Malignant Pleurisy Research Articles

Differential diagnosis of tuberculous pleurisy by the measurement of cytokine concentration in pleural effusion

Pleural fluids obtained from 26 patients with tuberculous pleurisy (T-group), 11 with parapneumonic pleurisy (B-group) and 21 with malignant pleurisy (M-group) were tested for their biologic parameters and cytokine concentrations. 1) The average age of T-group was over 10 years lower than that of M-group with a statistically significant difference. 2) The average CRP value of B-group and the positivity on PPD skin test of T-group were higher than those of the other groups, respectively. 3) Yellowish pleural fluids were mainly observed in T- and B-group, while bloody pleural fluids were mostly seen in M-group with a statistically significant difference. The average total protein amount and adenosine deaminase value in pleural fluid significantly increased in T-group. The percentage of polymorphonuclear leukocytes showed a significant increase in B-group, while lymphocytes significantly increased in T-group with a statistically significant difference. 4) Although no significant difference in concentrations of IL-1 beta, IL-2, IFN-gamma and TNF-alpha in serum was noticed among the three groups, the average concentrations of IFN-gamma and TNF-alpha in pleural fluid in T-group were significantly higher than those in the other groups. 5) TNF-alpha-mRNA of mononuclear cells in pleural fluid was strongly expressed in 3 out of 11 patients of T-group, while no expression was observed in 6 patients of M-group. In conclusion, the measurement of concentrations of two kinds of cytokines in pleural fluid, IFN-gamma and TNF-alpha, may be clinically useful for the differential diagnosis of tuberculous pleurisy from parapneumonic pleurisy and malignant pleurisy.

Malignant pleurisy and intrathoracic dissemination in carcinoma of the lung: Diagnostic, therapeutic and prognostic implications: Ishida T, Kohdono S, Hamatake M, Fukuyama Y, Tateishi M, Sugimachi K et al. Department of Surgery II, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812. Int Surg 1995;80:70–74

Of T4 disease of lung cancer, malignant pleurisy and intrathoracic dissemination are the greatest factor preventing a cure, despite the best efforts of surgery and various adjuvant therapy modalities. Preoperative evaluation of this disease is of first importance using conventional radiology and computed tomography. Of the 43 patients who were intraoperatively diagnosed to be the disease, 8 (18%) appeared on the conventional radiology as small amounts of pleural effusion, and 9 (21%) with a interlobar pleural thickening. Based on CT findings, 16 (67%) had one or more of some disseminated nodules, interlobar pleural thickening and broad pleural indentation. In patients with T4 disease, the 5-year survival rate was 14% in patients with malignant pleurisy and/or intrathoracic dissemination, compared with the 18% in those with direct invasion to great vessels, with no significant difference. According to intrapleural instillation as postoperative adjuvant therapy, the 5-year survival rate was 25% in the patients given interleukin-2, compared with 38 months of survival time for patients prescribed doxorubicin and 33 months for those underwent exploratory thoracotomy. A more favorable prognosis of patients whose malignant pleurisy and/or intrathoracic dissemination are first found at thoracotomy can be expected when postoperative intrapleural instillation of interleukin-2 is prescribed following the resection of the intrathoracic tumors.

OK-432 induces production of neutrophil chemotactic factors in malignant pleural effusion.

We investigated the changes in cellular components and neutrophil chemotactic factors in pleural fluid from 19 lung cancer patients who received intrapleural injection of OK-432 to treat malignant pleurisy. Not only neutrophil chemotactic activity (NCA) but also neutrophil count and percentage were increased significantly at 6 hours after OK-432 injection. The neutrophil count was significantly correlated with NCA level. The levels of C5a and IL-8 in pleural fluid were increased significantly after OK-432 injection. The increased IL-8 level was associated with a increase of both NCA and neutrophil count. OK-432 treatment also induced a marked increase of IL-1 beta and IL-6 in pleural fluid. Thus, intrapleural injection of OK-432 induced production of neutrophil chemotactic factors (IL-8 and C5a) and cytokines (IL-1 beta and IL-6), which eventually attracted neutrophils into the pleural space. These observations suggest that neutrophil migration mediated by these factors and cytokines may contribute to the sclerosing effects of OK-432 treatment.

Tumour necrosis factor-α and nitric oxide, determined as nitrite, in malignant pleural effusion

Pleurodesis treatment is often used to stop chronic pleural effusion in malignant pleurisy. During the treatment a strong intrapleural inflammation is induced leading to the cessation of exudation. In this study the concentrations of tumour necrosis factor (TNF-alpha) and nitric oxide (NO), determined as its immediate metabolite nitrite, were measured in pleural fluid, in order to investigate if they were involved in pleural inflammation and pleural fluid exudation. Determinations were made in pleural fluid from patients with malignant pleural effusion, before and during therapeutic quinacrine-induced pleural inflammation. TNF-alpha concentrations were measured by ELISA-technique and NO/nitrite by chemiluminescence. TNF-alpha increased significantly after quinacrine instillation. NO/nitrite was initially present at the same concentrations as found in normal serum, and increased significantly during treatment. Concentrations of TNF-alpha correlate with the amount of pleural fluid production after quinacrine instillation, in that a higher level of TNF-alpha is associated with more pleural fluid production. No correlation was found between TNF-alpha and NO/nitrite, whereas a weak but significant correlation was found between NO/nitrite and concentrations of another cytokine, interleukin-1 beta (IL-1 beta). The results suggest that TNF-alpha might contribute to pleural fluid exudation and that TNF-alpha and NO are of importance in induced pleural inflammation. IL-1 beta might be one of several stimuli for NO formation in this setting.

Pharmacokinetics of cisplatin instilled into the pleural cavity following panpleuropneumonectomy in patients with malignant pleurisy due to lung cancer : Yasumoto K, Shimokawa T, Nagashima A, Hirose N, Nakahashi H. Department of Chest Surgery, Kitakyushu Medical Center, Bashaku 2-1-1, Kokura-kita-ku, Kitakyushu, Fukuoka 802. J Surg Oncol 1993;54:67–70

Pharmacokinetics of cisplatin instilled into the pleural cavity following panpleuropneumonectomy in patients with malignant pleurisy due to lung cancer : Yasumoto K, Shimokawa T, Nagashima A, Hirose N, Nakahashi H. Department of Chest Surgery, Kitakyushu Medical Center, Bashaku 2-1-1, Kokura-kita-ku, Kitakyushu, Fukuoka 802. J Surg Oncol 1993;54:67–70

Induction of inflammatory cytokines in the pleural effusion of cancer patients after the administration of an immunomodulator, Ok-432: Role of IL-8 for neutrophil infiltration

When OK-432, a well-known streptococcal preparation for an anti-tumour drug, was administered into the pleural cavity of patients with malignant pleurisy, a rapid and prominent leukocytosis, predominantly consisting of neutrophils, was observed in the cavity. Neutrophil infiltration usually peaked 6-9 h after OK-432 administration, and levelled down after 24 h. Prior to the neutrophil accumulation, transient but marked elevation of various inflammatory cytokine levels including IL-1 beta, TNF-alpha, IL-8 and G-CSF was observed. In particular, IL-8 levels increased more than 10-fold, while GM-CSF did not change significantly. A good correlation between IL-8 levels and neutrophil chemotactic response was observed particularly during 0-3 h. Specific neutralization or removal of IL-8 by antibody column abrogated half of the neutrophil chemotaxis, while neutralization of C5a removed around 40%. Sequential removal of IL-8 and C5a abrogated totally 80% of chemotaxis, confirming that these two factors are mostly responsible for the neutrophil chemotaxis in the pleural fluids. These results have suggested that rapid neutrophil infiltration induced by OK-432 in vivo is ascribable largely to IL-8 and in part to C5a.

Pharmacokinetics of cisplatin instilled into the pleural cavity following panpleuropneumonectomy in patients with malignant pleurisy due to lung cancer

The pharmacokinetics of cisplatin instilled into the pleural cavity in patients with malignant pleurisy due to lung cancer were studied. Higher concentrations of total and free platinum in pleural effusion have been maintained for longer than 72 hours in patients who were subjected to panpleuropneumonectomy than in those who received simple drainage. Early rapid drop of total platinum within 6 hours was significant in the drainage group. Total platinum level in the serum of the panpleuropneumonectomy group gradually increased during 1-72 hours, however, that of the drainage group was highest at 1 hour after instillation and declined gradually with time. Free platinum in the serum was also present at lower concentrations in the panpleuropneumonectomy group than in the drainage group. These facts may be ascribed to the absorptive activity of parietal pleura which is present in the drainage group but absent in the panpleuropneumonectomy group. In summary, removal of the parietal pleura by panpleuropneumonectomy could cause cisplatin to be not only more active but also less toxic in patients with malignant pleurisy due to lung cancer.

Cooperation between Accessory Cells and T Lymphocytes in Patients with Tuberculous Pleurisy

We studied interleukin 1 (IL-1) activity of pleural fluid macrophages and peripheral blood monocytes obtained from ten patients with tuberculous pleurisy and ten patients with malignant pleurisy, using purified protein derivative (PPD) as a stimulating agent. Tuberculous pleural fluid macrophages and peripheral blood monocytes tended to produce higher IL-1 activity than malignant pleural fluid macrophages and blood monocytes and showed significantly more IL-1 activity than healthy control monocytes. However, no significant difference in IL-1 activity was observed between tuberculous pleural macrophages and blood monocytes. With the cooperation of these accessory cells, pleural fluid T lymphocytes in patients with tuberculous pleurisy showed a significant level of interleukin 2 (IL-2) activity in the presence of PPD. Tuberculous pleural fluid macrophages promoted greater IL-2 production than blood monocytes from either tuberculous pleural fluid or blood T lymphocytes despite relative equivalence in measured IL-1 production. Combination of tuberculous pleural fluid macrophages and pleural fluid T lymphocytes was the most effective for increasing IL-2 activity when compared with other combinations. These results suggest that tuberculous pleural fluid macrophages and T lymphocytes may contribute to the immunopathogenesis of tuberculosis at a local site of disease.

Intrapleural application of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer

Forty-three patients with malignant pleurisy due to lung cancer were entered into the trial to evaluate clinical efficacy of intrapleural instillation of recombinant interleukin-2 (RIL-2). Among 35 evaluable patients, serial cytological examinations of pleural effusion following the start of the treatment revealed disappearance of malignant cells in 26 (74%). Malignant cells were detected again in 7 of the 26, however, cytology remained negative in the other 19 patients for longer than 4 weeks. Pleural effusion disappeared roentgenographically in 13 of 35 evaluable patients. Additional 8 patients demonstrated marked decrease of pleural effusion. Complete response (CR) which means disappearance of both malignant cells and pleural effusion for longer than 4 weeks was obtained in 13 of the 35 patients (37%). No serious side effects were experienced in this trial. These results indicate that intrapleural RIL-2 is one of candidates to control intractable malignant pleurisy due to lung cancer.

Etiologic Considerations of Nonspecific Pleuritis

Twenty-three patients with nonspecific pleuritis were studied to determine clinical outcome. After a mean follow-up period of 6 months (1 to 36 months), a diagnosis was reached in 17 patinets, while 6 patients remained unknown.The causes of the nonspecific pleuritis diagnosed on initial pleural biopsy were tuberculosis (11 patients, 48%), neoplasm (2 patients, 8.7%), parapneumonic effusion (1 patient), subphrenic abscess (1 patient), congestive heart failure (1 patients), and nephrotic syndrome (1 patient).The diagnosis was made by therapeutic trials (tuberculosis: 11 patients, parapneumonic effusion: 1 patient, congestive heart failure: 1 patient), by repeat pleural biopsy in 1 hepatoma, by open thoractomy in 1 lung cancer, by exploratory laparotomy in 1 subphrenic abscess, and by kidney biopsy in 1 nephrotic syndrome.The WBC counts (more than 2,000/mm3) and lymphocyte percentage (more than 60%) in the pleural fluid were significantly elevated in the patients with tuberculosis compared to those with malignant pleurisy, and other laboratory data were meaningless.As a result of this investigation, we suggest that tuberculous pleurisy is the most common cause of nonspecific pleuritis in Korea and that therapeutic trial with antituberculous medication for patients with high WBC count and lymphocyte percent in pleural fluid can help to locate the nonspecific pleuritis.

Cytokine Content in Pleural Effusion: Comparison between Tuberculous and Carcinomatous Pleurisy

Tuberculous pleurisy is a good model for resolution of local cellular immunity. It would be expected that tuberculous pleural fluid contains a variety of immunologically important cytokines because of the accumulation of immunocompetent cells in the pleural cavity. We studied interleukin 1 (IL-1), interleukin 2 (IL-2), and interferon gamma (IFN-gamma) levels in pleural fluid of 20 patients with tuberculous pleurisy and compared them with those in pleural fluid of 20 patients with malignant pleurisy. We also evaluated adenosine deaminase (ADA) levels in both effusions. Tuberculous pleural fluid had higher levels of IL-1, IL-2, IFN-gamma, and ADA than malignant pleural fluid. Although the difference of IL-1 level between tuberculous and malignant pleural fluid was modest, that of IL-2, IFN-gamma, and ADA was dominant. These findings suggest that activated T lymphocytes in tuberculous pleural fluid concern the production of lymphokines at the morbid site and they effectively exert local cellular immunity through the action of such lymphokines.

Fluid production in malignant pleurisy - The role of the fibrinolytic and coagulation systems

Fluid production in malignant pleurisy - The role of the fibrinolytic and coagulation systems

Eosinophil Colony-stimulating Factor Induced by Administration of Interleukin-2 into the Pleural Cavity of Patients with Malignant Pleurisy

Systemic administration of interleukin (IL)-2 to patients with malignant diseases induces peripheral eosinophilia. In the present study, to clarify the mechanism of eosinophilia induced by IL-2, we examined the changes in the number of eosinophils and eosinophil colony-stimulating factor (Eo-CSF) activity in the pleural fluids of six patients with malignant pleurisy caused by lung cancer or malignant mesothelioma during and after intrapleural administration of IL-2. Results showed that intrapleural administration of IL-2 induced marked eosinophilia in the pleural fluid and moderate eosinophilia in the peripheral blood, and that during IL-2 administration, marked Eo-CSF activity appeared in the pleural fluid before increase in the number of eosinophils, but that this activity did not appear in the peripheral blood. This Eo-CSF activity was inhibited by a combination of anti-IL-5 antibody, anti-IL-3 antibody, and anti-granulocyte/macrophage colony-stimulating factor (anti-GM-CSF) antibody, but not by each antibody alone. Chemotactic activity for eosinophils was also detected in the pleural fluid during IL-2 treatment. These results suggest that eosinophilia in the pleural fluid induced by IL-2 injection into the pleural cavity of patients with malignant pleurisy is due to the Eo-CSF activities of various components, including IL-5, IL-3, and GM-CSF, and chemotactic factors for eosinophils induced locally in the pleural cavity by IL-2.

Effectiveness of intrathoracic chemothermotherapy for malignant pleurisy due to Ewing's sarcoma: A case report

This paper describes a case of malignant pleurisy which showed evidence of the effectiveness of a new mode of cancer treatment, intrathoracic chemothermotherapy (ICT). ICT consisted of a bolus intrathoracic injection of 50 mg cis-diamminedichloroplatinum (CDDP) and local heating using 8 MHz radiofrequency waves for 60 min. A patient with multiple lung metastases and malignant pleurisy on both sides due to Ewing's sarcoma was treated on the right side with ICT, along with concomitant systemic administration of 50 mg CDDP. Intrathoracic temperatures were monitored by insertion of thermocouple temperature sensors, and temperatures of 43 degrees C or over were successfully maintained for about 40 min during each of three treatments. Although the patient died 3 months later of advanced metastases in the left lung and malignant pleurisy on the left side, lung metastases in the right lung were stable on radiographs, and autopsy results showed no cancerous lesions in the right thoracic cavity, which had been treated with ICT. Since no effective response had been obtained clinically or histologically before starting ICT, despite frequent administration of anti-cancer drugs, we conclude that heat acted synergistically with CDDP on drug-resistant cells in this case.

Eosinophil colony stimulating activity induced by administration of interleukin-2 into the pleural cavity of patients with malignant pleurisy

Systemic administration of interleukin-2 (IL-2) in patients with malignant diseases induces peripheral eosinophilia. In the present study, to clarify the mechanisms of eosinophilia induced by IL-2, we examined the changes in the number of eosinophils and in eosinophil colony stimulating activity (Eo-CSA) in the pleural fluid of six patients with malignant pleurisy caused by lung cancer or malignant mesothelioma, during and after intrapleural administration of IL-2. Results showed that intrapleural administration of IL-2 induced marked eosinophilia in the pleural fluid and mild eosinophilia in the peripheral blood, and that during IL-2 administration, marked Eo-CSA appeared in the pleural fluid before increase in the number of eosinophils. The Eo-CSA seemed to be a polypeptide or protein because it was trypsin-sensitive and had a molecular weight of 40-60 kDa.

Hyperammonemia in Multiple Myeloma

Two patients with multiple myeloma who appeared to be producing ammonia are reported. Both patients showed hyperammonemia and amino acid disturbances, such as a low Fischer ratio. One patient had Bence Jones protein (lambda) type myeloma and became comatose, but the hyperammonemia and disturbance of consciousness were improved by chemotherapy for the myeloma. The other patient had IgA kappa type myeloma and somnolence and died of malignant pleurisy despite intensive chemotherapy. Autopsy showed widespread multiple myeloma and an almost normal liver. Ammonia levels in the supernatant of cultured myeloma cells from the patient's pleural effusion increased almost linearly from the time of cell seeding. These observations showed that ammonia was produced at a high level by these human myeloma cells. We also found that one of the common myeloma cell lines, RPMI 8226, could produce ammonia as well.

Effect of combined intrapleural administration of Lactobacillus casei (LC9018) and adriamycin on experimental malignant pleurisy in mice.

The combined effect of Lactobacillus casei YIT9018 (LC9018) and adriamycin (ADR) on malignant pleurisy was investigated using an experimental model in BALB/c mice in which Meth A fibrosarcoma cells were intrapleurally implanted. The control mice died from dyspnea due to pleural effusion, before significant growth of tumor nodules could be achieved in the thoracic cavity. Intrapleural (ipl) administration of LC9018 (20–200 μg/head) on days 1 and 5 reduced the effusion volume and induced pleural adhesions in a dose‐related manner. A statistically significant and reproducible prolongation of survival was observed at a dose of LC9018 200 μg/head: increase of lifespan (ILS) values of 15–39% were obtained. An ipl administration of ADR (2–4 mg/kg) on day 1 was also effective in prolonging survival without severe toxicity (ILS values of 100–122%). The combined use of ADR and LC9018 induced a high incidence of pleural adhesions, a delay in effusion accumulation, and an additive prolongation of lifespan (ILS values of 133–178%), compared with ADR monotherapy. In the combination therapy group, a marked and continuous ipl exudation of neutrophils, macrophages, and lymphocytes was observed with a significant decrease in pleural tumor cells. These findings suggest that ipl administration of LC9018 enhances the effect of ADR, probably through both host‐mediated tumoricidal activity and sclerosing effects on the pleura.

Activation of complements in pleural fluids from patients with malignant pleurisy.

Pleural fluids obtained from 17 patients- 7 with malignant pleurisy, 6 with infectious pleurisy, 4 with transudative pleurisy were analyzed for total hemolytic complement titers (CH 50), levels of six complement (C) components (C1q, C1s, C4, C3, factor B and C5), conversion products of C3, immune complexes (IC) and anti-complementary activities. The mean levels of each CH 50, C4 and C3 in the malignant group were significantly reduced compared with those in the infectious group (P<0.001, P<0.01, P<0.1 respectively) and also those in the transudative group (P<0.01, P<0.1, P<0.05 respectively). The mean level of C1q in the malignant group was lower than that in the infectious group (P<0.001). The mean level of conversion products of C3 in the malignant group (P<0.05) as well as that in the infectious group (P<0.1) increased compared with the transudative group. Neither IC nor anti-complementary activities were found in the malignant group. The above results suggested that the binding of tumor-specific antibodies to tumor cells might activate classical C pathway mainly and cause C depletion in malignant pleural effusions.

Immunohistochemical analysis of human lung cancers with anti-ras p21 monoclonal antibodies.

The expression of ras oncogene product p21 in human malignant pleurisy and primary lung cancer was studied immunocyto-histochemically with monoclonal antibodies (MoAbs) rp-28 and rp-35 against ras p21. In pleural effusion cells, cancer cells revealed more intensively positive reaction with MoAb rp-35 than with MoAb rp-28, especially in the plasma membrane, and no positive reaction was obtained in any kind of inflammation cells with the exception of faintly positive reaction in the cytoplasm of macrophages. In primary lung cancers, well or moderately differentiated adenocarcinoma tissues showed higher reactivity with MoAb rp-28 than those of poorly differentiated adenocarcinoma or any other histological subtype of lung cancer. With MoAb rp-35, intensively positive reaction was obtained in most of cases with all different histological subtypes of lung cancer. The staining in cancer cells was usually localized intensively to the plasma membrane and weakly to the cytoplasm with both MoAbs. Normal bronchial epithelial and glandular tissues showed only cytoplasmic staining. These two MoAbs, especially MoAb rp-35, may be useful in clinicopathological applications for the diagnosis of malignant pleurisy and primary lung cancer.

Treatment of Malignant Pleural Effusion

Two hundred consecutive patients with malignant pleural effusion were reviewed. The pathologic etiology of malignant pleurisy was: primary lung cancer in 123 cases; five, mesothelioma; and 72 cases secondary to metastatic tumors. Adenocarcinoma of the lung and mammary cancer were the most frequent tumors causing malignant pleural effusion. The modalities employed in local treatment consisted of thoracocentesis in 62 patients, tube thoracotomy in 111 cases with local instillation of adriamycin, MMC, CQ, 5FU, OK432 or talc. Surgical procedures including pleuropneumonectomy or reduction surgery of the tumor with decortication were performed in ten patients. Tube drainage with local instillation of drugs was more effective than thoracocentesis with or without local therapy. Excellent initial results were obtained in patients who received reduction surgery with decortication and pleurodesis. Results of cytologic investigation were positive in 157 cases (78.5 percent). The tumor cells disappeared in 79.4 percent of primary cancer pleurisy cases and 81.1 percent of patients with metastases while disappearance or significant decrease in pleural effusion following treatment was obtained in 75.2 and 77.8 percent respectively. The median survival was 11.3 months in primary cases, and 11.7 months in patients with metastases.