Effusions Of Cancer Patients Research Articles

Risk factors and outcomes of pericardial effusion in cancer patients receiving PD-1 inhibitors

BackgroundProgrammed cell death 1 (PD-1) inhibitors can induce various adverse reactions associated with immunity, of which cardiotoxicity is a serious complication. Limited research exists on the link between PD-1 inhibitor use and pericardial effusion (PE) occurrence and outcomes. MethodsWe conducted a retrospective study at the First Affiliated Hospital of Xi'an Jiaotong University from 2017 to 2019, comparing cancer patients who developed PE within 2 years after PD-1 inhibitor therapy to those who did not. Our primary outcome was the all-cause mortality rate at one year. We applied the Kaplan-Meier method for survival analysis. Multivariate logistic regression was utilized to identify PE risk factors, adjusting for potential confounders. ResultsA total of 91 patients were finally included, of whom 39 patients had PE. Compared to non-PE group, one-year all-cause mortality was nearly 5 times higher in PE group (64.10% vs. 13.46%, P < 0.001). Patients who developed PE within 2 years of taking PD-1 inhibitors were significantly associated with increased all-cause mortality compared with those who did not (HR: 6.26, 95%CI: 2.70–14.53, P < 0.001). Multivariable logistic regression showed that use of sintilimab (OR: 14.568, 95%CI: 3.431–61.857, P < 0.001), history of lung cancer (OR: 15.360, 95%CI: 3.276–72.017, P = 0.001), and history of hypocalcemia (OR: 7.076, 95%CI: 1.879–26.649, P = 0.004) were independent risk factors of PE development in patients received PD-1 inhibitors therapy. ConclusionsIn cancer patients receiving PD-1 inhibitors, PE was associated with higher one-year mortality. Use of sintilimab, and history of lung cancer or hypocalcemia were linked to PE occurrence.

Effect of sodium stibogluconate in recruiting and awakening immune cells in the pleural fluid of pancreatic cancer: preparation for immunotherapy.

Ascites and pleural effusion are recognized complications of pancreatic cancer. These diseases are accompanied by ascites and pleural effusion, and drug treatment is limited by high costs, long hospital stays, and failure rates. Immunotherapy may offer new option, but in most patients with late stages of cancer, immune cells may lose the ability to recognize tumor cells, how to activate their immune cells is a major problem, sodium glucosidate (SSG) is injected into ascites as a protein tyrosine phosphatase inhibitor to wake up immune cells and prepare for immunotherapy. We used single-cell RNA sequencing (scRNA-seq) to investigate whether and how SSG injected into ascites of pancreatic cancer elicits an immune response. Our study showed that the process of SSG fusion treatment of ascites and pleural effusion, the interaction between TandNK cells, MPs cells, monocytes and neutrophils was induced, and large numbers of genes were expressed, resulting in upregulation of immune response, which also approved that SSG is not only used as a protein tyrosine phosphatase inhibitor, but also it works as a protein tyrosine phosphatase inhibitor. It can also be used to regulate immune cell function, recruiting immune cells to the right place with the help of PD-1 or PD-L1 to fight cancer cells in ascites and pleural effusions in cancer patients.

1594P Outcome, mortality and 30-day readmission of pericardial effusion in cancer patients

A pericardial effusion (PE) with various inflammatory and non-inflammatory causes can range from an incidental finding to a life-threatening emergency such as a cardiac tamponade. In the literature, little is known about the outcomes of PE in cancer patients. The study's primary objective was to assess whether intervention in PE affects in-hospital mortality and 30-days readmission among cancer patients. A retrospective study of a nationally representative cohort of hospital admissions was conducted from January 1, 2016, to December 31, 2019. Data was collected from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project Nationwide Readmissions Database. All adult patients ≥18 years admitted with primary diagnosis of pericardial effusion in cancer patients were included in the study. We used the International Classification of Diseases, 10th revision, diagnostic codes to identify variable. The type of cancer included in the study were Breast, Lung, pancreatic, bladder, renal, colorectal, lymphoma and acute leukemia. The patients were stratified as PE in cancer patients underwent intervention versus no intervention. A total of 37,430 index hospitalizations for PE in cancer patients were identified for the years 2016-2019 in the NRD with the 27,980 index hospitalizations for PE without intervention, and 9,450 index hospitalizations for PE with intervention. There was no difference in in-hospital mortality for PE with and without intervention (4.5% vs 4.4%; p 0.76). However, PE without intervention had a significantly higher 30-day readmission rate than PE with intervention (31% vs 4.2.0%; p <0.001). The PE with intervention group had higher multi-organ complications including cardiogenic shock (8.6% vs 5.5%; p-value <0.001), Acute Kidney Injury (AKI) (29% vs 24.0%; p-value <0.001), respiratory failure (25% vs 20%, p-value <0.001), pneumonia (15% vs 12.6%, p-value 0.004), atrial fibrillation (27% vs 23.8%, p-value<0.001). Survival rates were not different between patients who received intervention and those who did not, but 30-day readmission rates were significantly higher for patients who did not receive intervention. Cancer patients would benefit from PE intervention.

Clinical outcomes of image-guided percutaneous drainage of pericardial effusion in cancer patients: A single-center retrospective analysis.

Catheter removal, survival, and recurrence rates after percutaneous pericardial effusion drainage in cancer patients are not fully understood. We evaluated the clinical outcomes of image-guided percutaneous pericardial effusion drainage in cancer patients. From January 2014 to September 2017, 113 percutaneous drainages for symptomatic pericardial effusion were performed in 100 cancer patients (median 60 years; range, 7-84 years) using ultrasound or angio-computed tomography. An 8-Fr drainage catheter was placed using the Seldinger technique via the subxiphoid (n=73), apical (n=23), or left parasternal (n=17) routes. Success rates, complications, and postprocedural clinical outcomes of drainages were retrospectively assessed. The technical and clinical success rates were 100% and 99%, respectively, without major complications. The median duration of catheterization and evacuated pericardial effusion volume were 6 days (range, 1-72 days) and 970ml (range, 140-7635ml), respectively. Catheters were removed after the first drainage in 86 cases (86%). Symptomatic pericardial effusion recurred in nine patients after catheter removal, in whom redrainages were performed 13 times with a median duration to redrainage time of 48 days (range, 13-529 days). During the follow-up period (median 106 days [range, 1-1396 days]), 61 patients died. The median survival was 140 days (95% confidence interval [CI], 95-276 days), and the median catheter-free survival was 111 days (95% CI, 60-152 days). Image-guided percutaneous pericardial effusion drainage for cancer patients is safe and helps alleviate symptoms. Additionally, catheter removal is possible in most patients, allowing a catheter-free period for patients.

Treatment of Pericardial Effusion in Cancer Patients

Pericardial effusion is the most common cardiac complication in cancer patients. Lung and breast cancers are the most common solid tumors associated with pericardial effusion. Multimodal tumor therapy improves the overall survival rate and reduces tumor complications. However, these patients need individualized treatment. This paper describes the treatment experience of pericardial effusion, from its pathophysiology, the correct classification of pericardial effusion related to malignant tumor, malignant pericardial effusion or pericardial cancer, to the methods of diagnosis and treatment. The incidence of pericardial effusion in our hospital was 12%. In 11 years of pericardial fenestration, pericardiectomy and subcutaneous catheter (tunneling) installation of pericardium or temporary pleurisy, the postoperative mortality was 1.2%, while the recurrence rate of pericardial effusion was 2.1%, and the recurrence rate of pericardial effusion was 33%. Malignant pericardial effusion is an oncologic emergency. It requires cost-effective management without increasing the incidence of patients who have deteriorated. Thoracoscopic pericardial fenestration (vats) and anterolateral small incision are ideal surgical approaches for malignant pericardial effusion.

ATRIAL FLUTTERS AS AN INITIAL PRESENTATION OF LUNG CANCER CAUSING MALIGNANT PERICARDIAL EFFUSION

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pericardial effusion is a devastating cardiac condition, resulting from various etiology. Cardiac arrhythmia is an uncommon presentation of pericardial effusion, while atrial fibrillation is the most common arrhythmia found in this condition. Atrial flutter, as an initial presentation of malignant pericardial effusion, has not yet been reported. We presented a case of an elderly man with atrial flutter from malignant cardiac effusion from a newly diagnosed lung cancer. CASE PRESENTATION: An 81-year-old man, with chronic obstructive pulmonary disease and hypertension, presented with acute onset shortness of breath. He used albuterol MDI but his symptoms were not improved. On evaluation, he had heart rate 179 beats per minute (bpm), blood pressure 172/118 mmHg without pulsus paradoxus, and respiratory rate of 26. He had good mental status and did not have jugular venous distention. Lungs exam was normal. Heart exam revealed tachycardia without murmur. His blood test was unremarkable. His ECG showed atrial flutter with rapid ventricular rate and 2:1 block. He received intravenous Diltiazem 20 mg and his heart rate decreased to 90. Point of care ultrasound (POCUS) showed large pericardial effusion without tamponade physiology and no signs of pulmonary edema. Computed tomography (CT) chest illustrated large pericardial effusion with new left upper lung mass. Cytology from pericardial effusion revealed squamous cell carcinoma. He was diagnosed as malignant pericardial effusion from advance stage squamous cell lung cancer. His hospital course was complicated with septic shock and eventually death. DISCUSSION: Lung cancer is the most common metastasis cancer to the heart and pericardium because of the proximity of the tumor to the heart [1]. There are several possible explanations of malignant pericardial effusion pathogenesis. First, it can be a result of cardiac lymphatic drainage occlusion by the tumor [2]. Second, local or hematogenous spread of the tumor lead to venous blood flow obstruction and an increase in hydrostatic pressure causing pericardial effusion [3]. Third, neoplastic pericardial involvement stimulates an overproduction of pericardial fluid [3]. Pericardial effusion in cancer patients may arise from complications of treatment, including chemotherapy and radiation, and hypoalbuminemia from malignancy-related cachexia. Cytology analysis of pericardial fluid and pericardial biopsy should be performed to confirm the diagnosis. Management includes pericardiocentesis, pericardial window, pericardial sclerosis, and radiation therapy. CONCLUSIONS: We presented a rare case of atrial flutter secondary to malignant pericardial effusion from newly diagnosis of advanced-stage lung cancer. Clinicians should have pericardial effusion as a differential diagnosis of patients with atrial flutter as this is a catastrophic condition, requiring urgent management. Reference #1: DeCamp MM, et al. Malignant effusive disease of the pleura and pericardium. Chest. 1997;112(4 Suppl):2915-2955. Reference #2: Chiles C, et al. Metastatic involvement of the heart and pericardium: CT and MR imaging. Radiographics. 2011;21(2):438-449. Reference #3: Scheinin SA, Sosa-Herrera J. Cardiac tamponade resembling an acute myocardial infarction as the initial manifestation of metastatic pericardial adenocarcinoma. Methodist Debakey Cardiovasc J. 2014; 10:124–128. DISCLOSURES: No relevant relationships by Nehad Shabarek, source=Web Response No relevant relationships by Kulachanya Suwanwongse, source=Web Response

Prognostic Impact of Pleural Effusion in Patients with Malignancy: A Systematic Review and Meta-Analysis

Background: Pleural effusion is a common complication of tumors, but the exact role of pleural effusion in the prognosis of tumor still remain unclear. We aimed to systematically review the prognostic value of pleural effusion in cancer patients. Methods: We did a systematic review and meta-analysis with a systematic literature search on five databases, including PubMed, Cochrane Library, Medline (accessed via OVID), Embase and Web of Science covering the time from the database creation to April 2, 2020. We included all cohort studies and case control studies with available overall survival and progression-free survival results for cancer patients with or without pleural effusion. The studies with patients below the age of 18 and study population less than 30 were excluded. We applied the Newcastle-Ottawa Scale to assess the study quality. Mantel-Haenszel method was used to calculate the pooled HR and 95% CI. Heterogeneity and publication bias were examined. Subgroup analysis and sensitivity analysis were performed. Findings: A total of 12189 studies were identified by the search and 47 studies with 146117 patients were included in the analysis. For overall survival, the pooled data demonstrated that pleural effusion is a poor prognostic factor for tumor patients (HR 1·58, 95% CI 1·43-1·75; I2 94·8%). For subgroup analysis, pleural effusion is a poor prognostic factor for lung cancer patients (HR 1·44, 95% CI 1·35-1·54; I2 60·8%), hematological tumor patient (HR 2·79, 95% CI 1·63-4·77; I2 29·4%) and other kinds of tumor patients (HR 2·08, 95% CI 1·43-3·01; I2 55·1%). Only in malignant pleural mesothelioma patients, pleural effusion is not a prognostic factor (HR 1·72, 95% CI 0·79-3·71; I2 91·9%). Whether or not malignant effusion is clearly diagnosed, the results cannot be affected. For progression-free survival, pleural effusion is a poor prognostic factor for cancer patients (HR 1·61, 95% CI 1·28-2·03; I2 42·9%). We also observed that massive pleural effusion is a poor prognostic factor (HR 1·32, 95% CI 1·13-1·55; I2 58·0%) compared to minimal pleural effusion, but metachronous pleural effusion is not a poor prognostic factor (HR 1·29, 95% CI 0·60-2·76; I2 93·3%) compared to synchronous pleural effusion. Interpretation: Whether or not malignant effusion is clearly diagnosed, pleural effusion has a poor prognostic value in tumor patients except malignant pleural mesothelioma. It is a prognostic risk factor both in OS and PFS. Massive pleural effusion patients have a worse prognosis than minimal pleural effusion patients. The time of discovery of pleural effusion is not a prognostic factor for tumor patients. However, future evidence of other pleural effusion characteristics such as bilateral pleural effusion or unilateral pleural effusion, bloody pleural effusion or no-bloody pleural effusion is still needed. Funding Statement: This work was supported by grants from Beijing Municipal Administration of Hospitals’ Mission Plan (No. SML20150301), Beijing Nova program (Z171100001117015), Beijing Talents Foundation (2017000021223ZK38) and “1351 Talents Program” of Beijing Chao-Yang Hospital (WXZXZ-2017-01 and CYXX-2017-35). Declaration of Interests: We declare no competing interests.

224 Malignancy associated pericardial effusion- do we need to drain them all?

Abstract On Behalf Cardiac Team, Department of Medicine, Queen Elizabeth Hospital Background Management of significant pericardial effusion in cancer patients is controversial. These patients have poor prognosis, and avoiding unnecessary intervention is important. Close monitoring of symptoms and echocardiogram is often a reasonable option, but inherits risk of cardiac tamponade. Whether pericardial drainage by means of percutaneous pericardiocentesis or surgical pericardiotomy could prevent future deterioration or affect survival is unknown. Purpose To evaluate the benefit of elective pericardial drainage in malignancy associated pericardial effusion without echocardiographic or clinical evidence of tamponade effect. Methods From 1st Jul 2014 to 31st Dec 2017, all patients with new onset malignancy-associated pericardial effusion with size more than 1cm were retrospectively analyzed. Patients with clinical or echocardiographic evidence of cardiac tamponade were excluded. We compared pericardial drainage versus monitoring for short-term (30-day), mid-term (90-day) and long term (1 year) survival without need for drainage. Results 101 patients were retrospectively analyzed. 40 (39.6%) patients underwent drainage. Overall median survival free from drainage was 4 months. There were no significant difference in short-term (30-day), mid-term (90-day) and long term (1-year) survival free from drainage or mortality between treatment and monitoring group. Size of pericardial effusion did not predict mortality or future need of drainage. Chemotherapy was associated with improved 30-day mortality (RR 0.53 CI 0.32-0.87 p = 0.025) but not survival free from drainage or longer term mortality. Conclusion Close monitoring could be a feasible strategy in cancer patients with significant pericardial effusion without tamponade effect. Baseline characteristics Factor Drainage (n = 40) monitoring (n = 61) p-value method of drainage pericardiocentesis alone 17 NA pericardiotomy alone 13 both 10 Male 19 (47.5%) 27 (44.3%) 0.749 mean size (cm) 1.93 2.77 &amp;lt;0.001 mean age 60.9 63.1 0.357 on chemotherapy 27 (67.5%) 38 (62.3%) 0.593 Abstract 224 Figure. Survival free from drainage

Abstract 9773: Outcomes of Cancer Patients Undergoing Percutaneous Pericardiocentesis for Pericardial Effusion

Objectives: We evaluated outcomes of cancer patients undergoing percutaneous pericardiocentesis for pericardial effusion and assessed the procedure’s safety in patients with thrombocytopenia. Background: Pericardial effusion is common in cancer patients. The optimal therapeutic approach is not well defined and in practice depends on patient characteristics and local hospital expertise. Percutaneous pericardiocentesis is less invasive than surgery, but its effectiveness and safety are not well documented. Methods: Cancer patients who underwent percutaneous pericardiocentesis for pericardial effusion between November 2009 and October 2014 at MD Anderson Cancer Center were included. Procedure-related complications, effusion recurrence rate, and overall survival were analyzed. Results: Of 1645 cancer patients referred for pericardial effusion, 212 (13%) underwent percutaneous pericardiocentesis; procedure was successful in 99% of the cases, and there were no procedure-related deaths. Four patients had major procedure-related bleeding necessitating blood transfusions and/or surgical intervention. Procedure-related bleeding did not differ between patients with normal platelet counts and thrombocytopenic patients. Effusion recurred in 26 (12%) patients. Patients with catheter drainage for 3-5 days had the lowest recurrence rate (10%). Median overall survival was 143 days (95% CI, 95-221). Age&gt;65 years, lung cancer, platelet count &lt;20,000/μL, and malignant pericardial fluid were independently associated with poor prognosis. In lung cancer, but not breast cancer, median survival was shorter in patients with malignant effusions than in those with nonmalignant effusions. Conclusion: Percutaneous pericardiocentesis with extended catheter drainage, as primary treatment for pericardial effusion in cancer patients, is safe and effective, including in those with thrombocytopenia. Malignant pericardial effusion significantly shortens the survival outcome of lung cancer patients, but not breast cancer patients.

Abstract 316: Development of a novel 3D cancer model by cultivation of malignant effusions in a 3D cell culture system

Abstract Introduction: Metastatic spread and the occurrence of tumour cell resistance to therapeutic interventions can be induced by different molecular processes. Among those, tumour stroma interactions play a crucial role. So far only few cell culture models exist to study these cell processes. Therefore, we describe the development of a hanging drop technology for 3D culture of primary cells isolated from malignant effusion obtained from cancer patients. Methods: A 96-well hanging drop microtiter plate (InSphero AG, Zürich, Switzerland) was applied for the 3D cultivation of cells. Primary cells were isolated either from malignant ascites or pleura effusion of cancer patients. Cells were seeded either into 2D cell culture plates or into hanging drops for an incubation period of ten days. Apart from conventional histology (H&amp;E), protein expression was displayed immunohistochemically (IHC) and by flow cytometry. The applied antibodies displayed the expression of e-cadherin, vimentin, Ki67, CD31, CD45, Epcam, Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) and α-smooth muscle actin (α-SMA). In addition, viability of all samples was determined by an AnnexinV/Propidium Iodide staining using flow cytometry. Results: Microtissue aggregation differed significantly depending on whether the malignant cell effusions displayed expression of Epcam. Effusions consisting of a high number of Epcam positive cells formed solid and viable microtissues. The viability of microtissues remained high (&amp;gt;80%) similar to cells cultivated in 2D cell culture plates. Tumour cells, defined as e-cadherin and Epcam positive by flow cytometry were still detected in microtissues after ten days of incubation in 3D. Furthermore, endothelial cells, defined as CD31 and Lgr5 positive could also be discriminated in microtissues. Conclusion: We demonstrate that our method is a promising tool for the generation of tumour microtissues consisting of primary isolated cells from malignant effusions. Therefore, our technology represents a promising method to investigate tumour stroma interactions in an in vitro system that reflects more closely the in vivo environment. Citation Format: Arno Amann, Marit Zwierzina, Julia M. Huber, Gabriele Gamerith, Stefan Koeck, Mario Bitsche, Edith Lorenz, Heinz Zwierzina. Development of a novel 3D cancer model by cultivation of malignant effusions in a 3D cell culture system. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 316. doi:10.1158/1538-7445.AM2015-316

Pleurodesis in malignant pleural effusions: Outcome and predictors of success

Malignant pleural effusion is a common clinical problem in cancer patients. Many therapeutic techniques have been investigated, including pleurodesis. Little is known about the factors that may affect the success rate of such a procedure. The main objective of this study is to assess the success rates of pleurodesis performed on malignant pleural effusions in cancer patients at AUBMC and to identify the predictors of a successful pleurodesis. Patients diagnosed with malignant pleural effusions and who have undergone pleurodesis between years 2004 and 2013 at the American University of Beirut Medical Center were identified. Relevant information including patient, tumor and pleural effusion characteristics and outcome after pleurodesis was recorded. Data analysis was done to assess the success rate of pleurodesis as well as for the presence of statistically significant association between success of pleurodesis and the different clinical characteristics. Pleurodesis success rates were as follow: 17.7% had complete success, 12.9% had partial success, 40.3% had failed pleurodesis, 3.2% died shortly after pleurodesis, and 25.8% were lost to follow-up. When this failure rate was further analyzed in terms of the different clinical markers, only two parameters were found to be associated with different success rates of pleurodesis, namely the mean pH of the pleural fluid and the tube used to perform pleurodesis. The conclusions of this study will benefit future cancer patients presenting with malignant effusions. Based on this study's results a well as those of future studies, clinicians will cautiously plan the management of malignant pleural effusion and also refine the technique used.

Palliative treatment for symptomatic malignant pericardial effusion†.

Consensus has yet to emerge regarding the optimal choice of therapy in the management of malignant pericardial effusion. We review the literature to evaluate the existing evidence on the clinical effectiveness of surgical and interventional cardiological approaches. A formal literature search for all studies addressing the treatment of pericardial effusion in cancer patients was undertaken using predefined keywords. Abstracts were screened and reviewed, and data extracted. Data on intervention type, number of patients treated, number of patients surviving the procedure, effusion recurrences, need for further interventions and procedure-related complications were obtained from each study and collated in a quantitative synthesis. Of 1181 articles identified, 59 contained sufficient quantitative information to be included in the synthesis. A total of 2322 patients with symptomatic pericardial effusion were identified, of which 1399 patients were reported to have underlying malignancy. Three surgical approaches were described in a total of 19 studies, with overall success rates ranging from 93.3 to 100% and associated complication rates ranging from 4.5 to 10.3%. The remaining 40 studies reported four non-surgical treatment modalities, with success rates of 55.1-90.4% and complication rates of 5.9-32%. Data from the literature suggest that surgical drainage of the pericardium is superior to non-surgical approaches for symptom relief, effusion recurrence and morbidity; however, the lack of randomized controlled trials means that selection bias remains an important limitation to the field and definitive adequately controlled trials should be a priority.

Abstract A24: Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) induces apoptosis via ectodomain shedding mediated by a disintegrin and metalloproteinase 9

Abstract Objectives: Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a type-II membrane protein that can induce apoptosis in immune cells including peripheral lymphocytes and natural killer cells after converted to a secreted type by proteolytic processing referred to as “ectodomain shedding.” So far, over 150 scientific reports have been published concerning the biological functions and clinical significance of RCAS1. Because RCAS1 not only helps tumor cells to evade immune surveillance but also induces cancer stromal tissue remodeling, RCAS1 is believed to exaggerate aggressive characteristics of human malignancies. Clinically, RCAS1 expression correlates with several pathological variables including tumor size, stage, invasion depth, and lymph node metastasis and is a negative predictor of overall survival in 15 different kinds of cancer derived from brain, oral cavity, lung, pleural mesothelium, esophagus, stomach, bile duct, gallbladder, pancreas, colon, gastrointestinal mesenchyme, kidney, prostate, uterine cervix, and endometrium. RCAS1 is secreted significantly higher in serum and pleural effusion in cancer patients than non-cancer individuals and its level is changed in response to treatment. We here studied regarding ectodomain shedding that affects the biological activity of membrane proteins such as growth factors, growth factor receptors, cell-adhesion molecules, extracellular matrix proteins by altering their localization and mode of action. The objective of this study is to investigate (1) a key protease involved in RCAS1 shedding and (2) an association between tumor protease expression and serum RCAS1 concentration in uterine cancer patients. Materials and Methods: (1) The key protease involved in RCAS1 shedding was investigated using two cell lines: a human cervical adenocarcinoma cell line SiSo and a breast adenocarcinoma cell line MCF-7. Both SiSo and MCF-7 express RCAS1, but RCAS1 secretion is undetectable in MCF-7. The protease expression was evaluated by microarray analysis and immnocytochemistry. The expression and secretion of RCAS1 were measured by using flow cytometry and ELISA after knockdown or introduction of protease expression. The induction of apoptosis in an erythroleukemia cell line K562, which express a putative RCAS1 receptor, was investigated. K562 cells were co-cultured with SiSo, MCF-7, and protease cDNA transfected MCF-7 to follow RCAS1 secretion in apoptosis initiation. (2) The association between tumor protease expression and serum RCAS1 concentration was studied in 50 cases of uterine cancer patients. The tumor protease expression was evaluated by immunohistochemistry and serum RCAS1 concentration was measured by ELISA. Results: (1) Microarray analysis revealed that SiSo expressed MMP-28, ADAM9, and ADAM21 at significantly higher levels than did MCF-7. The association of RCAS1 and ADAM9 was detected by immunocytochemistry in SiSo. ADAM9 cDNA transfection in MCF-7 induced RCAS1 secretion and reduced its expression, on the other hand, ADAM9 siRNA transfection in SiSo suppressed RCAS1 secretion and augmented its expression. Growth inhibition and apoptosis were induced by ADAM9 cDNA tansfected MCF-7 but not parent cell. Therefore, it was revealed that ADAM9 is a key protease for RCAS1 shedding. (2) There was a significant correlation between tumor ADAM9 expression and serum RCAS1 concentration in uterine cancer. Conclusions: Further exploration regarding the regulatory mechanisms involved in the conversion of membrane-anchored RCAS1 into its soluble form by ADAM9 should aid the development of novel therapeutic strategies against human malignancies by targeting RCAS1. Citation Format: Kenzo Sonoda. Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) induces apoptosis via ectodomain shedding mediated by a disintegrin and metalloproteinase 9. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A24.

RCAS1 is a promising therapeutic target against cancer: its multifunctional bioactivities and clinical significance

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a type II membrane protein that can induce apoptosis in immune cells, including peripheral lymphocytes and natural killer cells, after being converted to a secreted type by ectodomain shedding. So far, over 140 scientific reports have been published concerning the biological functions and clinical significance of RCAS1. Since RCAS1 not only helps tumor cells to evade immune surveillance but also induces cancer stromal tissue remodeling, RCAS1 is believed to exaggerate aggressive characteristics of human malignancies. Clinically, RCAS1 expression correlates with several pathological variables including tumor size, stage and invasion depth, and lymph node metastasis, and is a negative predictor of overall survival in 15 different kinds of cancer. RCAS1 is secreted in significantly greater quantities in serum of pleural effusion in cancer patients than noncancer patients, and its level is changed in response to treatment. Novel therapeutic st...

Demonstration of anti-tumor activity of oncolytic measles virus strains in a malignant pleural effusion breast cancer model

Breast cancer is the second leading cause of malignant effusions in cancer patients. Pleural effusion indicates incurable disease with limited palliative treatment options and poor outcome. Here, we demonstrate the therapeutic efficacy of measles virus (MV) vaccine strain derivative against malignant pleural effusion in an MDA-MB-231 xenograft model of advanced breast cancer. Both systemic intravenous (i.v.) and intrapleural (t.t.) administered virus caused massive infection and syncytia formation in the pleural tumor deposits. Intrapleural administration of 1.5 x 10(6) plaque-forming units (PFU) total dose of MV significantly improved median survival by approximately 80% compared to the control animal group. Furthermore, we tested human dendritic cells as carriers for delivery of oncolytic MV infection to breast cancer pleural metastases. Carrier-delivered MV infection prevented accumulation of the pleural exudate and also significantly improved the survival of the treated mice. This is the first demonstration of the therapeutic potential of oncolytic virotherapy against malignant pleural effusions in a pre-clinical model of advanced breast cancer.

MN/CA9: a potential gene marker for detection of malignant cells in effusions

Many cancers cause malignant effusions. The presence of malignant cells in effusions has implications in diagnosis, tumour staging and prognosis. The detection of malignant cells currently presents a challenge for cytopathologists. New adjunctive methods are needed. Although the effusions provide excellent materials for molecular assay, the available molecular markers are extremely limited, which hinders its clinical application. MN/CA9 has proved to be a valuable marker in many cancers such as lung, breast, colon, kidney, etc. The present study was to evaluate MN/CA9 as a new molecular marker for the detection of cancer cells in pleural effusions. Seventy-one pleural effusions including 59 malignant effusions from patients with cancer, and 12 patients with benign diseases as a control, were subjected to RT-PCR for detection of MN/CA9 gene expression. MN/CA9 gene expression was detected in 53/59 (89.8%) pleural effusions from cancer patients (15/16 for breast cancers, 10/11 for lung cancers, 4/4 for ovary cancers, 2/3 for colon–rectal cancers, 5/6 for cancers of unknown site, 7/8 for mesothelioma and 10/11 for other cancers). Furthermore, MN/CA9 was positive in 13/18 (72.2%) of cytologically negative effusions of cancer patients. MN/CA9 was detected in only 1/12 (8.3%) effusions from the control patients (p<0.01). The sensitivity and specificity of MN/CA9 gene expression were, respectively, 89.8% and 91.7%. Our preliminary results suggest that MN/CA9 could be a potential marker for the detection of malignant cells in effusions. A large-scale study is needed to confirm these results.

A Review of the Economic Burden of Pleural and Pericardial Effusions in Cancer Patients.

OBJECTIVES: Pleural and pericardial effusions can lead to severe outcomes. Cancer accounts for an estimated 40% of all pleural effusions. About half of the effusions diagnosed in cancer patients are malignant, while the rest are nonmalignant and may occur as complications of the cancer treatments themselves. Pleural and pericardial effusions are associated with increased morbidity and mortality as well as high healthcare costs. The objective of this study was to review the economic burden of pleural and pericardial effusions in cancer patients.METHODS: A systematic search of the English-language medical literature published between 1990 and 2006 was conducted. Additional publications and conference proceedings were retrieved from the article bibliographies and included in the review. Articles selected include prospective or retrospective studies specifically designed to examine burden of illness, direct medical costs, indirect costs, or cost drivers associated with pleural or pericardial effusions in cancer patients. All original costs were reported, with adjusted figures (to 2006 US dollars) presented in parentheses using the medical care component of the consumer price index from the US Bureau of Labor Statistics.RESULTS: Of 15 studies identified, 11 met selection criteria and were reviewed in detail. Seven references reported data on costs associated with pleural or pericardial effusions in cancer patients. The cost per episode of pleural effusion ranged from $3,391 (2006 US $4,387) for outpatient treatment with pleural catheter to $20,996 ($37,341) for talc pleurodesis. The most common treatment for malignant pleural effusion is chest tube insertion and drainage with instillation of a sclerosing agent. Key cost drivers for significant pleural effusions included operating room costs, surgeon fees, and drugs such as sclerosing agents. Resources used for management of low grade pleural effusions include chest x-rays, physician outpatient visits, diuretics, and corticosteroids. For the treatment of pericardial effusion, the costs of performing pericardiocentesis and a pericardial window procedure were estimated to be $4,446 and $14,641 (2006 US$), respectively. Cost components for pericardial effusions, depending on treatment modality selected, included echocardiogram (3–10%), intensive care unit (17–56%), sclerosant (1–4%), surgeon fees (28–29%), anesthesia fees (20%), and operating room costs (31%).CONCLUSIONS: Pleural and pericardial effusions lead to significant direct medical costs, contributing to the total cost of care among patients treated for cancer. These costs should be included in the economic evaluation of therapies that increase the risk of pleural and pericardial effusions. Given the scarcity of published analyses in this area, additional research is warranted to better understand the burden of pleural and pericardial effusions.

Elevated levels of angiostatin in effusions from patients with malignant disease

The aim of this study was to determine the presence of angiostatin in ascitic and pleural effusions from cancer patients, as well as of metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA), both involved in angiostatin generation in in vitro models. Ascitic fluids, pleural exudates, and sera from 21 cancer patients were analyzed for the presence of angiostatin by western blot, whereas gelatinases MMP-2 and MMP-9, and uPA were evaluated by zymography. Our study revealed elevated levels of angiostatin in effusions of cancer patients, contrasting with mostly intermediate levels in less than half of their sera, and undetectable levels in normal sera. Despite the observation of enhanced levels of HMW-uPA and MMP-2 in malignant effusions from cancer patients, their analysis in individual samples showed no association between angiostatin presence and the enzymes, suggesting that the latter would not play an unimportant role, if any, in in vivo generation of angiostatin.

Usefulness of pig-tail catheter for palliative drainage of malignant pleural effusions in cancer patients.

We retrospectively collected data from patients enrolled between 1996 and 1997, to evaluate the efficacy of sono-guided pig-tail-catheter drainage in cancer patients with large, symptomatic, amounts of malignant effusion and to evaluate the hemodynamic change after effusion drainage. A total of 477 pig-tail catheter drainage procedures were performed on 342 cancer patients. Sonographic findings, volume drained within 36 h after pig-tail insertion, heart rate and respiratory rate 24 h before and after drainage, and dyspnea sensations were recorded. We found that unilateral right-side effusion was the most frequent presentation. The mean amount of effusion drained within 36 h was 1,747 ml in cancer patients. The decreases in heart rate (from 97/min to 91/min) and in respiratory rate (from 23/min to 21/min) were both statistically significant. There was no significant correlation between the amount of effusion before drainage and the heart rate or respiratory rate. The amount drained within 36 h was correlated significantly with the changes in heart and respiratory rates. Dyspnea sensations decreased or subsided in 91% of the patients within this time period. There were few complications with the pig-tail drainage procedure. Sono-guided pig-tail drainage is a safe and convenient method of effusion drainage in cancer patients. It not only provides temporary relief of symptoms from massive pleural effusions, but can also be used for pleurodesis if needed.

167 O - Gm-csf and interferon-γ modulate cytotoxicity and cytokine production of malignant effusion - derived macrophages

The role of tumor - associated macrophages (TAM) as potential effector cells for eradicating malignant cells is not yet entirely clarified. In the present study TAM were isolated from malignant effusions by gradient separation and phenotypically and functionally characterised by the following parameters: surface epitopes (moAb 27EIO, 2SF9), respiratory burst activity, cytotoxicity and cytokine production (TNF-α., TGF-β, IL-6) measured in culture supernatants by bioassay, ELISA/RIA. Additionally mRNAs of these cytokines was detected in TAM by in situ hybridisation and RT-PCR. Incubation of TAM with rh-GM-CSF and rh-IFN-y resulted in an augmentation of cytotoxicity. Furthermore, cell-bound as well as released TNF- a increased significantly following incubation with GM-CSF. In contrast, OM-CSP, as well as IFN-γ reduced the production of TGF-β by TAM, as verified by ELISA assay as well as by in situ hybridisation and RT-PCR. Our studies show that TAM obtained from malignant effusions of cancer patients can be stimulated by GM-CSF and IFN-γ for cytotoxicity and cytokine production. TGF-β release was reduced. Whether this observation is of therapeutical relevance has to be determined by further studies.