The Inflammatory Cytokine Profile of Patients with Malignant Pleural Effusion Treated with Pleurodesis.

Patients with malignant pleural effusion (MPE) who underwent successful pleurodesis survive longer than those for whom it fails. We hypothesize that the therapy-induced inflammatory responses inhibit the cancer progression, and thereby lead to a longer survival. Thirty-three consecutive patients with MPE that were eligible for bleomycin pleurodesis between September 2015 and December 2017 were recruited prospectively. Nineteen patients (57.6%) achieved fully or partially successful pleurodesis, while 14 patients either failed or survived less than 30 days after pleurodesis. Two patients without successful pleurodesis were excluded because of missing data. Interleukin (IL)-1 beta, IL-6, IL-10, transforming growth factor beta, tumor necrosis factor alpha (TNF-α), and vascular endothelial growth factor in the pleural fluid were measured before, and after 3 and 24 h of pleurodesis. Their pleurodesis outcome and survival were monitored and analyzed. Patients who underwent successful pleurodesis had a longer survival rate. Patients without successful pleurodesis had significantly higher TNF-α and IL-10 levels in their pleural fluid than in the successful patients before pleurodesis. Following pleurodesis, there was a significant increment of IL-10 in the first three hours in the successful patients. In contrast, significant increments of TNF-α and IL-10 were found in the unsuccessful patients between 3 and 24 h after pleurodesis. 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 study of the underlying mechanism may shed light on cytokine therapies as novel approaches.

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy.

Targeted therapy is an efficient treatment for patients with epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Therapeutic resistance invariably occurs in NSCLC patients. Many studies have focused on drug resistance mechanisms, but only a few have addressed the metabolic flexibility in drug-resistant NSCLC. In the present study, we found that during the developing resistance to tyrosine kinase inhibitor (TKI), TKI-resistant NSCLC cells acquired metabolic flexibility in that they switched from dependence on glycolysis to oxidative phosphorylation by substantially increasing the activity of the mitochondria. Concurrently, we found the predominant expression of monocarboxylate transporter 1 (MCT-1) in the TKI-resistant NSCLC cells was strongly increased in those cells that oxidized lactate. Thus, we hypothesized that inhibiting MCT-1 could represent a novel treatment strategy. We treated cells with the MCT-1 inhibitor AZD3965. We found a significant decrease in cell proliferation and cell motility in TKI-sensitive and TKI-resistant cells. Taken together, these results demonstrated that gefitinib-resistant NSCLC cells harbored higher mitochondrial bioenergetics and MCT-1 expression. These results implied that targeting mitochondrial oxidative phosphorylation proteins or MCT-1 could serve as potential treatments for both TKI-sensitive and -resistant non-small cell lung cancer.

Clinical outcomes of chemical pleurodesis using a minocycline.

BACKGROUND: Pleurodesis is often used to prevent the re-accumulation of a malignant pleural effusion (MPE). Intrapleural urokinase (IPUK) therapy facilitates lung re-expansion for patients with loculated MPE or a trapped lung that allows subsequent pleurodesis. MPE management has been traditionally regarded as a symptomatic treatment. We tried to evaluate their impact on patient survival. METHODS: There were 314 consecutive patients with symptomatic MPE that underwent minocycline pleurodesis with ( n = 109) and without ( n = 205) the antecedent IPUK therapy between September 2005 and August 2015, who were recruited for the pleurodesis outcome and survival analysis. RESULTS: The rate of successful pleurodesis was similar between the simple pleurodesis group and the IPUK therapy group followed by the pleurodesis group (69.0% versus 70.5%; p = 0.804). The patients who succeeded pleurodesis had a longer survival rate than those who failed in either the simple pleurodesis group (median, 414 versus 100 days; p < 0.001) or the IPUK therapy followed by pleurodesis group (259 versus 102 days; p < 0.001). The survival differences remained when the lung and breast cancer patients were studied separately. CONCLUSION: Successful pleurodesis translated into a better survival rate that promotes performing pleurodesis on lung re-expansion. 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. The successfully induced inflammatory response by minocycline is supposed to prohibit the tumor invasion and metastasis. Further studies are warranted to clarify the mechanism and provide opportunities to develop novel therapeutic strategies.

Conventional transbronchial needle aspiration is promising for identifying EGFR mutations in lung adenocarcinoma.

BACKGROUND: Conventional transbronchial needle aspiration (TBNA) is advantageous for the one-step diagnosis and staging of lung adenocarcinoma under topical anesthesia and conscious sedation. We examined its efficacy for identifying EGFR mutations. METHODS: Forty-seven patients with proven or suspected lung adenocarcinoma indicated for hilar-mediastinal lymph node (LN) staging between June 2011 and December 2017 were enrolled. The cellblock was prepared using the plasma-thrombin method. TaqMan PCR was used to detect mutations. Considering cost effectiveness, only the sample with the highest tumor cell fraction in the same patient was chosen for analysis. RESULTS: TBNA provided positive results of malignancy in 27 patients. Seventeen patients (63.0%) had cellblocks eligible for mutation testing. Bronchial biopsy (n = 6), neck LN fine needle aspiration (n = 1), and brushing (n = 1), provided higher tumor cell fractions for analysis in eight patients. TBNA was the exclusive method used in nine patients (19.1%). For patients with an inadequate TBNA cellblock, bronchial biopsy (n = 5), neck LN fine needle aspiration (n = 3), computed tomography-guided transthoracic needle biopsy (n = 1), and brushing (n = 1) were used for analysis. Modification to specimen processing to prevent exhaustion by cytology after June 2016 improved the adequacy of cellblock samples (9/10, 90% vs. 8/17, 47.1%; P = 0.042). CONCLUSIONS: These findings suggest the promising role of conventional TBNA and highlight the challenges of doing more with less in an era of precision medicine.

G-Protein Coupled Estrogen Receptor in Breast Cancer.

The G-protein coupled estrogen receptor (GPER), an alternate estrogen receptor (ER) with a structure distinct from the two canonical ERs, being ERα, and ERß, is expressed in 50% to 60% of breast cancer tissues and has been presumed to be associated with the development of tamoxifen resistance in ERα positive breast cancer. On the other hand, triple-negative breast cancer (TNBC) constitutes 15% to 20% of breast cancers and frequently displays a more aggressive behavior. GPER is prevalent and involved in TNBC and can be a therapeutic target. However, contradictory results exist regarding the function of GPER in breast cancer, proliferative or pro-apoptotic. A better understanding of the GPER, its role in breast cancer, and the interactions with the ER and epidermal growth factor receptor will be beneficial for the disease management and prevention in the future.

Estrogen, Estrogen Receptor and Lung Cancer.

Estrogen has been postulated as a contributor for lung cancer development and progression. We reviewed the current knowledge about the expression and prognostic implications of the estrogen receptors (ER) in lung cancer, the effect and signaling pathway of estrogen on lung cancer, the hormone replacement therapy and lung cancer risk and survival, the mechanistic relationship between the ER and the epidermal growth factor receptor (EGFR), and the relevant clinical trials combining the ER antagonist and the EGFR antagonist, to investigate the role of estrogen in lung cancer. Estrogen and its receptor have the potential to become a prognosticator and a therapeutic target in lung cancer. On the other hand, tobacco smoking aggravates the effect of estrogen and endocrine disruptive chemicals from the environment targeting ER may well contribute to the lung carcinogenesis. They have gradually become important issues in the course of preventive medicine.

Pleural fluid osteopontin, vascular endothelial growth factor, and urokinase-type plasminogen activator levels as predictors of pleurodesis outcome and prognosticators in patients with malignant pleural effusion: a prospective cohort study.

BACKGROUND: Rapidly growing cancer cells secrete growth-promoting polypeptides and have increased proteolytic activity, contributing to tumor progression and metastasis. Their presentation in malignant pleural effusion (MPE) and their predictive value for the outcome of pleurodesis and survival were studied. METHODS: Between February 2011 and March 2012, MPE samples were prospectively collected from 61 patients. Twenty-five patients with non-malignant pleural effusion in the same period were included as controls. Pleural fluid osteopontin (OPN), vascular endothelial growth factor (VEGF), and urokinase-type plasminogen activator (uPA) concentrations were measured. RESULTS: Patients with MPE had higher pleural fluid OPN, VEGF, and uPA concentrations than those with non-malignant pleural effusion, but only differences in VEGF were statistically significant (p = 0.045). Patients with distant metastases had significantly elevated pleural fluid VEGF concentrations than those without (p = 0.004). Pleural fluid OPN, VEGF, and uPA concentrations were positively correlated in most patients. However, there was no significant difference in pleural fluid OPN, VEGF, and uPA concentrations between patients with successful pleurodesis and those without. There was also no significant difference in cancer-specific survival between sub-groups with higher and lower pleural fluid OPN, VEGF, or uPA concentrations. Patients with successful pleurodesis had significantly longer cancer-specific survival than those without (p = 0.015). CONCLUSIONS: Pleural fluid OPN, VEGF, and uPA concentrations are elevated in MPE but are not satisfactory predictors of pleurodesis outcome or survival. Patients with higher pleural fluid VEGF concentration have higher risk of distant metastasis. Evaluating the benefits of therapy targeting the VEGF pathway in these patients warrants further studies.

Comparison of 19-gauge eXcelon and WANG MW-319 transbronchial aspiration needles.

Conventional transbronchial needle aspiration (TBNA) using 19-gauge needles can obtain larger histological specimens for hilar-mediastinal diagnosis. A new 19-gauge eXcelon needle was introduced in Taiwan in July 2012. We prospectively enrolled patients with hilar-mediastinal lesions and pathology results of suspected benign origin or lymphoproliferative processes, to perform TBNA using a 19-gauge eXcelon needle, between July 2012 and December 2012. The results were compared with historical control of TBNA using a WANG MW-319 needle between January 2011 and June 2012. The procedure was performed by the same pulmonologist, and rapid on-site cytologic evaluation was used. The 19-gauge eXcelon needle was used in nine patients with 15 lymph nodes aspirated, with a mean diameter of 23.3 ± 10.7 mm. The mean number of needle passes was 2.7 ± 1.4, with a diagnostic accuracy of 77.8%. The MW-319 needle was used in 12 patients with 18 lymph nodes aspirated, with a mean diameter of 21.3 ± 5.7 mm. The mean number of needle passes was 2.2 ± 0.4, with a diagnostic accuracy of 75.0%. Neither technical nor major clinical complications were noted in either group. We concluded that the 19-gauge eXcelon needle was as safe and effective as the MW-319 needle. A more adequate specimen could be obtained and fewer needle passes were required with the MW-319 needle, although the difference did not reach significance.

Safety of interventional bronchoscopy through complication review at a cancer center.

BACKGROUND AND AIMS: There have been rapid advances in the area of interventional bronchoscopy over the past 15 years, but associated complications have been rarely discussed. A longitudinal evaluation of the same operator's performance at a cancer center is reported. METHODS: A detailed record review of diagnostic and therapeutic bronchoscopy between January 1997 and March 2013 was conducted. RESULTS: Among the 1358 diagnostic bronchoscopies, there were nine major complications requiring premature termination and three pneumothoraces found during follow-up (0.88%). An escalation in the level of care was required for four patients with massive bleeding, asthma attack, sedation intoxication and myocardial ischemia, respectively. Six cases occurred after brushing (0.71%), and five cases before any sampling procedure was conducted. The complication rate was highest for peripheral lesions (1.03%). Among the 109 therapeutic bronchoscopies, no major patient-specific complication occurred except for excessive granulation tissue formation following metallic stenting in one patient with benign tracheal stenosis. CONCLUSION: The complication rate with regard to bronchoscopy is comparable with historical controls according to the related literature, and their occurrence appears to be sporadic, not relevant to patient characteristics and mostly related to the bronchoscopy itself rather than the introduction of new techniques. Bronchoscopy remains safe along with technical innovations. However, risk recognition and effective prevention is essential.

Second primary lung cancers among breast cancer patients treated with anti-estrogens have a longer cancer-specific survival.

BACKGROUND/AIM: Estrogen is thought to play an important role in lung cancer carcinogenesis and progression. The incidence and survival of second primary lung cancer among breast cancer patients with and without anti-estrogen therapy were evaluated. PATIENTS AND METHODS: All women diagnosed with breast cancer and treated at the Sun Yat-Sen Cancer Center between January 2000 and December 2009 were included and followed-up for occurrence and/or death from lung cancer until December 2011. RESULTS: Twenty-six women developed second primary lung cancer among 6,361 breast cancer patients. All but one were adenocarcinoma and none had a smoking habit. Seventeen (65.4%) patients had previously received anti-estrogen treatment. The relative risk of developing second primary lung cancer among those who have received anti-estrogens for breast cancer and those who have not was 1.01 (95% confidence interval (CI)=0.45~2.28; p=0.970). Second primary lung cancer patients who have received anti-estrogens had a longer cancer-specific survival (p=0.007). The multivariate Cox proportional hazards analysis showed that anti-estrogen therapy remained an independent prognostic factor with a hazard ratio of 0.11 (95% CI=0.01~0.97, p=0.002) for second primary lung cancer patients. CONCLUSION: The results of this study further support the fact that estrogen adversely affects the prognosis of patients with lung cancer. However, the role of estrogen in lung cancer carcinogenesis remains to be determined.

Estrogen adversely affects the prognosis of patients with lung adenocarcinoma.

Estrogen has been postulated to contribute to the development and progression of lung cancer. We examined the epidemiologic evidence, explored the characteristics of estrogen receptors (ER) in lung adenocarcinoma, and investigated the effect of estrogen on lung cancer cell migration, including the signaling pathway involved. For epidemiologic evidence, a total of 1434 consecutive non-small cell lung cancer patients who underwent standardized staging and homogenous treatment were prospectively enrolled from January 2002 to December 2008, and followed until December 2012. The possible prognostic factors to be analyzed included stage, age, gender, menopausal status, smoking history and histology. For laboratory study, lung cancer cell lines A549 and PE089 and malignant pleural effusions from the patients with lung adenocarcinoma were used. We found that the premenopausal patients had more advanced disease and a shorter survival among the never-smoking female patients with lung adenocarcinoma. ERß was the predominant ER in the lung cancer cell lines. We proposed a different pathway that estrogen upregulated the expression of osteopontin and then promoted cell migration through αvß3 integrin binding and activated MEK-ERK signaling pathway, which is a common downstream pathway with epidermal growth factor receptor (EGFR) activation. An additive effect of ER antagonists and EGFR antagonists on the inhibition of cell migration was also noted. Our results suggest that estrogen adversely affects the prognosis of patients with lung adenocarcinoma. Osteopontin contributed to the cross-talk between ER and EGFR signaling pathways. Estrogen, with its receptor, has the potential to be a prognosticator and a therapeutic target in lung cancer.

Multimodality treatment and long-term follow-up of the primary pulmonary lymphoepithelioma-like carcinoma.

INTRODUCTION: Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a very rare subtype of non-small-cell lung cancer. Most cases are reported in Southeast Asia and are associated with Epstein-Barr virus infections. Because of its rare incidence, the optimal treatment and the results of long-term follow-up are not well understood. This study is an attempt to discover the multimodality treatment results of the primary pulmonary LELC. METHODS: This retrospective study enrolled 21 patients with primary pulmonary LELC treated at 2 hospitals with a multimodality approach, including surgery, chemotherapy, radiotherapy, and targeted therapy. RESULTS: The median follow-up time is 5.9 years and the median survival is 6.4 years. The median overall survival for patients with stage III and with stage IV disease is 3.4 years. In early-stage primary pulmonary LELC, surgery and adjuvant chemotherapy provided good treatment outcome. Advanced primary pulmonary LELC is relatively more chemosensitive and radiosensitive. CONCLUSION: Patients with primary pulmonary LELC showed better prognosis than those with other types of non-small-cell lung cancer and achieved longer survival under multimodality treatment. This disease character is similar to that of nasopharyngeal carcinoma. Accurate pathologic diagnosis is recommended before the treatment. For advanced diseases, platinum-based doublet chemotherapy can be considered the first-line treatment. Radiation dose should consider tumor location, and 5000 to 7000 cGy is frequently applied for pulmonary LELC.

Sex-associated differences in non-small cell lung cancer in the new era: is gender an independent prognostic factor?

BACKGROUND: Women with non-small cell lung cancer (NSCLC) appear to have better survival. This study aimed to evaluate sex differences in NSCLC in recent years. The true effect of gender on the overall survival was analyzed taking other prognostic factors into account. METHODS: A cohort of consecutive NSCLC patients was prospectively enrolled from January 2002 to December 2005, and followed-up until December 2006. They were clinically and pathologically staged and underwent homogenous treatment algorithms. Demographics, histology, and disease stage between sexes were compared. The clinical prognostic factors to be analyzed in addition to gender included stage, age, smoking history and histology. The overall survival of females and males within relevant subgroups defined by smoking history and histology was also compared. RESULTS: Of the 738 patients, 695 were analyzed with a definite stage (94.2%; 315 females and 380 males), which was similar in both sexes. Females were younger (median age: 59.5 years vs. 65.0 years; P<0.001) and more likely to have adenocarcinoma (81% vs. 60.5%; P<0.001). Patients with earlier stage, younger patients, never-smokers and females had better overall survival in univariate analyses and no significant survival difference was noted between adenocarcinoma and squamous cell carcinoma. Multivariate analyses demonstrated age, smoking history and gender to have a hazard ratio 1.46 (95% confidence interval, CI 1.21-1.76; P<0.001), 1.27 (95% CI 0.97-1.65; P=0.082), and 1.18 (95% CI 0.90-1.55; P=0.226), respectively. Subgroup analyses revealed the survival of never-smoker males with adenocarcinoma was similar to that of females. CONCLUSIONS: There are sex-related differences in the clinico-pathologic characteristics and survival of NSCLC patients. The survival advantages of females could be attributed to the younger age and lower smoking prevalence. Never-smokers with adenocarcinoma should be given special attention regardless of sex as they imply better survival with different treatment outcomes.

Characteristics of integrated 18F-FDG PET/CT in Pulmonary Cryptococcosis.

BACKGROUND: Pulmonary cryptococcosis is an uncommon cause of pulmonary nodules found by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) scans. It is rarely reported but may mislead interpretation. PURPOSE: To describe the (18)F-FDG PET/CT findings of pulmonary cryptococcosis. MATERIAL AND METHODS: The (18)F-FDG PET/CT images of seven patients with pulmonary cryptococcosis were evaluated. RESULTS: The (18)F-FDG PET/CT exams showed single or multiple nodular lesions. The standardized uptake values (SUV) in early images varied significantly for the seven patients (ranging from 2.2 to 11.6). Delayed SUVs showed significant increases in four patients. CONCLUSION: Pulmonary cryptococcosis mimics primary or metastatic lung cancer on (18)F-FDG PET/CT scan. Tissue confirmation should be considered for any suspicious pulmonary nodules found on (18)F-FDG PET/CT scan with an SUV score higher than 2.5, in order to avoid overdiagnosis or overstaging.

Novel use of a disposable curved stent insertion plastic device for silicone stent placement in patients with limited neck extension.

As granulation tissue formation frequently complicates the insertion of metallic tracheobronchial stents in patients with longer life expectancy, the inert silicone tracheobronchial stent remains the treatment of choice for inoperable benign tracheal stenosis. Similarly, the Y silicone stent insertion also plays an important role for refractory malignant stenoses involving the carina and tracheobronchial junction. The classic insertion method of a straight or Y silicone stent requires rigid bronchoscopy under general anesthesia with a hyperextended neck. This is not an option for patients with limited neck extension. We report a novel method of silicone stent insertion using a disposable curved stent insertion plastic device to solve the problem in 2 patients. The new device may have a role in managing patients with central airway obstruction but limited neck extension. As a valuable alternative to conventional rigid bronchoscope, it also adds to the ease of the silicone stent placement.

Transbronchial needle aspiration accurately diagnoses subcentimetre mediastinal and hilar lymph nodes detected by integrated positron emission tomography and computed tomography.

OBJECTIVE AND BACKGROUND: Integrated PET and CT (PET/CT) is accurate in detecting hilar-mediastinal metastases. However, it has a moderate positive predictive value, necessitating pathological verification, especially in situations in which the result would make a difference to treatment. This study aimed to evaluate the performance of transbronchial needle aspiration (TBNA) for hilar-mediastinal lesions suspicious on PET/CT. METHODOLOGY: A retrospective study was conducted on 19 patients with a total of 25 positive hilar-mediastinal lymph nodes localized on PET/CT. Standard TBNA technique with rapid on-site cytopathology was performed. RESULTS: The mean short-axis diameter of the positive lymph nodes identified on PET/CT was 9.9 +/- 3.0 mm. The sensitivity, specificity and diagnostic accuracy of PET/CT-guided TBNA were 81.8%, 100% and 84%, respectively. The number of needle passes to successful lymph node aspiration or a diagnosis of cancer was 2.36 +/- 0.49. Nine of the 25 positive lymph nodes (36%) on PET/CT were smaller than 1.0 cm. The accuracy and sensitivity of TBNA for these subcentimetre nodes was 88.9% and 87.5%, respectively. TBNA replaced surgical sampling in 15 patients (78.9%) with positive lymph nodes on PET/CT. In seven non-small cell lung cancer patients, diagnosis and staging were possible in the one procedure. No complications were encountered. CONCLUSION: PET/CT can identify small malignant lymph nodes that can then be successfully biopsied by TBNA with on-site cytopathology.

Computed tomography characteristics of primary pulmonary lymphoepithelioma-like carcinoma.

Primary pulmonary lymphoepithelioma-like carcinoma is a very rare subtype of lung cancer. This report documents the CT features of 16 Chinese patients diagnosed with primary pulmonary lymphoepithelioma-like carcinoma from January 1999 to December 2005. A pre-treatment CT was used to assess the tumour site, size, borders, pleural and vascular involvement, and the presence of lymph node involvement. The majority of the patients were female non-smokers with centrally located tumours. Lymph node involvement and bronchial and vascular encasement were frequent. In an Epstein-Barr virus endemic area, primary pulmonary lymphoepithelioma-like carcinoma is an important differential diagnosis to consider.

Identification of alpha-enolase as an autoantigen in lung cancer: its overexpression is associated with clinical outcomes.

PURPOSE: Although existence of humoral immunity has been previously shown in malignant pleural effusions, only a limited number of immunogenic tumor-associated antigens (TAA) have been identified and associated with lung cancer. In this study, we intended to identify more TAAs in pleural effusion-derived tumor cells. EXPERIMENTAL DESIGN: Using morphologically normal lung tissues as a control lysate in Western blotting analyses, 54 tumor samples were screened with autologous effusion antibodies. Biochemical purification and mass spectrometric identification of TAAs were done using established effusion tumor cell lines as antigen sources. We identified a p48 antigen as alpha-enolase (ENO1). Semiquantitative immunohistochemistry was used to evaluate expression status of ENO1 in the tissue samples of 80 patients with non-small cell lung cancer (NSCLC) and then correlated with clinical variables. RESULTS: Using ENO1-specifc antiserum, up-regulation of ENO1 expression in effusion tumor cells from 11 of 17 patients was clearly observed compared with human normal lung primary epithelial and non-cancer-associated effusion cells. Immunohistochemical studies consistently showed high level of ENO1 expression in all the tumors we have examined thus far. Log-rank and Cox's analyses of ENO1 expression status revealed that its expression level in primary tumors was a key factor contributing to overall- and progression-free survivals of patients (P < 0.05). The same result was also obtained in the early stage of NSCLC patients, showing that tumors expressing relatively higher ENO1 level were tightly correlated with poorer survival outcomes. CONCLUSIONS: Our data strongly support a prognostic role of ENO1 in determining tumor malignancy of patients with NSCLC.

Intrapleural urokinase for the treatment of loculated malignant pleural effusions and trapped lungs in medically inoperable cancer patients.

BACKGROUND: Pleural fluid loculations or trapped lungs frequently render patients with symptomatic malignant pleural effusions (MPEs) unsuitable for pleurodesis. Thoracoscopic surgery or thoracotomy with decortication is generally not feasible for patients with a poor performance status. MPEs have augmented procoagulant and depressed fibrinolytic activity that contributes to fibrin deposition within the pleural space. The authors conducted an observational prospective cohort study to investigate the use of intrapleural urokinase (IPUK) for such patients and made a comparison with a historical control group. METHODS: Between March of 2000 and August of 2005, 48 consecutive patients with symptomatic MPEs with an average Karnofsky performance scale score of 46.7% were recruited. Dyspnea persisted with the presence of substantial residual loculated MPEs in 36 patients and trapped lungs in 12 patients, when the effectiveness of 8-French intrapleural catheter drainage had decreased despite regular saline flushes. Urokinase was instilled daily through the catheter at a dose of 100,000 IU diluted in 100 ml of normal saline for 3 days. Additional IPUK instillation was required upon partial improvement. The records and chest radiographs of another 52 patients with symptomatic MPEs had met these eligibility criteria between January of 1995 and February of 2000 and received saline flushes only were also reviewed. RESULTS: Immediate lung reexpansion and resolution of dyspnea was achieved in 29 of the 48 patients who underwent IPUK therapy (60.4%). The mean dose of urokinase instillations per patient was 360,000 IU. There were no major complications. A significant association of earlier intervention with the success of IPUK therapy was noted. Responders also had a significantly increased drainage within the 24 hours after the first dose of IPUK. Minocycline pleurodesis was subsequently performed for the 29 IPUK responders. Eighteen patients were followed up until death, with a median survival of 6.5 months. The other remained alive at the time of analysis with a median follow-up of 5 months. Two patients had an immediate failure of pleurodesis at 1 month. Three relapses occurred at 3, 4, and 7 months from pleurodesis, respectively. Twenty-three patients (79.3%) had lifelong pleural symphysis, including 21 having loculated MPEs and two having trapped lungs, respectively. Compared with the historical control group, the IPUK study group had significantly greater improvement on chest radiography and a shorter duration of pleural drainage. CONCLUSION: These results suggest that IPUK is a safe and useful nonsurgical adjunct therapy for loculated MPEs or trapped lungs in medically inoperable cancer patients.

Analysis of host versus tumor interaction in cancer patients: opposing role of transforming growth factor-beta1 and interleukin-6 in the development of in situ tumor immunity.

A different degree of immunodeficiency is often found at tumor sites in cancer patients. At the late stage many patients develop malignant effusion that contains large numbers of tumor cells and host immune cells that constantly interact with each other. These sites may provide an ideal model to examine in situ anti-tumor immunity. The T cells in effusion were found to be immunodeficient, which suggested a defective anti-tumor cytotoxic T lymphocytes response. To pursue the mechanism for the T cell deficiency, we determined the production of immunomodulating cytokines in the effusion and detected the presence of transforming growth factor-beta1 (TGFbeta), prostaglandin E2, IL-6, IL-10, and IFNgamma. There was no detectable IL-2, IL-4, IL-12, or TNFalpha. The most prominent feature was the presence of TGFbeta and IL-6 at a very high level. Thus, the possible role of these two cytokines on T cell competence was further determined. TGFbeta was found to induce T cell anergy and reduced the production of perforin in T killer cells and their lytic activity. These events lead to the induction of peripheral T cell tolerance with profound T cell deficiency. IL-6 did not affect perforin production or cytolytic activity of the T killer cells. But the CD4+ CD25+ regulatory T cells (TR) that were often employed by TGFbeta to suppress T cell response were reduced in the malignant effusion, consistent with the fact that IL-6 down-regulates TR and this may represent the host's vigorous response to the tumor's subversion. These results show that TGFbeta and IL-6 might play pivotal but opposing roles in the host tumor interaction that, together with other immunomodulating components, determines the outcome for the development of local tumor immunity.