the following study we shortened chemotherapy to 3 days and started with GM-CSF on day 4. The main objective of this study was to test whether the earlier administration of GM-CSF allowed treatment intervals to be reduced or the dose to be escalated. After 10 patients had received a starting dose of AIO (A, 50 mg/m2 on day 1; I, 2 g/m2 on days 1–3; 0,2 mg on day 1) alternating with cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 1–3), the dose of ifosfamide and etoposide was escalated to 2.5 g/m2 on days 1–3 and 200 mg/m2 on days 1–3 in the next 10 patients. Treatment was given at 2-week intervals when leucocytes were > 3500/mm3 and thrombocytes were > 100 000 mm3 on day 14. At each dose level patients were randomized to receive either rhGM-CSF 250 μg/m2 s.c. on days 4–12 or no GM-CSF. In this study, rhGM-CSF markedly shortened the duration of leukopenia. Reinstitution of chemotherapy on day 15 was possible at dose level 1 in 1/4 patients without and in 3/4 patients with GM-CSF, and at dose level 2 in 0/5 patients without and in 5/5 patients with GM-CSF. However, the degree of myelosuppression was not improved by GMCSF. In a third study we tried to apply rhGM-CSF simultaneously with chemotherapy. After 3 patients had received GM-CSF starting on day 1 concurrent to AIO chemotherapy, we noticed an increase of myelosuppression with prolonged neutropenia and thrombocytopenia and stopped this investigation. Considering all patients included in these three consecutive pilot studies, there is no difference in response rates and survival between patients with and without rhGM-CSF treatment. Optimal scheduled rhGM-CSF application shortens the period of myelosuppression and allows reinstitution of chemotherapy at 2-week intervals. Whether these modifications are able to improve the overall treatment results, has to be determined in future clinical trials.

Haemorrhagic disorders are known to occur during septicaemia. We studied the role of elastase-like protease (ELP) of human granulocytes in the activation and consumption of clotting factors and their specific inhibitors. Patients with septicaemia and severe bacterial infection were examined for ELP content in polymorphonuclear leukocytes (PNL), as well as plasma levels of ELP complexed to alpha-1 protease inhibitor, total alpha-1 protease inhibitor (alpha-1 PI), clotting factor VII and partial thromboplastin time (PTT). In all patients, a decrease in ELP content of PNL was accompanied by an increase in plasma ELP complexes. The degree to which ELP content of PNL was lowered was related both to the clinical diagnosis and the course of illness. The ELP content of PNL showed a significant positive correlation with plasma factor VII and significant negative correlations with PTT and alpha-1 PI. These data suggest that ELP release is accompanied by stimulation of the production of alpha-1 PI, and may contribute in vivo to the consumption of coagulation factors. The correlation with PTT might point to an activation of Hageman factor, which may activate both intrinsic coagulation and ELP release. The estimation of ELP content in PNL in patients with septicaemia is likely to represent intravascular ELP release during the inflammatory process. It appears to be useful in combination with the assay of ELP complex in plasma the level of which is influenced by the capacity of the reticuloendothelial system for clearance.

In 42 patients with septic shock, 29 of whom underwent substitution with antithrombin III concentrate and fresh frozen plasma for coagulation disorders, the proteinase-inhibitor complexes thrombin-antithrombin III and neutrophil elastase-alpha 1 proteinase inhibitor, were elevated on admission. On admission, the elastase complex was significantly higher in the patients receiving substitution (p = 0.0039), but at the endpoint it was higher in the non-survivors (p = 0.0040). The elastase decrease was confined to the substitution group with the thrombin complex decreasing in both groups. Initially the thrombin complex correlated with prothrombin times and factor XIII, while the elastase complex correlated with creatinine, thrombocyte count and prothrombin times in the late stages. Hemostatic disturbance, thrombin generation and neutrophil elastase release were favorably influenced by substitution. Furthermore, in this uncontrolled pilot study, the survival rate was higher in the treated (16 of 29) than in the untreated (1 of 13) patients, although the treated patients initially had pronounced hemostatic disturbances.

In septic shock both bleeding and clotting may occur: a hemorrhagic diathesis due to a lack of coagulation factors as well as disseminated intravascular coagulation (DIC) leading to impaired organ perfusion. Proteolytic systems appear to be involved in both the enhanced turnover of hemostatic proteins and the damage of microcirculation. The classical concept of DIC implicates the action of thrombin and plasmin, the key enzymes of coagulation and fibrinolysis, resprectively. In the past decade evidence has been accumulated1,2 that neutral proteases from neutrophil granulocytes may contribute to the above mentioned complications, and thus influence the prognosis of septic shock. The appearance of active proteases in the plasma is immediately followed by the formation of complexes with their specific inhibitors. Such proteinase-inhibitor complexes (PIC) were determined in 43 patients with septic shock.