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Malignant pleural effusion diagnosis and therapy

  • Liangliang Yang and Yue Wang EMAIL logo
Published/Copyright: February 28, 2023
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Open Life Sciences
From the journal Open Life Sciences Volume 18 Issue 1

Abstract

Malignant pleural effusion (MPE) is a serious complication of advanced tumor, with relatively high morbidity and mortality rates, and can severely affect the quality of life and survival of patients. The mechanisms of MPE development are not well defined, but much research has been conducted to gain a deeper understanding of this process. In recent decades, although great progress has been made in the management of MPE, the diagnosis and treatment of MPE are still major challenges for clinicians. In this article, we provide a review of the research advances in the mechanisms of MPE development, diagnosis and treatment approaches. We aim to offer clinicians an overview of the latest evidence on the management of MPE, which should be individualized to provide comprehensive interventions for patients in accordance with their wishes, health status, prognosis and other factors.

Keywords: malignant pleural effusion; mechanism; diagnosis; therapy; treatment

1 Introduction

Malignant pleural effusion (MPE) is a pleural effusion (PE) that is caused by a malignant tumor originating in the pleura or by a metastatic malignant tumor from another site that has invaded the pleura [1]. Almost all advanced malignant tumors can invade the pleura and cause MPE. Among the tumors that cause MPE, adenocarcinoma is the most common pathological type, and lung cancer is the most common cause, leading to approximately 1/3 of all MPEs, followed by breast cancer, lymphoma and malignant mesothelioma [2]. Lung cancer is currently the most prevalent malignancy with the highest morbidity and mortality rates globally, and 50–60% of lung cancer patients already have advanced disease at the time of diagnosis. Approximately 10–15% of patients with advanced lung cancer at the initial diagnosis are affected by MPE [3], and the incidence of MPE among re-diagnosed patients is even higher, at more than 50% [4]. Each year, there are one hundred and fifty thousand new cases of MPE in the USA and one hundred thousand in Europe [2,5]. The development of MPE indicates that the tumor has spread or progressed to an advanced stage, and significantly shortening the patients’ survival. The median survival duration of patients at the first diagnosis of MPE is only 3–12 months [6].

In recent decades, research on the mechanisms of MPE has progressed, but there is a lack of effective diagnostic methods and treatments. The management of MPE is currently focused on relieving the symptoms of dyspnea, but the efficacy of such approaches is poor, and patients experience a high recurrence rate and many adverse effects. As molecular targeted therapies have been developed, new diagnostic procedures and treatments are available for patients with advanced tumors. Therefore, it is meaningful to explore new diagnostic and therapeutic treatments for MPE to enhance the quality of life and prolong the survival of patients with MPE. In this article, we review the mechanisms of MPE development, and progress made in diagnosis and treatment techniques.

2 Mechanism and composition of MPE

In the past few years, the mechanisms of MPE development have been increasingly studied and have shifted from a single factor, initially considered to be a blockage of lymphatic return, in favor of a combination of multiple factors, even down to the level of molecular mechanisms. A variety of cells are present in the pleural cavity microenvironment, including host cells (e.g., pleural mesothelial cells and endothelial cells) as well as cells of myeloid origin and the lymphatic system, which interact with tumor cells to accelerate angiogenesis and increase vascular permeability and inflammatory responses in tumor tissues, ultimately leading to the development of MPE [7,8]. MPE is the result of integrated interactions between host and tumor cells, as summarized by Stathopoulos and Kalomenidis [7]. Many effector molecules, from either the host or tumor cells, are involved in its pathogenesis. These effectors can generally be classified into two categories, including immunoregulatory effectors and modulators, which increase vascular permeability (Figure 1). The immunoregulatory factors include interleukin (IL)-2, tumor necrosis factor (TNF) and interferons. Important regulators of the induction of vascular permeability are vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) [9]. Among these effector regulators, VEGF plays a central role in PEs [10].

Figure 1 Pathogenesis of MPE. Many effector molecules from host cells or tumor cells are involved in the pathogenesis of MPE. These effectors can generally be divided into two categories. The first kind of effector molecules are important immune regulatory factors, including IL-2, TNF and interferons (IFNs). The second group of effector molecules is an effective regulator to increase vascular permeability, including VEGF, MMPs and many other molecules. CCL, IL, KRAS, MMPs, TNF; VEGF and VEGFR.
Figure 1

Pathogenesis of MPE. Many effector molecules from host cells or tumor cells are involved in the pathogenesis of MPE. These effectors can generally be divided into two categories. The first kind of effector molecules are important immune regulatory factors, including IL-2, TNF and interferons (IFNs). The second group of effector molecules is an effective regulator to increase vascular permeability, including VEGF, MMPs and many other molecules. CCL, IL, KRAS, MMPs, TNF; VEGF and VEGFR.

MPE is mostly hematogenous, massive, rapidly, growing composed of lymphocytes with protein content more than 30 g/L and LDH more than 500 U/L [11,12]. Approximately 40–90% of MPEs have been found to contain malignant tumor cells. Malignant tumor cells in MPE often have enlarged nuclei of different sizes, aberrant nuclei, and hyperchromatic nuclei. If the range of pleural lesions is widespread, it is difficult for glucose and acidic metabolites to penetrate the pleura. Both glucose and pH are low, indicating that the tumor is widely infiltrated and the patient’s survival time is short [13,14].

2.1 Tumor angiogenesis and increased vascular permeability

Tumor angiogenesis and increased vascular permeability are vital factors in the formation of MPE. VEGF has been found to maintain endothelial cell survival through tyrosine phosphorylation of focal adhesion kinase, which plays a key role in the chemotactic response of VEGF and can also influence angiogenic signaling pathways, unlike in benign PE [10,15]. VEGF is mainly mediated by vascular endothelial growth factor receptor 2 (VEGFR-2), which promotes increased vascular permeability by disrupting endothelial cell integrity, disrupting junctions and increasing cellular gaps [16]. Angiopoietin 1/2, a factor secreted by tumor cells, also has a role in promoting increased vascular permeability [17]. In addition, it has been shown that mast cells have a significant effect on the formation of MPE and that the release of trypsin-α/β1 and interleukin-1β increases pulmonary vascular permeability and induces the activation of inhibiting nuclear transcription factor (NF-κB) in the pulmonary vasculature, promoting fluid accumulation and tumor growth [18]. The above findings provide new directions for the treatment of MPE, and therapeutic approaches targeting increased tumor angiogenesis and permeability, such as a recombinant human vascular endothelial inhibitors and VEGF monoclonal antibodies, have improved efficacy in the treatment of MPE.

2.2 Immune microenvironment

Due to the increasing interest in the cellular microenvironment and immune responses, there has been increasing attention on the immune microenvironment of the MPE locus, including the interaction of immune cells, cytokines and tumor cells, which together form a microenvironment that promotes MPE development. Mononuclear macrophages are the main immunoinflammatory cells involved in MPE formation, and CD14+ macrophages are specifically highly expressed in MPE and therefore can serve as an immunodiagnostic marker for MPE [19]. Principe et al. showed that autocrine Interleukin-6 (IL-6) from tumor cells promoted MPE development by inducing activation of the Stat3 pathway and upregulating VEGF expression [20]. In addition, the number of Th1, Th17, Th9 and Th22 cells, which also play a role in the PE microenvironment by secreting cytokines, was increased in MPE compared to in peripheral blood [21]. In addition, chemokine (CC motif) ligand 20 (CCL20) and CCL22 can recruit peripheral blood Th17 cells to infiltrate the pleural space [22]. Thus, an imbalance of immune cells can also induce angiogenesis, increase vascular permeability, and promote the development of tumor metastasis and inflammatory responses, ultimately fostering the formation of MPE.

3 MPE diagnosis

3.1 Chest ultrasonography

Ultrasound of the chest is recommended to examine PE, and is an accurate indicator of the volume and depth of PE, the presence of contralateral PE, echogenicity, compartmentalization, intracavitary effusion, presence of pleural thickening and nodules, and diaphragm position and motion [23]. Metastatic pleural tumors show the typical ultrasound findings of relatively small hypoechoic crystalloid-like masses, blunt chest wall margins, or masses or nodules with complex echogenic intensity [24]. Only 9% of patients with nonmalignant PE present with this phenomenon. Another retrospective study analyzing the ultrasound characteristics of 104 patients with MPE found that 95 (91.35%) had nonmalignant PE, and nine (8.65%) had MPE, additionally the pleural nodules with intercostal wall thickening >10 mm and diaphragmatic thickening >7 mm were significant predictors of MPE on ultrasound (sensitivity 73% and specificity 100%) [25]. Both studies indicated that on ultrasound, pleural thickening, nodules and non-encapsulated effusions are reliable indicators for diagnosing MPE. The use of ultrasound guidance during pleural surgery can result in greater success rates and a reduced risk of complications, including parenchymatous organ injury. Ultrasound guidance also provides valuable information about the accessibility of the PE sac, and Doppler imaging helps to localize and avoid intercostal vessel injury prior to pleural intervention, contributing to a reduction in complications [23].

3.2 Computed tomography (CT)

Chest CT can be useful in identifying benign and malignant pleural diseases, including through signs such as thickening of the wall pleura or mediastinal pleura greater than 1 cm. Irregular pleural cavities and pleural nodules suggest a high probability of MPE with a high specificity (88–94%) but low sensitivity (36–51%), and approximately 50% of patients with MPE show no pleural abnormalities on CT [26,27]. Chest CT should be performed before the fluid is completely drained so that the pleural phase contrast can be used to obtain better clarity to better visualize pleural abnormalities [28]. Mediastinal and pleural thickening and pleural nodules suggest a possible MPE [27]. Although CT scans may not necessarily reveal abnormalities other than PE, CT scans can also provide evidence of underlying primary tumor and metastases.

3.3 Positron emission tomography-computed tomography (PET-CT)

The fluorodeoxyglucose PET imaging is based on the different metabolism between normal and abnormal tissues, in which the metabolism of fluorodeoxyglucose is accelerated and reflected by higher uptake in tumor cells; however, this method has a false-positive rate in the presence of metabolically active inflammation and infection [29]. Although its popularity influenced by false-positive results for inflammation and infection, PET-CT can be applied to stage pleural disease [30]. Nonetheless, one study showed that PET-CT can identify benign and MPE with a sensitivity of 83.3% and specificity of 92.2% and developed and validated a PET-CT parameter score, which can help physicians distinguish PE [31].

3.4 Cytology

The criteria for the diagnosis of MPE are the detection of cancer cells by pleural fluid cytology or the detection of cancer cells by pleural biopsy. Cytological diagnosis is used as a traditional diagnostic tool, but its sensitivity is not high if there are few tumor cells [32]. Several studies have shown that the sensitivity of pleural fluid cytology is approximately 40–87%, with low positive rates. The volume of cytological fluid extracted by diagnostic thoracentesis is currently controversial, and some studies have shown that at least 75 mL of pleural fluid is required for cytopathological diagnosis [15]. The sensitivity of a pleural fluid cytology sample taken in the first thoracentesis for the diagnosis of malignancy is 60%, with an increased sensitivity of 27% in the second procedure, but after the third, the diagnostic rate no longer increases, and the additional procedure instead delays diagnosis and treatment [33]. The use of cytology in combination with pleural biopsy increases the sensitivity of the diagnosis [34]. Although pleural fluid cytology is the least invasive, slowest and least effective method for diagnosing malignancy, the cytological diagnosis is also dependent on the underlying primary tumor, sample preparation and the experience of the cytologist [1].

3.5 Pleural biopsy

Pleural biopsy is the gold standard for the diagnosis of MPE [6]. In CT-guided or ultrasound-guided biopsies can be performed to collect pleural tissue for diagnosis, and this method has a sensitivity of 76–88% and specificity of up to 100% for the diagnosis of MPE [6]. When pleural thickening >1 cm is found in MPE, the diagnostic sensitivity of CT-guided pleural biopsy is comparable to that of thoracoscopy (96 versus 95%) [35]. Pleural biopsy in addition to of pleural fluid cytology can increase the diagnostic sensitivity for MPE by 7–27% [27]. When pleural thickening is obvious, pleural biopsy via thoracoscopic surgery can help simultaneously visualize the pleura, biopsy the involved area and drain the effusion. In addition, if the pleura is infiltrated and there is no trapped lung, pleural fixation can be performed [23].

3.6 Medical thoracoscopy (MT)

MT is both a diagnostic and a therapeutic method, and this method has a sensitivity of 92–97% and a specificity of 99–100% for the diagnosis of MPE [36,37]. The indications for MT, from a diagnostic point of view, include: cytologically negative and predominantly lymphocytic exudate, and the need for tumor staging, for additional tissue for molecular analysis, and to identify lung cancer, breast cancer and mesothelioma; from a therapeutic point of view, the goals of MT include pleural fixation by spraying in talcum powder, and drainage of MPE, especially complex pneumonia-like MPE, and the absolute contraindications, include extensive adhesions of the lung to the mural pleura, hypercapnia, severe dyspnea, uncontrollable cough, and myocardial infarction within the last 4 weeks [38]. Endoscopic thoracoscopy is a safe procedure with low complications and mortality rates and high diagnostic performance. Procedures requiring general anesthesia are very useful if more invasive procedures, such as video-assisted thoracic surgery (VATS), are performed for patients considered unsuitable for surgery or who are at increased risk for complications [39,40]. These procedures (medical or surgical thoracoscopy) have similar performances, with low mortality and major complication rates (between 0–0.34% and 1.2–1.8%, respectively [41,42].

3.7 Liquid biopsy

Gene expression of different tumors has become a pillar of diagnosis, therapeutic monitoring and precise medical guidelines. Numerous studies on liquid biopsies have demonstrated this diagnostic utility of this method in diagnosing disease, predicting prognosis and detecting cell-free deoxyribonucleic acid (DNA) in plasma [43]. MPE is often enriched with tumor cells, and extracellular vesicles and cell-free DNA are the two main targets currently explored in MPE. Therefore, MPE can be used as a source of biomarkers for the study of tumor mutations in liquid biopsies. Compared to tissue biopsy, the liquid biopsy method is less invasive and can show dynamic changes in the tumor in real time by using circulating biomarkers, including cell-free DNA, circulating tumor DNA, extracellular vesicles, messenger ribonucleic acid (mRNA), micro-ribonucleic acid (miRNA), circulating tumor cells and exosomes [44–46]. With the continuous development of detection technologies, multigene sequencing and second-generation sequencing (NGS) methods to detect the differences between mutations in pleural fluid and tissue specimens are also a hot topic of research [47,48]. Lin et al. simultaneously collected pleural fluid and plasma specimens from 63 patients and extracted free DNA and precipitated cell-free DNA from the pleural fluid supernatant and cell precipitate, respectively. All samples were analyzed through received NGS for 416 cancer-associated genes and showed that in cohort 1 with matched tumor tissues, 93.1% of tissue-assayed driver mutations were detected in MPE cell-free DNA, including activin-like kinase (ALK), v-raf murine sarcoma viral oncogene homolog B1, EGFR, kirsten rats arcomaviral oncogene homolog (KRAS), neuro kinin, neurofibromin 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha and proto-oncogene tyrosine-protein kinase receptor ret, whereas only 62.1% were detected in plasma cell-free DNA [49]. PE cell-free DNA had the highest detection rate of EGFR mutations in the entire cohort (71% overall, 68 and 59% for PE cell-free DNA and plasma cell-free DNA, respectively) [50]. In bleeding or cytology-negative PE samples, PE cell-free DNA had a higher sensitivity for mutation detection than plasma cell-free DNA. This suggests that MPE sampling could be a potential alternative to liquid biopsies and that genetic analysis of disease by detecting circulating tumor cells and exosomes in PEs could be explored in the future [51,52]. In addition, the different sensitivities and specificities of different sequencing platforms still require further study in clinical studies and standardization and are worthy of further investigation in the future.

3.8 MPE diagnostic summary

The sensitivity of the first PE cytology sample to diagnose malignant tumors was 60%, and the sensitivity of the second PE cytology sample increased by 27% [53]. However, after the third pleural puncture, the diagnostic rate would not increase, and the diagnosis and treatment would be delayed. Therefore, when the second cytological examination is negative yet MPE is highly suspected, the next step should be imaging guided pleural biopsy or thoracoscopic pleural biopsy. It has been reported that pleural biopsy based on pleural fluid cytology can increase the diagnostic rate of MPE by 7–27% [54]. The sensitivity of ultrasound or CT guided pleural biopsy was higher than that of blind pleural biopsy. The sensitivity of ultrasound guided pleural biopsy in the diagnosis of MPE was 70–94% [54]. Some studies believed that five-eight needles of image guided pleural biopsy have high diagnostic sensitivity, and six needles are recommended at least [53]. The sensitivity and specificity of MT in the diagnosis of MPE were 92–97.0 and 99–100%, respectively, which were similar to those of VATS [36]. The methods for diagnosing MPE and its causes are increasingly updated, which has improved the diagnostic accuracy of MPE to a certain extent, but they still have certain limitations. It is still to be confirmed by prospective studies with large samples to determine whether any better or integrated approach, which can make the diagnosis more accurate in the future.

4 Management of MPE

The aim of MPE treatment is to relieve symptoms such as dyspnea, improve quality of life and prolong survival. The British Thoracic Society guidelines for the management of MPE and the American Thoracic Society (ATS) guidelines recommend that patients with MPE should be observed for only if the MPE is asymptomatic [55], and that for symptomatic patients, it should first be determined if their symptoms are related to MPE, and these patients should be assessed for lung distension [4]. Treatments for MPE currently include therapeutic pleurodesis, chemical pleural fixation, thoracoscopic pleural fixation, long-term tube drainage, pleurodesis and thoraco-abdominal shunts. Pleural fixation and thoracic drainage are the two most commonly used methods in clinical practice. It is also worth exploring whether a difference exists in the efficacy of tyrosine kinase inhibit (TKI) therapy for patients with EGFR mutations and MPE and intrathecal therapy in combination with TKI, as the standard first-line treatment option for patients with EGFR mutations [56].

4.1 Thoracentesis

Thoracentesis is the most commonly used clinical modality to treat MPE and provides rapid relief of dyspnea symptoms; furthermore, confirmatory evidence of diagnosis can be obtained by thoracentesis in more than two-third of patients [57]. Repeated thoracentesis may be considered for patients with short expected survival duration and those who are unable to tolerate more invasive procedures and treatments, but clinicians need to adequately prevent the various complications that may arise from repeated thoracentesis, such as infection, bleeding and pneumothorax. The timing and scope of thoracentesis depends on the type and location of the primary tumor and the general condition of the patient. In the early stages of MPE, the effusion can be left untreated, but a clear diagnosis is needed as soon as possible, while progressive MPE needs to be treated promptly; otherwise, the patients are prone to developing irreversible pulmonary atelectasis and lung atrophy. Repeat chest CT or X-ray is required after thoracentesis to avoid medically induced pneumothorax or hemothorax [4]. Care should also be taken to avoid the rapid extraction of fluid by thoracentesis. Rapidly extracting more than 1.5 L of fluid from the pleural cavity in a 24 h period may result in redundant pulmonary edema in the affected lung, a complication that has a mortality rate of up to 20%, so it is recommended that each thoracentesis aspiration be limited to 1.0–1.5 L [4]. Successful thoracentesis can provide the patient with a clear diagnosis of MPE, as well as rapid recovery from the compressed lung tissue, which is relevant to the success of subsequent chemical pleural fixation [58].

4.2 Pleurodesis

The purpose of pleural fixation is to induce an inflammatory response in the pleura, forcing the two layers of the pleura to adhere in order to prevent fluid accumulation. The main focus of pleural fixation is the choice of sclerosing agents, including chemotherapeutic agents, bio-immunotherapy agents, talc, iodophor, silver nitrate, herbal preparations and autologous blood. Of these, talc is the most widely used and effective pleural fixation agent [23]. A thin flexible catheter is placed under ultrasound or CT guidance and secured to the chest wall, and a drainage bag or water seal bottle is attached to drain the pleural fluid; these devices have the advantage of being easy to operate, safe and not especially painful for the patient. Adequate chest drainage can be followed by the intrapleural application of antitumor drugs (e.g., bleomycin) or nontumor drugs (e.g., talcum powder) as sclerosing agents and adhesives to achieve pleural fixation. As the most commonly used clinical pleural adhesion agent, medical talc has the advantages of a high success rate for pleural fixation (approximately 93%) and low cost [59]. Talc can be injected into the chest cavity not only through a drainage tube, but also as a dry powder that can be sprayed uniformly throughout the chest cavity during surgical thoracoscopy [60]. The most significant side effect of pleural fixation is a local inflammatory response in the pleura leading to fever and chest pain, and pleural inflammation is thought to be directly related to successful pleural fixation, although a recent analysis of the TIME 1 trial dataset showed no difference in pain scores between patients with successful and unsuccessful pleural fixation, and elevated C-reactive protein levels were associated with successful pleural fixation [61]. Other rare complications include local infection, chest sepsis, arrhythmias, cardiac arrest, myocardial infarction and hypotension. Complications such as acute respiratory distress syndrome, acute pneumonia, and respiratory failure have also been occasionally reported [60]. In a multicenter retrospective study, none of the 558 patients who underwent pleural fixation with talc developed acute respiratory distress syndrome [62], and another study showed that pleural fixation with talc resulted in a lower recurrence rate for pleural fluid than pleural fixation with bleomycin (relative risk [RR] 0.64; 95% confidence interval [CI] 0.34–1.20), compared with the use of a talc solution. Spraying dry talc powder resulted in more effective fixation of the pleura and a lower recurrence rate for pleural fluid (RR 0.21; 95% CI 0.05–0.93) than other pleural fixation methods [63]. Nonrandomized studies have shown that patients who underwent successful pleural fixation survived longer than those who did not, which may indicate a biological role for pleural fluid in cancer progression [64]. A recent meta-analysis found no correlation between large and smallbore chest drains for successful pleural fixation between groups of patients [65]. Other factors such as turning the patient after sclerotherapy injection, intermittent open chest tube drainage and the application of multiple chest tube drains did not lead to a difference in fixation outcomes.

4.3 Indwelling pleural catheter (IPC)

The IPC is a silicone catheter placed in the pleural cavity and is carried through a subcutaneous tunnel. It has a cuff at the distal end that forms fibrous adhesions in the subcutaneous tissue over time, holding the IPC in place and preventing ascending infection. The IPC is discharged through a vacuum bottle with a one-way valve that uses negative suction to monitor flow and volume. The IPC offers the advantage of outpatient/home management of MPE and has gained great popularity in the last decade due to the reduction in hospital admission time [66–68]. A meta-analysis of 1,348 patients with MPE treated with IPC showed that 95.6% of patients had improved dyspnea symptoms and 45.6% had spontaneous pleural adhesions after a mean of 52 days [69]. Given their ease of insertion and management, IPC has become the management modality of choice in many centers around the world. However, IPC is associated with a higher rate of complications, among which, the complication of greatest concern is pleural infection, particularly in patients receiving chemotherapy [70]. In a large multicenter study of 1,021 patients with IPC, pleural infections occurred in 50 (4.9%) patients, 94% of whom had a mortality rate of less than 0.3%, with the mortalities being associated with the control of pleural infections by antibiotics [71]. In patients with irreversible atelectasis or pulmonary atrophy due to prolonged fluid compression or recurrent massive MPE following chest tube drainage, chest tube drainage may not adequately and effectively drain the pleural fluid; additionally, if the patient requires outpatient treatment or treatment at home with a tube, chest tube drainage may be a suitable alternative to closed chest tube drainage because it requires more medical care (e.g., tube management). However, closed chest drainage can be used as an alternative to chest tube drainage [70,72], allowing patients to be more easily treated in outpatient clinics with easier care [73]. A drain thicker than a subclavian venipuncture tube can be placed subcutaneously for a longer distance, which reduces the chance of infection, and several studies have shown that closed chest drains are safe and effective, with a treatment efficiency of approximately 90% and low rate of long-term complications (including pain, local cellulitis and chest tube dislodgement) [74]. Additionally, approximately 26–58% of patients develop spontaneous pleural fixation and eventually have their chest tubes removed after a period of closed chest drainage [75]. In a single-center retrospective study from the Netherlands, 17 patients with recurrent MPE underwent closed chest drainage, with 70–80% of patients experiencing significant symptomatic relief. The mean indwelling time of the tube was 2.3 months (range 1–6 months), and the mean drainage volume was 360 ml (range 150–1,000 mL) [76]. For patients requiring long-term drainage, the overall results of closed chest drainage are satisfactory and can significantly improve patient quality of life.

4.4 Anti-angiogenic agents

In recent years, intracavitary biotherapy has been a hot research topic in MPE treatment. Domestic studies have confirmed that recombinant human vascular endothelial inhibitor combined with the intracavitary administration of chemotherapy can control malignant plasma cavity effusion with a control rate of approximately 60% [77], suggesting the promising application of anti-angiogenic drugs in the treatment of malignant thoracic and abdominal effusion; moreover, combinations with other thoracic drugs (cisplatin, etc.) have improved efficiency compared with single drugs. Bevacizumab is a recombinant humanized monoclonal antibody that binds to VEGF, thereby preventing neovascularization [78]. Du et al. reported that among 72 patients with MPE were randomly assigned to an intracavitary bevacizumab combined with cisplatin group and groups, combination treatment was more effective than treatment with a single agent (83.3 vs 50.0%, P < 0.05), leading to prolonged progression-free survival (PFS) 5.3 vs 4.5 months, P < 0.05), with a trend toward longer overall survival (OS) [79]. In a study by Tao et al. [80] 21 patients with advanced lung adenocarcinoma with MPE treated with bevacizumab in combination with chemotherapy (paclitaxel in combination with platinum, gemcitabine in combination with platinum and pemetrexed alone) had a median PFS and median OS of 7.8 and 25.8 months, respectively. The MPE control rates at weeks 6, 12, 24, 48 and 96 were 95.2, 90.0, 89.5, 73.7 and 43.8%, respectively. Thus, bevacizumab, whether administered intrathecally or intravenously, may be more effective in controlling MPE than chemotherapy alone.

4.5 EGFR-TKI targeted agents

Most non-small cell lung cancer (NSCLC) patients are in advanced stage at the time of diagnosis, and the probability of accepting surgical resection is less than 30% [3]. Among them, patients with EGFR gene mutation and echinoderm microtubule-associated protein-like 4 (EML4-ALK) gene rearrangement can use targeted drug therapy [81,82]. Several studies have now established EGFR-TKI as the treatment of choice in patients with EGFR mutations [83]. It is worth considering whether intrathecal drugs can control MPE patients better with EGFR mutations and MPE, or whether receiving single-agent TKI therapy can control MPE while avoiding the adverse effects of intrathecal drugs such as fever, bone marrow suppression and chest pain. Kashiwabara et al. [56] analyzed the efficacy of EGFR-TKI in combination with talcum powder in patients with MPE and lung adenocarcinoma, 34 of whom received TKI as first-line therapy. It was suggested that TKI-targeted therapy combined with pleural fixation is more effective than pleural fixation alone in controlling MPE in patients with EGFR mutations and MPE. EGFR-TKIs treatment can significantly improve the prognosis of patients with advanced NSCLC, especially those with EGFR gene mutation. However, a retrospective study showed that the response of PE of lung cancer patients with EGFR mutation and MPE to EGFR-TKIs (including gefitinib, alfatinib and oxitinib) was worse than that of solid malignant tumors [84]. In NSCLC patients, anaplastic lymphoma kinase (ALK) gene or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) rearrangement accounts for 5 and 1%, respectively [85]. They are sensitive to the treatment of coxotinib, seretinib, aletinib and bugatinib. Compared with chemotherapy, all ALK inhibitors can significantly improve the PFS of lung cancer patients in this group. Compared with coxotinib and seretinib, aletinib and bugatinib can better improve the PFS of patients, especially in patients with advanced stage [86,87]. However, there is no large clinical study confirmed that the prognosis of patients with advanced lung cancer with MPE is different from that of patients with advanced lung cancer without MPE.

4.6 The thoracoperitoneal shunt

For patients whose lungs cannot be expanded or trapped due to MPE, a thoracoabdominal shunt tube can be placed, which is a subcutaneous tunnel from the chest to the abdomen [88]. The liquid is pumped manually, but due to the limited capacity of the pump chamber, it needs to be pumped frequently [89]. A retrospective study on thoracoperitoneal shunt showed that the remission rate was 95%, but the complication rate was 15%, including technical failure and infection [90]. The presence of ascites is a contraindication of thoracoperitoneal shunt.

4.7 Biological agent treatment

The commonly used biological agents in clinic are mainly IL-2 and TNF [91]. IL-2 is a thymus dependent lymphocyte growth factor, which can induce the secretion of interferon and a variety of cytokines, including promoting the long-term survival of T cells, enhancing the killing activity of T cells, promoting the proliferation and activation of natural killer (NK) cells, lymphokine activated killer cells, tumor infiltrating lymphocyte cells, etc. [92]. It is clinically used for tumor adjuvant therapy and the treatment of cancerous PE. Studies have shown that the use of IL-2 alone or in combination with other anti-cancer therapies can bring survival benefits to patients with advanced cancer. TNF-α is a cytokine secreted by monocytes/macrophages [93]. Its anti-tumor mechanisms mainly include directly killing tumor cells to induce tumor cell apoptosis, anti-tumor angiogenesis and enhancing immune function. TNF-α thoracic perfusion therapy for MPE has shown good efficacy whether alone or in combination [94]. The clinical application is limited due to its expensive price, high fever and other side effects.

4.8 Immunotherapy

Immunotherapy consists mainly of immune cell therapy and immune checkpoint (programmed death-1/programmed cell death-ligand-1 and cytotoxic T lymphocyte-associated antigen-4) inhibitor therapy [95,96]. Intrathoracic autoimmune cell infusion therapy is an alternative approach to control MPE, and the effectiveness correlates with a higher frequency of peripheral blood effector T cells [97]. Although the efficacy is limited, it is less adverse, well tolerated, and not limited by the patient’s liver or kidney function status or physical status score, and has good promise in the palliative treatment of MPE. For advanced non-squamous NSCLC and squamous lung cancer with negative driver genes, including patients with combined MPE, immune checkpoint inhibitors alone or in combination with chemotherapy and anti-angiogenic drugs can improve patient prognosis [98].

5 Future directions

Most of the interest is the early translational work which shows that the proliferation of cancer cell culture is promoted by seeding cells in pleural fluid [99]. This growth-promoting property of pleural fluid opens up the possibility that pleural fluid may not be a bystander to malignant disease, requiring only drainage to relieve symptoms, but may be an active promoter of cancer progression, thus emphasizing the importance of early control of PE. Current treatment strategies are focused on mechanical drainage and pleural cavity sealing [28]; however, significant efforts should be directed toward more complex areas of biomarker analysis and validation, and subsequent treatment with intrapleural immune agents and targeted therapies, for many years to come. If successful, this therapeutic strategy has the potential to bring about real step change in the management of MPE [100]. However, there are significant challenges in this regard, especially the research evidence that the clinical heterogeneity of MPE depends on primary tumors and intrapleural therapy. So far, the results of MPE are mixed.

6 Prognosis

Researchers have investigated several predictors of survival in patients with MPE. The most established method for predicting the prognosis of MPE patients is the LENT score [101] which includes the human l-lactate dehydrogenase (L-LDH) level, Eastern Cooperative Oncology Group (E-ECOG), N-neutrophil to lymphocyte ratio, T-tumor type and divides patients into low (score 0–1), moderate (score 2–4) or high (5–7) risk with a median survival of 319, 130 and 44 days. Additionally, as the LENT score (Table 1) has been developed using patients presenting with their first episode of MPE, regardless of previous cancer treatment, it is widely applicable and relevant in the clinical setting. It not only guides the treatment of MPE, but also helps predict the survival of MPE patients. It is the first validated risk stratification system for predicting the survival of MPE patients and is superior to ECOG performance status alone in predicting survival in individual patients.

Table 1

The LENT score calculation

Variable Score
L -LDH level in pleural fluid (IU/L) <1,500 0
>1,500 1
E-ECOG PS 0 0
1 1
2 2
3–4 3
N-NLR <9 0
>9 1
T-tumor type Lowest risk tumor types Mesothelioma hematological malignancy 0
Moderate risk tumor types Breast cancer gynecological cancer 1
Highest risk tumor types Renal cell carcinoma
Lung cancer other tumors types 2
Total score
Risk categories Low risk 0–1
Moderate risk 2–4
High risk 5–7

Patients with MPE are a highly diverse group of patients, with great variation in primary tumor involvement (particularly the ability to expand the lungs), major comorbidities, performance status, expected survival and patient wishes. More patient-based studies are likely to be performed in the future. In addition to research studies on pain, dyspnea and quality of life as well as studies on supportive treatments such as exercise training, nutritional interventions and psychological support should be conducted and may play an important role for MPE and may also offer useful adjuncts to interventions for MPE. Adjunctive treatments, such as exercise and dietary interventions, may also be useful adjuncts to pleural interventions [102].

7 Conclusions

There have been significant advances in the management of MPE. However, patients with advanced malignancies remain severely ill. Recent discoveries in the pathophysiological mechanisms of MPE have highlighted the role of molecular factors and mutations in the disease. There remains a need for individualized treatment. Predictive scores in clinical practice help to determine prognosis and guide treatment.

The current treatment for MPE is individualized and multidisciplinary. Some patients in poor general condition, especially those with an expected survival of only a few weeks to a few months, typically opt for less invasive methods of pleural fluid control, such as repeated thoracentesis or closed chest drainage, which are ideal for reducing both the length of hospital stay and discomfort of the patient. With the continuous development of treatment techniques and tools, VATS techniques can not only relieve the clinical symptoms associated with MPE but also allow for clear pathological results and direct observation of tumors progression in the thoracic cavity, as well as facilitate various therapeutic operations such as pleurectomy and pleural fixation. Because it is performed under direct vision, surgical thoracoscopic pleural fixation is more uniform and thorough in spraying sclerosing or adhesive agents. This method is therefore more accurate, and a combination of treatments is recommended based on patient’s specific situation. In the near future, improved treatment for oncological disease and a better understanding of the pathophysiological mechanisms of MPE will help to improve the prognosis of patients with MPE. Many unanswered questions remain and ongoing research will help clinicians to enhance the care for this group of patients with MPE.

tel: +86-0431-84995852, fax: +86-0431-84995852

Acknowledgements

The authors would like to thank the anonymous reviewers for their contribution to the improvement of the manuscript.

  1. Funding information: This work was supported by Science and Technology Development Plan Project of Jilin Province, China (No. 20200603006SF).

  2. Author contributions: All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2022-10-12
Revised: 2023-01-09
Accepted: 2023-01-22
Published Online: 2023-02-28

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0575
Keywords for this article
malignant pleural effusion; mechanism; diagnosis; therapy; treatment
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers
  3. Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis
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  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
  77. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine
  78. Inhibition of TAZ impairs the migration ability of melanoma cells
  79. Molecular complexity analysis of the diagnosis of Gitelman syndrome in China
  80. Effects of maternal calcium and protein intake on the development and bone metabolism of offspring mice
  81. Identification of winter wheat pests and diseases based on improved convolutional neural network
  82. Ultra-multiplex PCR technique to guide treatment of Aspergillus-infected aortic valve prostheses
  83. Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2
  84. Immune checkpoint inhibitors in cancer patients with COVID-19
  85. Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses
  86. Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma
  87. Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy
  88. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway
  89. Lung abscess by Fusobacterium nucleatum and Streptococcus spp. co-infection by mNGS: A case series
  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
  99. Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis
  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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