Mikiko Muramatsu

Monocyte-derived microparticles may be a sign of vascular complication in patients with lung cancer

We measured and compared the levels of plasma monocyte-derived microparticles (MDMP) and platelet activation markers [plasma platelet-derived microparticles (PDMP), CD62P binding to platelets; plt-CD62P, CD63 binding to platelets; plt-CD63], to develop a better understanding of their potential contribution to vascular complications of lung cancer. The concentrations of MDMP and PDMP in lung cancer patients were significantly higher (P < 0.01) than those in normal subjects. Levels of plt-CD62P and plt-CD63 were significantly higher (P < 0.001 for each) in lung cancer patients than in controls. Levels of sE-selectin were also higher in lung cancer patients than in control subjects. MDMP correlated positively with plt-CD62P, plt-CD63, and PDMP with its relation to PDMP being particularly significant. The number of MDMPs and PDMPs are patients who are non-small cell lung cancer were significantly higher than that in small cell lung cancer patients. In addition, levels of sE-selectin were higher in non-small cell lung cancer than in small cell lung cancer patients. These findings suggest that elevated MDMPs may be a sign of vascular complication in lung cancer patients, particularly those who suffer from non-small cell lung cancer.

Gefitinib affects functions of platelets and blood vessels via changes in prostanoids balance.

Prostaglandins (PGs) and thromboxane (TX) produced by cyclooxygenase (COX) have a great influence on vascular systems and platelet functions. The serum levels of epidermal growth factor (EGF) and PGs were measured in patients with lung cancer treated with gefitinib, and the influence of EGF on platelet aggregation was investigated. Twenty patients were investigated. The serum level of TXB2 increased significantly in all patients who received gefitinib for 2 weeks (before vs. after = 94.1 ± 47.3 vs. 190.9 ± 54.3, p<0.01). TXB2 also increased significantly in responders without concurrent chemotherapy (before vs. after = 79.3 ± 35.5 vs. 194.5 ± 58.1, p<0.05), but not in non-responders (before vs. after = 106. 5 ± 65.8 vs. 162. 2 ± 52.8, N.S.). PG 6-keto F1α and PGE2 did not exhibit significant changes. Furthermore, EGF showed no significant change (after vs. before = 234 ± 35 vs. 276 ± 72, N.S.). Although there was no correlation between the levels of EGF and TXB2 (N.S.), the PG 6-keto F2α/TXB2 ratio decreased significantly (before vs. after = 0.054 ± 0.018 vs 0.033 ± 0.015, p<0.05). The secondary platelet aggregation observed after high-dose adenosine diphosphate stimulation was inhibited after a 1-minute preincubation with EGF. Platelet aggregation in patients after gefitinib administration tended to accelerate and secondary aggregation was observed after low-dose adenosine diphosphate stimulation. We conclude that careful observation is needed for patients with chronic obstructive pulmonary disease, pulmonary fibrosis, and thromboembolic diseases receiving gefitinib. Furthermore, measurement of prostanoids may be a good predictor of the beneficial and adverse effects. Moreover, the combination of gefitinib with a COX inhibitor that regulates TXA2/PGI2 balance should be evaluated.

Analysis of cytotoxic T lymphocytes and Fas/FasL in Japanese patients with non-small cell lung cancer associated with HLA-A2.

Abstract Purpose. In recent years, the use of immunotherapy for malignant tumors has been proposed. To explore the significance of immunotherapy for lung cancer, we examined two systems : the HLA class I and cancer-reactive CTL system, and the Fas-FasL system. Methods. HLA class I (HLA-A, -B, and -C) antigens were determined in 61 patients with lung cancer and in 30 healthy controls. The HLA class I phenotype was investigated by serological techniques. HLA-A2 alleles were investigated by polymerase chain reaction sequence-specific primer analysis. We analyzed lymphocytes isolated from 61 patients with two-color surface labeling and flow cytometry. Furthermore, we analyzed sFas and sFasL expression by enzyme-linked immunosorbent assay (ELISA). We also examined lung cancer cell line-induced apoptosis of CD8+ lymphocytes using confocal laser scanning microscopy. Results. The HLA-A2 allele was observed in 27 of 61 patients with lung cancer. There were no differences in HLA-A2 allele classifications between lung cancer patients and controls. Thirty-six of the 61 lung cancer patients (57%) had elevated levels of sFas, and 16 of the 61 patients (26.2%) had elevated levels of sFasL. The sFas level of lung cancers with HLA-A2 was significantly higher than that of cancers without HLA-A2 (P<0.01). This tendency was observed in every lung cancer tissue type, and the sFas levels of lung cancers with HLA-A2 associated significantly with the CTL levels of lung cancers with HLA-A2. Furthermore, compared to lung cancers without HLA-A2, CD8+ T-cell levels were elevated in lung cancers with HLA-A2. In contrast, sFas levels of non-small cell lung cancers without HLA-A2 were higher than those in lung cancers with HLA-A2. In an in vitro experiment using lung cancer cell lines, we observed apoptosis of CD8+ lymphocytes induced by lung cancer cells. Lung cancer-reactive CTLs are mobilized easily by restriction of HLA-A2, but this restriction is not always specific. In addition, FasL derived from lung cancer cells can induce apoptosis of CD8+ T-cells, and the frequency of this phenomenon is increased in small cell lung cancers without HLA-A2. Conclusion. Our findings suggest that the effect of immunotherapy may be insufficient for non-small cell lung cancer without HLA-A2.

Acute myocardial infarction with lung cancer during treatment with gefitinib: the possibility of gefitinib-induced thrombosis.

administration of gefi tinib was then started. A good response was observed but with a grade 1–2 skin adverse toxicity ( table 1 , period A). Two months later she complained of severe fatigue, and electrocardiography (ECG) revealed ischemic changes ( table 1 , period B). She was diagnosed with acute myocardial infarction. Therefore, the administration of gefi tinib was halted. On admission day, ECG revealed sinus rhythm with an ST elevation in leads V 1–3 and a T wave inversion in leads V 3–6 ( fi g. 1 ). However, there were neither changes in ECG fi ndings nor abnormalities in laboratory tests over the next 24 h ( table 1 , period C). On the other hand, echocardiographic fi ndings were consistent with a diagnosis of myocardial infarction in the left anterior descending area. After 2 weeks’ observation, the administration of gefi tinib was restarted under the continued treatment with aspirin ( table 1 , period D). Following about 2 weeks’ administration of gefi tinib, a minor response of the lung cancer was observed. An analysis of platelet aggregation, stimulated by ADP or collagen before and after 2 weeks of receiving gefi tinib, was performed. Both ADP and collagen-induced aggregations were suppressed before the restart of gefi tinib. However, both the aggregations exhibited a tendency towards enhancement after the restart of gefi tinib.

Fiberoptic bronchoscopy induces platelet activation

Activated platelets are implicated in various clinical conditions. For example, soluble (s)P-selectin or platelet-derived microparticles have been detected in patients with diabetes mellitus, hypertension, hyperlipidemia and coronary artery diseases [1–3]. In addition, activated platelets are implicated in thrombosis after percutaneous coronary intervention [3, 4]. However, to our knowledge, there have been few studies on the relationship between activated platelets and fiberoptic bronchoscopy (FOB). Complications associated with FOB examination sometimes occur. Most often these are due to tissue damages during the FOB procedure. We measured levels of soluble selectins in citrated plasma and evaluated platelet counts in the peripheral blood of 12 patients who had underwent FOB without any complications, because these factors are capable of causing the FOB-related proinflammatory process. Blood samples were collected from the patients before and after FOB. Although platelet counts significantly decreased until 4 h after FOB (before FOB vs. 4 h after FOB; 221 43 10/ml vs. 183 39 10/ml, P<0.01), they then increased at 24 h after FOB (207 44 10/ml). In contrast, the serum levels of sP-selectin were significantly increased after FOB (before FOB vs. 24 h after FOB; 236 65 vs. 314 78ng/ml, P<0.01). However, the serum levels of sE-selectin and sL-selectin exhibited no significant changes. The significant decrease of platelet counts after FOB may be due to consumption of platelets following focal tissue damage. When platelet activation and agglutination occur in the damaged area, the activated platelets release several cytokines and upregulate P-selectin [1, 5, 6]. Um et al. [7] reported that platelet activation and post-bronchoscopy fever occurred in relation to the severity of bleeding during FOB. In addition, it has been reported that sP-selectin is elevated in acute lung injury and after severe trauma [8, 9]. Our results accord with these previous reports. Some sP-selectins are generated from endothelial cells [1]. On the other hand, increases in sE-selectin in the blood can be used to quantify endothelial activation [10]. The lack of elevation of sE-selectin in the present study indicates minimal activation of the epithelium. Therefore, we consider that the elevation of sP-selectin after FOB was mainly released from platelets. The sP-selectin also could modulate leukocyte adhesion to the P-selectin expressed on platelets and endothelial cells [1]. We conclude with the following hypotheses. The tissues and microvascular system receive damage during the FOB procedure and therefore platelet agglutination and activation occur. Several cytokines and chemokines are released from the activated platelets and up-regulate P-selectin in the damaged area. Leukocyte chemotaxis and migration into the damaged pulmonary region are subsequently induced, thus triggering the activation of other inflammatory cells. However, sP-selectin can inhibit the interaction between leukocytes and endothelial cells. The FOB procedure probably induces the proinflammatory process in most cases. Nevertheless, complications such as severe fever or pneumonia are rare. One of the reasons for this