| 摘要: | 惡性肋膜積水病人經常需要接受肋膜沾粘治療 (pleurodesis) 以防止肋膜積水的再蓄積。對於肋膜沾粘形成的機轉及其對病人存活的影響並沒有完全了解。我們收集61位病人之惡性肋膜積水測定其中與凝血作用平衡、纖維增生與分解平衡及血管新生相關之尿激酶型纖維蛋白溶酶原活化劑 (urokinase-type plasminogen activator，u-PA)、纖維蛋白溶酶原活化物第一型抑制劑 (plasminogen activator inhibitor-1，PAI-1) 及血管內皮細胞生長因子 (vascular endothelial growth factor，VEGF) 濃度。結果顯示肋膜沾粘成功與失敗病人 u-PA 及VEGF 濃度並無顯著差異。高、低濃度 u-PA 及 VEGF病人間存活並無差別，但肋膜沾粘成功的病人有較長的存活期。接著回溯性分析205位單純接受 minocycline 肋膜沾粘治療病人及109位引流後肺擴張不全先進行肋膜腔內注射尿激酶 (urokinase) 治療再施行 minocycline 肋膜沾粘治療病人，兩組肋膜沾粘成功的病人皆有較長的存活期。個別分析肺癌及乳癌病人，此存活差別仍在。肋膜積水引流後呈現間隔性肋膜積水或侷限肺等肺擴張不全情形的病人較肺完全擴張的病人存活短。前者對肋膜腔內注射尿激酶治療無反應的病人，其存活與兩組肋膜沾粘失敗的病人相當。兩組肋膜沾粘成功的病人存活則無差異。如此觀察降低了纖維形成阻絕癌細胞入侵單純物理因素所扮演的角色。後續收集33位接受 bleomycin 肋膜沾粘治療病人。於沾粘藥物注入前後測定肋膜積水中代表性發炎細胞激素-白细胞介素interleukin (IL)-1 beta、IL-6、IL-10、轉化生長因子-β transforming growth factor beta (TGF-β)、腫瘤壞死因子-α tumor necrosis factor alpha (TNF-α) 及VEGF 濃度。沾粘成功的病人，沾粘藥物注入後前3小時， IL-10 有較明顯的上升。沾粘未成功的病人沾粘前有較高的 TNF-α 及 IL-10，沾粘藥物注入後3至24小時 TNF-α 及 IL-10 有較明顯的上升。其他細胞激素則無差別。沾粘藥物注入後肋膜腔內特定細胞激素的產生對沾粘成功與存活有決定性的影響，追蹤其變化有助於幫病人選擇適當的肋膜積水處理方式。觀察沾粘藥物誘發間皮細胞 (mesothelial cells) 或肋膜腔內其他細胞如巨噬細胞等發炎細胞激素的釋放。肋膜積水培養液、發炎細胞激素如 IL-10、 TNF-α 等及其拮抗劑對癌細胞的影響，有助於了解其機轉及發展發炎細胞激素為新的腫瘤治療方法。
Chemical pleurodesis is often used to prevent the pleural fluid re-accumulation in patients with malignant pleural effusions (MPE). However, the mechanism of pleurodesis and its impact on patient survival remains incompletely studied. Pleural fluid urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and vascular endothelial growth factor (VEGF) concentrations, with respect to coagulation cascade, and angiogenesis were measured in 61 patients with MPE. There was no significant difference in the pleural fluid uPA, PAI-1, and VEGF concentrations between the patients with successful pleurodesis and those without. There was also no significant difference in the survival between the sub-groups with higher and lower pleural fluid uPA, PAI-1, or VEGF concentrations. However, patients with successful pleurodesis had significantly longer cancer-specific survival than those without. Retrospective analysis of another 314 consecutive patients with symptomatic MPE who underwent minocycline pleurodesis with (n = 109) and without (n = 205) preceding intrapleural urokinase (IPUK) therapy confirmed the survival advantage of the patients who succeeded pleurodesis. The survival differences remained when the lung and breast cancer patients were studied separately. The apparent shorter survival of the patients with loculated MPE or trapped lung, and those that did not respond to the IPUK therapy, lowered the probability of the survival benefit through the simple physical barrier by the fibrin formation to prevent the tumor spreading. Thirty-three consecutive patients with MPE eligible for bleomycin pleurodesis were studied prospectively. Interleukin (IL)-1 beta, IL-6, IL-10, transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and VEGF in the pleural fluid were measured before, and after three and 24 hours of pleurodesis. Following pleurodesis, there was a significant increment of IL-10 in the first three hours in the succeeded patients. Patients without successful pleurodesis had a significantly higher TNF-α and IL-10 levels in their pleural fluid before pleurodesis, and significant increments of TNF-α and IL-10 between three and 24 hours after pleurodesis. There was no difference of the IL-1, IL-6, TGF-β, and VEGF levels. The ability to produce specific cytokines in the pleural space following pleurodesis may be decisive for the patient’s outcome and survival. Serial measurement of cytokines can help allocate the patients to adequate treatment strategies. Further studies of the release of inflammatory cytokines from mesothelial cell, or other cells, e.g. macrophage in the pleural space and the effects of conditional media from the MPE, specific cytokines, e.g. IL-10, TNF-α and their antagonists on cancer cells will shed light on the cytokine therapies as novel approaches. |
