Utility of atezolizumab plus bevacizumab, carboplatin, and paclitaxel combination for the treatment of advanced non-squamous non-small cell lung cancer patients with malignant pleural effusion.

Background: Malignant pleural effusion (MPE) remains a negative prognostic factor in non-small cell lung cancer (NSCLC), even after the emergence of immune checkpoint inhibitors. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of MPE. Bevacizumab, a humanized monoclonal antibody against VEGF, is a key agent for patients who develop MPE. However, it is unclear whether MPE is a poor prognostic factor in patients with advanced non-squamous NSCLC receiving treatment with the atezolizumab plus bevacizumab, carboplatin, and paclitaxel (ABCP) regimen. Moreover, the effect of ABCP on MPE control is unknown. This study aimed to elucidate the efficacy and safety of ABCP for non-squamous NSCLC patients with MPE. Methods: We retrospectively analyzed consecutive patients with advanced non-squamous NSCLC who received treatment with ABCP (January 2019-September 2023). Patients were divided into two groups (non-MPE and MPE), and treatment outcomes were compared. In the MPE group, treatment efficacy for MPE control and toxicity were evaluated. Results: Of the 46 patients enrolled, 17 and 29 were included in the non-MPE and MPE groups, respectively. The objective response and disease control rates were not significantly different between the non-MPE and MPE groups (76.5% vs. 51.7%, P=0.13; 88.2% vs. 82.8%, P>0.99; respectively). Similarly, the median progression-free survival and median overall survival were not significantly different (9.9 vs. 10.1 months, P=0.87; 16.0 vs. 19.9 months, P=0.87, respectively). In the MPE group, 25 patients (86.2%) achieved MPE control lasting >8 weeks from the initiation of treatment with ABCP; the median progression-free survival without an unequivocal increase in MPE was 15.0 months. The incidence rates of grade ≥3 non-immune- and immune-related adverse events were 83% and 17%, respectively. There was no treatment-related death. Conclusions: The ABCP regimen may be a promising treatment option for non-squamous NSCLC patients with MPE.

Lymph nodes rather than pleural metabolic activity in 18F-FDG PET/CT correlates with malignant pleural effusion recurrence in advanced non-small cell lung cancer.

Background: Frequently recurrent malignant pleural effusion (MPE) significantly hampers the life quality of advanced non-small cell lung cancer (NSCLC) patients. We aimed to explore the effects of progression patterns and local intervention on MPE recurrence and apply fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to establish a predictive model for MPE recurrence in NSCLC. Methods: We retrospectively recruited two cohorts of patients including treatment-naïve NSCLC diagnosed with MPE at the onset and receiving PET/CT scanning, as well as those with MPE and undergoing first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Pleural maximum standardized uptake value (SUVmax), metabolic tumor burden (MTV), total lesion glycolysis (TLG), and uptake patterns as well as SUVmax of lymph nodes (LN) were extracted. The primary outcome was MPE recurrence defined as re-accumulation of cytologically proven ipsilateral MPE. Step-wise multivariate Cox regression was used to identify candidate variables. Cox regression analysis and random survival forest were applied to establish models. Results: A total of 148 treatment-naïve patients with EGFR-TKI treatment and MPE were recruited during the median follow-up period of 683 days, with 69 (46.6%) and 35 (23.6%) witnessing MPE recurrence at least once and twice. Intrapleural perfusion therapy at first recurrence was a protective factor for the second MPE recurrence (P=0.006), while intrapleural perfusion therapy at baseline could not benefit the first MPE recurrence (P=0.14). Conversely, prior systemic progression indicative of the change of systemic treatment was a protective factor for time to the first MPE recurrence (P<0.001); instead, the change of systemic treatment at the first MPE recurrence was not associated with second MPE recurrence (P=0.53). In another cohort with treatment-naïve NSCLC patients with MPE and PET/CT scanning, 103 patients regardless of the actionable mutation status were recruited during the median follow-up period of 304 days. Multivariate analysis suggested that the LN SUVmax >4.50 g/mL [hazard ratio (HR), 2.54; P=0.01], female gender (HR, 0.40; P=0.01), bone metastases (HR, 3.16; P=0.001), and systemic treatment (targeted therapy vs. chemotherapy: HR, 0.32; P=0.002; immunotherapy therapy vs. chemotherapy: HR, 0.99; P=0.97) could collectively indicate MPE recurrence with an optimal 300-day area under the curve (AUC) of 0.83. For patients with actionable mutation, LN SUVmax >4.50 g/mL (P=0.02) could forecast MPE recurrence independently. Conclusions: In summary, LN rather than pleural metabolic activity or uptake patterns could predict MPE recurrence for patients with or without targeted therapy. We should re-consider the application of intrapleural perfusion treatment for first-onset MPE and prompt it more at the moment of recurrent MPE. Promisingly, we could probably apply the non-invasive tool to identify the risk factors for MPE recurrence.

Establishment of lung cancer cell lines and tumorigenesis in mice from malignant pleural effusion in patients with lung cancer.

Background: Lung cancer was often diagnosed by malignant pleural effusion (MPE). Excessive MPE is generally discarded. The establishment of cell lines and the generation of cancer mouse models have the potential to be directly linked to personalized medicine. This study aimed to establish cell lines and generate mouse models using MPE. Methods: Cells derived from 5 mL of MPE were cultured in several conditions, including 100% MPE supernatant and Roswell Park Memorial Institute-1640 supplemented with 10% fetal bovine serum (FBS) or 10% MPE supernatant. When steady cell growth was observed, fewer cells were spread and the colonies were selected to establish the cell line. Cells derived from 10 mL of MPE were inoculated subcutaneously into non-obese diabetic-severe combined immunodeficiency (NOD-scid) and NOD.Cg-Prkdcscid Il2rgtmlWjl /SzJ (NSG) mice to assess tumorigenic potential. Results: MPEs were obtained from 28 lung cancer patients, 23 of whom had adenocarcinoma. Cell lines were established from 5 patients (18%). Tumorigenesis was observed in 6 of 28 cases (21%). However, in 7 cases, the mice (7 NSG and 1 NOD-scid mice) became progressively weaker, lost their hair, and died within 12 weeks without tumorigenesis. The appearance and pathological findings were consistent with graft-versus-host disease. Cell line establishment and tumorigenesis in mice were associated with a lower response to first-line therapy and poorer prognosis of patients. Conclusions: When MPEs were simply utilized, the cell line establishment rate was 18% and the engraftment rate in mice was 21%. The prognosis of patients who underwent cell line establishment and engraftment in mice was poor.

EGFR mutations in patients with lung adenocarcinoma and malignant pleural effusion: a propensity score-matched analysis of a single-center database.

Background: Malignant pleural effusion (MPE) is associated with poor prognosis in patients with advanced lung adenocarcinoma (LUAD), and abnormal activation of epidermal growth factor receptor (EGFR) plays a crucial role in the development of LUAD. This study aimed to investigate the correlation between EGFR mutations and the occurrence of MPE in patients with LUAD and evaluate the effect of EGFR mutations on the prognosis of patients with LUAD with MPE. Methods: A case-control study design was adopted that included patients pathologically diagnosed with LUAD. Clinical data were collected, and patients were divided into the MPE group and the non-MPE (N-MPE) group based on the presence of MPE. Propensity score matching (PSM) was used to control for confounding factors. The correlation between EGFR mutations and the occurrence of MPE in LUAD was initially examined. Additionally, various factors affecting the overall survival (OS) of patients with LUAD and MPE were evaluated. Results: A total of 849 patients were included in the study. After 1:2 PSM, there were 180 patients in the MPE group and 360 in the N-MPE group. The EGFR mutation rate was significantly higher in the MPE group compared to the N-MPE group [62.7% vs. 50.2%; odds ratio (OR) =1.668; P=0.006]. This difference was primarily attributed to the T790M mutation (8.3% vs. 1.3%; OR =8.015; P<0.001), but no significant differences observed in other mutation sites between the groups. Further evaluation of factors affecting OS in patients with LUAD and MPE revealed that EGFR mutation was an independent protective factor for OS [hazard ratio (HR) 0.662, 95% CI: 0.456-0.962; P=0.03]. For patients with LUAD, MPE, and EGFR mutations, treatment with third-generation EGFR-tyrosine kinase inhibitors (TKIs) alone (HR 0.466, 95% CI: 0.233-0.930; P=0.03) or sequential first- and third-generation EGFR-TKIs (HR 0.385, 95% CI: 0.219-0.676; P=0.001) was associated with better median OS compared to first-generation EGFR-TKIs alone (first-generation EGFR-TKIs: 35 months, 95% CI: 28.4-41.6; third-generation EGFR-TKIs: 50 months, 95% CI: 37.3-62.7; sequential first- and third-generation EGFR-TKIs: 51 months, 95% CI: 45.6-56.4; P<0.001). Conclusions: This study found there to be a positive correlation between EGFR mutations, particularly the T790M mutation, and MPE in patients with LUAD. EGFR mutation was associated with improved OS in patients with LUAD and MPE. For patients with LUAD, MPE, and EGFR mutations, sequential treatment with first- and third-generation EGFR-TKIs or third-generation EGFR-TKIs alone is recommended, as these regimens provide significant benefit to OS.

Prognostic significance of malignant pleural effusions in patients with advanced luminal B breast cancer.

BACKGROUND: Though the survival of breast cancer (BC) patients with malignant pleural effusion (MPE) has been studied, this has not been specifically studied in the luminal B subtype. Therefore, this study investigated the characteristics and survival of luminal B-BC patients presenting with MPE. METHODS: We retrospectively analyzed 141 patients diagnosed with postoperative advanced Luminal B breast cancer, including 54 cases with MPE and 87 cases without MPE at the Tianjin Cancer Hospital from January 2012 to January 2015. We assessed the clinical characteristics between the groups. RESULTS: The mean age of all patients was 47 years, with no significant difference between the two groups. Altogether, 29 (33%), 24 (28%), 28 (32%), 45 (52%), and 10 (11%) patients had lung, liver, bone, lymph node, and chest wall metastases, respectively. In addition. The difference in overall survival between the two groups was not significant (P>0.05). However, cox regression analysis showed that only the tumor clinical stage at initial diagnosis was related to short overall survival. Further, we conducted a subgroup analysis and found that the higher the clinical stage at initial diagnosis in age < 50 years patients, the shorter the overall survival, while age > 50 years patients was not. (P < 0.05). CONCLUSIONS: There was no difference in the overall survival between luminal B-BC patients with MPE and those without. Clinical stages at initial diagnosis were an independent prognostic factor for age < 50 years luminal B BC with MPE overall survival. Our results may help clinicians make positive decisions regarding personalized treatment of luminal B-BC with MPE.

The diagnostic value and validation of IL-22 combimed with sCD40L in tuberculosis pleural effusion.

BACKGROUND: There is substantial evidence indicating that cytokines play a role in the immune defense against tuberculosis. This study aims to evaluate the levels of various cytokines in pleural effusion to ditinguish between tuberculosis pleurisy and malignant pleurisy. METHODS: A total of 82 participants with pleural effusion were included in the training cohort, and 76 participants were included in the validation cohort. The individuals were divided into tuberculosis and malignant pleurisy groups. The concentrations of interleukin-1ß (IL-1ß), IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, interferon-γ (IFN-γ), soluble CD40 ligand (sCD40L) and tumor necrosis factor-α (TNF-α) in pleural effusion were measured using a multiplex cytokine assay. The threshold values were calculated according to the receiver operating characteristic (ROC) curve analysis to aid in diagnosing tuberculosis pleurisy. Furthermore, the combined measure was validated in the validation cohort. RESULTS: The levels of all 14 cytokines in pleural effusion were significantly higher in participants with tuberculosis compared to those with malignant pleurisy (all P < 0.05). The area under the curve (AUC) was ≥ 0.920 for the IL-22, sCD40L, IFN-γ, TNF-α and IL-31, which were significantly increased in tuberculous pleural effusion (TPE) compared to MPE in the training cohort. Threshold values of 95.80 pg/mL for IFN-γ, 41.80 pg/mL for IL-31, and 18.87 pg/mL for IL-22 provided ≥ 90% sensitivity and specificity in distinguishing between tuberculosis pleurisy and malignant pleurisy in the training cohort. Among these, IL-22 combined with sCD40L showed the best sensitivity and specificity (94.0% and 96.9%) for diagnosing tuberculosis pleurisy, and this finding was validated in the validation cohort. CONCLUSION: We demonstrated that the levels of IL-1ß, IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, IFN-γ, sCD40L and TNF-α in pleural effusion had significant difference between tuberculosis pleurisy and malignant pleurisy. Specifically, IL-22 ≥ 18.87 pg/mL and sCD40L ≥ 53.08 pg/mL can be clinically utilized as an efficient diagnostic strategy for distinguishing tuberculosis pleurisy from malignant pleurisy.

Case report: Intrapleural plus systemic Tislelizumab injection combined chemotherapy in RET gene fusion-positive lung adenocarcinoma presenting refractory malignant pleural effusion.

RET fusions were discovered in non-small cell lung cancer (NSCLC), and the efficacy of RET-targeted treatment in these patients has been previously established. However, patients with required resistance to RET-TKIs have limited treatment options. Herein, we describe a case of critical and advanced lung adenocarcinoma harboring RET fusion. Despite a significant response to Prasetinib previously, the patient developed refractory malignant pleural effusion after 24 months of treatment. He was treated simultaneously with intrapleural plus systemic Tislelizumab injection combined chemotherapy, thereby achieving an excellent clinical benefit maintaining control of pleural effusion for over 6 months. Hence, we would like to discuss intrapleural immunotherapy as an additional treatment method in refractory malignant pleural effusion while demonstrating good treatment tolerance.

The Cytological Diagnosis of a Malignant Effusion Is Independent of the Volume of Fluid Processed.

BACKGROUND: The relationship between pleural fluid volume and cytological diagnosis of malignancy has been often investigated with conflicting conclusions on whether or not a minimum fluid volume should be defined. The primary objective of this retrospective investigation is to evaluate the relationship between fluid volume and cytological diagnosis of malignancy. METHODS: A total of 511 body fluid specimen reports received between January 2018 and December 2019 were examined to investigate the relationship between diagnosis of malignancy to volume and biochemical properties. Pleural fluid (n = 252) and peritoneal fluid (n = 250) specimens were binned into two volume groups (< 75 mL, ≥ 75 mL). Pericardial fluid specimens (n = 9) were excluded due to small sample size. RESULTS: Prevalence of malignancy for pleural and peritoneal fluids was 20.2% and 20.08%, respectively, with no significant difference between the two volume groups. Malignant pleural effusions were associated with a serum to fluid protein ratio > 0.5 and malignant peritoneal effusions were associated with a serum ascites albumin gradient (SAAG) < 1.1 g/dL. CONCLUSIONS: Our study did not find a significant difference in the diagnosis of malignancy between volumes ≥ 75 mL and < 75 mL in either pleural or peritoneal fluid. Fluid volume is, therefore, not an adequacy criterion for detecting malignancy in either pleural or peritoneal fluid. Our analysis on the biochemical properties of each malignant fluid type was supportive of current use of Light's criteria and SAAG for effusion fluid evaluation.

To correlate clinical and biochemical profile of pleural effusion: a retrospective study in tertiary care centre of central India.

BACKGROUND: Pleural effusion indicates an imbalance between pleural fluid formation and removal. Classified into exudative and transudative, with common symptoms of dry cough, dyspnea and pleuritic chest pain. Confirmed etiology has to be established for effective treatment. OBJECTIVE: Correlate clinical and biochemical profile of various etiologies of pleural effusion. MATERIALS & METHODS: Retrospective observational study of 2 years in the department of respiratory medicine, GMC Bhopal on 280 cases of pleural effusion. RESULTS: Most common etiology was tubercular 202 (72.4%) followed by malignant in 36 (12.8%). With respect to tubercular, malignant pleural effusion has relative risk (RR) of 0.138 (p value < 0.05) in the age group of 51-60 years, which is statistically significant. Patients of tuberculosis complained of fever 158 (78.2%) whereas with malignancy complained of chest pain 16 (44.4%) followed by hemoptysis 12 (33.3%). For hemoptysis, with respect to tubercular, malignant effusion has RR of 5.68 (p value < 0.05) which is significant. History of smoking was significant in malignant effusion with RR of 2.57 (p value < 0.05) as compared to tubercular. Pleural fluid ADA was >70 in 83.7% in tubercular effusion, glucose was <60 mg/dl in 79% tubercular, malignant and bacteriological cause, LDH was >1000 in 88.4% in bacteriological and 72.3% in malignant effusion. CONCLUSION: Lack of tools for confirming diagnosis leads to diagnostic dilemma and delay in treatment initiation, leading to deterioration and untoward fatality in some cases. Our goal is early diagnosis by correlating clinical symptoms with biochemical profile and help initiate rapid treatment.

Association of PET/CT and VATS findings with histology analysis in the study of pleural effusions.

INTRODUCTION: Histological analysis of the pleura obtained by video-assisted thoracoscopic surgery (VATS) is the best diagnostic technique in the study of neoplastic pleural effusions. This study evaluates the relationship between Positron Emission Tomography (PET)/Computed Tomography (CT) and VATS findings, the result of the first pleural biopsy, and the final diagnosis of malignancy or non-malignancy. METHODS: Prospective study of consecutive patients with pleural effusions undergoing PET/CT and VATS from October 2013 to December 2023. The following variables were recorded: PET/CT score (nodular pleural thickening, pleural nodules with standardized uptake value (SUV) > 7.5, lung mass or extra pleural malignancy, mammary lymph node with SUV > 4.5 and cardiomegaly); VATS data (drained volume, visceral and parietal pleural thickening, nodules or masses, septa, plaques, fluid appearance, trapped lung, and suspected diagnosis of the procedure), as well as the histological study of the first pleural biopsy (benign or malignant) and the final diagnosis of benign or malignant pleural effusion. A logistic regression study of the variables was performed. RESULTS: 95.8% of the patients with PET/CT and pleuroscopy not suggestive of malignancy had non-malignant histological findings, while 93.2% of the patients with PET/CT and pleuroscopy suggestive of malignancy had malignant histological findings. PET/CT, pleuroscopy, and the result of the first pleural biopsy showed a significant association with the final diagnosis of pleural effusion. CONCLUSIONS: There is a strong association between PET/CT findings, VATS and pleural histology.

Complete response and long-term survival to endocrine monotherapy in a patient with metastatic breast cancer in a low-income country: a case report.

BACKGROUND: Breast cancer is the most common cancer in women. Progression-free survival for hormone receptor-positive/human epidermal growth factor receptor-2-negative metastatic breast cancer treated with endocrine therapy in combination with cyclin4/6-dependent kinase is approximately 25 months. This case represents metastatic breast cancer treated with endocrine therapy, leading to long-term survival. CASE PRESENTATION: A 40-year-old Syrian woman diagnosed with hormone receptor-negative breast cancer was treated surgically with adjuvant chemotherapy and radiotherapy. She developed local and nodal recurrences that were hormone receptor-positive, followed by a recurrence of malignant pleural effusion. She was initially treated with chemotherapy and then placed on endocrine therapy with a complete response from 2014 until now. The patient also suffered from adverse events of medications, such as heart failure and osteoporosis, which were treated appropriately. CONCLUSION: This case demonstrates a long-lasting complete response to metastatic breast cancer with malignant pleural effusion. This shows the validity of endocrine therapy in recurrent hormone receptor-positive breast cancer, especially in countries that cannot afford targeted therapies or genetic tests. It also highlights the necessity for a better understanding of the prognostic and predictive factors.

Challenging the Norm: Occurrence of Synchronous Pleural and Peritoneal Mesothelioma in a Female Patient.

Here, we present a unique case involving a female patient in her 40s with synchronous malignant pleural and peritoneal mesothelioma, despite lacking a history of asbestos exposure. The patient's initial symptoms included dyspnoea, chest pain, cough, fever, appetite loss, and weight loss over a month. Clinical evaluation led to the identification of right-sided pleural effusion, prompting consideration of differential diagnoses, such as tubercular or malignant pleural effusion. A thoracoscopy-guided biopsy, followed by histopathological examination and immunohistochemical staining, confirmed the diagnosis of mesothelioma. Chemotherapy was initiated as part of the treatment plan. The prognosis for this condition is generally bad; however, unusual cases of extended survival have been documented. The complexities of our case underscore the critical necessity for a thorough and aggressive evaluation of pleural effusion cases to unveil rare underlying causes, such as mesothelioma.

A common secretomic signature across epithelial cancers metastatic to the pleura supports IL-6 axis therapeutic targeting.

Background: Many cancers metastasize to the pleura, resulting in effusions that cause dyspnea and discomfort. Regardless of the tissue of origin, pleural malignancies are aggressive and uniformly fatal, with no treatment shown to prolong life. The pleural mesothelial monolayer is joined by tight junctions forming a contained bioreactor-like space, concentrating cytokines and chemokines secreted by the mesothelium, tumor, and infiltrating immune cells. This space represents a unique environment that profoundly influences tumor and immune cell behavior. Defining the pleural secretome is an important step in the rational development localized intrapleural immunotherapy. Method: We measured cytokine/chemokine content of 252 malignant pleural effusion (MPE) samples across multiple cancers using a 40-analyte panel and Luminex multiplexing technology. Results: Eleven analytes were consistently present in concentrations ≥ 10.0 pM: CXCL10/IP10 (geometric mean = 672.3 pM), CCL2/MCP1 (562.9 pM), sIL-6Rα (403.1 pM), IL-6 (137.6 pM), CXCL1/GRO (80.3 pM), TGFß1 (76.8 pM), CCL22/MDC (54.8 pM), CXCL8/IL-8 (29.2 pM), CCL11/Eotaxin (12.6 pM), IL-10 (11.3 pM), and G-CSF (11.0 pM). All are capable of mediating chemotaxis, promotion of epithelial to mesenchymal transition, or immunosuppression, and many of are reportedly downstream of a pro-inflammatory cytokine cascade mediated by cytokine IL-6 and its soluble receptor. Conclusion: The data indicate high concentrations of several cytokines and chemokines across epithelial cancers metastatic to the pleura and support the contention that the pleural environment is the major factor responsible for the clinical course of MPE across cancer types. A sIL-6Rα to IL-6 molar ratio of 2.7 ensures that virtually all epithelial, immune and vascular endothelial cells in the pleural environment are affected by IL-6 signaling. The central role likely played by IL-6 in the pathogenesis of MPE argues in favor of a therapeutic approach targeting the IL-6/IL-6R axis.

Utility of the Ratio of Adenosine Deaminase and Serum C-reactive Protein in Differentiating Parapneumonic, Tuberculous, and Malignant Pleural Effusions.

Introduction Pleural effusion is a challenging diagnosis at times, especially due to the overlap of symptoms in effusions of various etiologies. In this study, we aimed to identify if pleural fluid adenosine deaminase (ADA) or serum C-reactive protein (CRP) can be used as an additional novel biomarker for ADA in diagnosing tubercular, parapneumonic, and malignant pleural effusions. Materials and methods A prospective, observational, cross-sectional study was conducted on 79 patients diagnosed with tubercular, parapneumonic, or malignant pleural effusion from August 2022 to April 2024 at the Department of Respiratory Medicine at Dr. D. Y. Patil Medical College, Hospital & Research Centre, Pimpri, Pune. The pleural fluid ADA/serum CRP ratio was identified in each group, and analysis was done to compare the ratio in each group. The correlation with pleural fluid ADA was also identified. Results A total of 79 patients were enrolled in this study. Out of these patients, 53 (67.1%) were identified as having tubercular pleural effusion, 10 (12.7%) patients had parapneumonic effusion, and 16 (20.3%) had malignant pleural effusion. For malignant effusions, the area under the curve (AUC) using the receiver operating characteristic (ROC) for the ADA/CRP ratio was observed to be 0.862. Sensitivity was 87.50% and specificity was 82.54% at a cut-off value of ≤0.5. The positive predictive value was found to be 56%, and the negative predictive value was found to be 96.3%. For parapneumonic effusions, the AUC using the ROC for the ADA/CRP ratio was observed to be 0.880. Sensitivity was 100% and specificity was 69.57% at a cut-off value of ≤0.67. The positive predictive value was found to be 32.3%, and the negative predictive value was found to be 100%. For tubercular effusions, the AUC using the ROC for the ADA/CRP ratio was observed to be 0.955. Sensitivity was 92.45% and specificity was 88.46% at a cut-off value of >0.54. The positive predictive value was found to be 94.2%, and the negative predictive value was found to be 85.2%. The Pearson correlation coefficient (r) of 0.633 indicates a moderately strong positive linear relationship between ADA and ADA/CRP levels. Conclusion The pleural fluid ADA-to-serum CRP ratio can be used as a useful diagnostic tool for differentiating between tubercular, parapneumonic, and malignant pleural effusions. ADA/CRP ratio has added diagnostic value over ADA. In clinically puzzling scenarios, the ADA/CRP ratio can be a cost-effective tool before opting for a more expensive and invasive procedure, which is also often difficult to obtain in resource-limited healthcare settings. More research with a larger sample size is indicated to incorporate the ADA/CRP ratio as an added diagnostic tool along with ADA.

Comparative genomic and immunopathologic analysis of lung adenocarcinomas with and without cytology-proven malignant pleural effusions.

BACKGROUND: Lung cancer complicated by malignant pleural effusions (MPEs) is associated with significantly increased morbidity and mortality, yet the mechanisms of MPE development remain poorly understood. This study sought to elucidate whether there were specific genomic alterations and/or immunologic biomarkers associated with the presence of MPEs. METHODS: Analysis of comprehensive genomic and immunologic profiling for 275 locally advanced (stage III) or advanced (stage IV) lung adenocarcinomas was subcategorized into cytology-confirmed MPE-positive (MPE+; n = 139 stage IV) and MPE-negative (MPE-; n = 30 stage III + n = 106 stage IV) groups. RESULTS: Smoking frequency (p = .0001) and tumor mutational burden (p < .001) were demonstrated to be lower in the MPE+ group compared to the MPE- group. Median overall survival in the MPE+ group was shorter than in the MPE- group across all data (2.0 vs. 5.5 years; p < .0001) and for smokers (1.2 vs. 6.4 years; p < .0001). There were a number of differences at the genomic level across all cases and when stratifying by smoking status, including a higher frequency of EGFR mutations and a lower frequency of STK11 mutations in the MPE+ cohort. Finally, investigation of the comutational profiles of tumors by MPE status revealed differences in TP53- and STK11-mutant tumors between the two groups. CONCLUSIONS: Overall, these findings imply that there are both clinical and genetic factors associated with advanced lung adenocarcinoma MPEs. Future studies of these alterations may prove important both for understanding the pathophysiology of MPE development in advanced cancer and for the earlier detection of at-risk patients.

Pleural pro-gastrin releasing peptide is a potential diagnostic marker for malignant pleural effusion induced by small-cell lung cancer.

Background: Serum pro-gastrin releasing peptide (proGRP) is a well-recognized diagnostic marker for small cell lung cancer (SCLC). Pleural effusion is common in patients with advanced SCLC. The diagnostic accuracy of pleural proGRP for malignant pleural effusion (MPE) has not yet been established. This study aimed to evaluate the diagnostic accuracy of pleural proGRP for MPE. Methods: We prospectively recruited patients with undiagnosed pleural effusions from two centers (Hohhot and Changshu). An electrochemiluminescence immunoassay was used to detect pleural fluid proGRP. The diagnostic accuracy of proGRP for MPE was evaluated using a receiver operating characteristic (ROC) curve. Results: In both the Hohhot (n=153) and Changshu (n=58) cohorts, pleural proGRP in MPE patients did not significantly differ from that in patients with benign pleural effusions (BPEs) (Hohhot, P=0.91; Changshu, P=0.12). In the Hohhot and Changshu cohorts, the areas under the curves (AUCs) of proGRP were 0.51 [95% confidence interval (CI): 0.41-0.60] and 0.62 (95% CI: 0.47-0.77), respectively. However, patients with SCLC-induced MPE had significantly higher proGRP levels than those with BPE and other types of MPE (P=0.001 for both). In the pooled cohort, the AUC of proGRP for SCLC-induced MPE was 0.90 (95% CI: 0.78-1.00, P=0.001). At a threshold of 40 pg/mL, proGRP had a sensitivity of 1.00 (95% CI: 0.61-1.00) and specificity of 0.59 (95% CI: 0.52-0.66). The positive likelihood ratio was 2.61 (95% CI: 1.99-3.41), and the negative likelihood ratio was 0. Conclusions: Pleural proGRP has no diagnostic value for MPE, but has high diagnostic accuracy for SCLC-induced MPE. In patients with proGRP levels <40 pg/mL, MPE secondary to SCLC can be excluded.

Pleural fluid biomarkers: a narrative review.

Background and Objective: Pleural fluid is a source from which various biomarkers can be obtained and measured to facilitate the management and prognostication of various conditions. This narrative review aims to summarise a few selected applications of pleural fluid biomarker analysis based on the latest literature. Methods: A literature search for articles published in English regarding human subjects from the period January 2000 to December 2023 was performed through PubMed. Publications considered by the authors to be relevant were included in this review, with additional references added based on the authors' judgement. This review considered both prospective and retrospective cohort studies analysing the clinical value of a range of pleural fluid biomarkers. Key Content and Findings: The biomarkers selected in this narrative review have either established clinical applicability or promising initial results which require further research. Pleural fluid adenosine deaminase, mesothelin and N-terminal pro-B-type natriuretic peptide can optimize the diagnosis of tuberculous pleuritis, malignant mesothelioma and heart failure-related pleural effusion respectively. The detection rate for epidermal growth factor receptor mutations for lung cancer is higher in the pleural fluid than in the pleural tissue or plasma. Suitable targeted therapy in patients with detectable mutations can offer survival benefits. The pleural fluid neutrophil-lymphocyte ratio, soluble urokinase plasminogen activator receptor and plasminogen activator inhibitor 1 carry prognostic implications and can potentially guide subsequent treatment decisions. These biomarkers used individually, or in conjunction with other clinical parameters, should only be utilised in pre-defined, appropriate clinical conditions to maximize their clinical value. Conclusions: A great variety of different biomarkers are available for analysis in pleural fluid. Further research and development are necessary to widen the spectrum and enhance the clinical utility of pleural fluid biomarkers. Comparison with the diagnostic utilities of serum biomarkers and other investigation parameters, such as radiological findings, could be considered when evaluating the performance of pleural fluid biomarkers.

Tumor markers determination in malignant pleural effusion: pearls and pitfalls.

Serum and pleural fluid tumor markers are well-recognized auxiliary diagnostic tools for malignant pleural effusion (MPE). Here, we discuss some pearls and pitfalls regarding the role of tumor markers in MPE management. The following issues are discussed in this article: What is the appropriate clinical scenario for evaluating pleural tumor markers? Which tumor markers should be advocated for diagnosing MPE? Can extremely high levels of tumor markers be employed to establish a diagnosis of MPE? Does the serum-to-pleural fluid ratio of a tumor marker have the same diagnostic efficacy as the measurement of that marker alone in the pleural fluid? Can tumor markers be used to estimate the risk of specific cancers? What should be considered when interpreting the diagnostic accuracy of tumor markers? How should tumor marker studies be performed? We addressed these issues with published works, particularly systematic reviews and meta-analyses.

miR-16-5p specifically inhibits IFN-γ-regulated memory T helper cell differentiation in malignant pleural effusion of non-small cell lung cancer.

Background: The mechanism for memory T helper (Th) cell differentiation in malignant pleural effusion (MPE) of non-small cell lung cancer (NSCLC) is poorly understood. MicroRNAs (miRNAs), as small non-coding RNA that regulate gene expression, play a crucial role in the regulation of memory Th cell differentiation. However, whether miRNAs can inhibit the differentiation of memory Th cells in MPE of NSCLC has not been reported. This study aimed to explore miR-16-5p specifically inhibits interferon-gamma (IFN-γ)-regulated memory Th cell differentiation in MPE of NSCLC. Methods: A total of 30 patients with NSCLC and 30 age- and sex-matched patients, who were clinically diagnosed as benign pleural effusion (BPE) of lung disease and had not received any intervention, were collected. The expression of nucleic acids, miRNAs, and cytokines was detected by polymerase chain reaction (PCR), miRNA microarray, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and western blotting. Results: The expression of CD4+CD69+ T cells in NSCLC with MPE was lower than that in lung disease BPE. CD4+CD69+ T cells highly express CD45RO+ and mainly secrete anti-tumor cytokines IFN-γ, interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α). The expression of miR-16-5p in CD4+CD69+ CD45RO+ T cells in MPE was higher than that in BPE. Moreover, miR-16-5p can bind to both IFN-γ promoter and its 5'untranslated region (5'-UTR), suggesting that IFN-γ may be the target gene directly affected by miR-16-5p. IFN-γ also affects the differentiation of memory CD4+ T cells by regulating T-bet. Conclusions: We believe that miR-16-5p may regulate the decrease of differentiation of naïve CD4+ T cells into memory CD4+CD69+ T cells through its target gene IFN-γ in MPE, thus reducing the number of cytokines that produce anti-tumor effects. It may be the main reason for the low response rate of lung cancer with MPE immunotherapy.

Enzyme-Dynamic Extracellular Vesicles for Metalloimmunotherapy of Malignant Pleural Effusions.

Malignant pleural effusions (MPEs) are hard to treat, and their onset usually signals terminal cancer. Immunotherapies hold promise but must overcome the immunosuppressive MPE microenvironment. Herein, we treat MPEs via synergistically combining two emerging cancer therapy modalities: enzyme-dynamic therapy (EDT) and metalloimmunotherapy. To do so, a nanoplatform termed "A-R-SOME" was developed which comprises MPE-targeted M1 type extracellular vesicles (EVs) loaded with (1) a manganese-based superoxide dismutase (SOD) enzyme, (2) stimulator of interferon genes (STING) agonist diABZI-2, and (3) signal transducer and an activator of transcription 3 (STAT3) small interfering RNA. Endogenous reactive oxygen species within tumors induced immunogenic cell death by EDT, along with STING activation by both Mn and diABZI-2, and suppression of the STAT3 pathway. Systemically administered A-R-SOME alleviated the MPE immunosuppressive microenvironment, triggered antitumor systemic immunity, and long-term immune memory, leading to the complete eradication of MPE and pleural tumors with 100% survival rate in an aggressive murine model. A-R-SOME-induced immune effects were also observed in human patient-derived MPE, pointing toward the translation potential of A-R-SOME as an experimental malignancy treatment.