Intrapleural injection of brucea javanica oil emulsion provided a long-term benefits in patient with malignant pleural effusion from pleural mesothelioma: A case report.

Malignant pleural mesothelioma (MPM) is a severe form of cancer that originates from mesothelium cells. Around 54-90% of mesotheliomas are associated with pleural effusions. Brucea Javanica Oil Emulsion (BJOE) is the processed oil derived from the seeds of Brucea javanica, which has shown potential as a treatment option for several types of cancer. Here, we present a case study of a MPM patient with malignant pleural effusion who received intrapleural injection of BJOE. The treatment resulted in the complete response of pleural effusion and chest tightness. While the precise mechanisms underlying the therapeutic effects of BJOE for pleural effusion are not yet fully understood, it has demonstrated a satisfactory clinical response without significant adverse effects.

Hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy for the malignant effusion: a multi-center randomized clinical trial.

OBJECTIVE: To compare the efficacy and safety of hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy in the treatment of malignant pleural or peritoneal effusion. METHODS: A randomized clinical trial was carried out in 8 cancer centers across China. Patients with malignant pleural or peritoneal effusion were randomly assigned to the study group or control group. Patients in the study group were treated with cisplatin-based hyperthermic intrathoracic chemotherapy (HITHOC) or hyperthermic intraperitoneal chemotherapy (HIPEC), while the control group was treated with conventional intrapleural or intraperitoneal chemotherapy using same chemotherapeutic regime as the study group. The objective response rate (ORR) was analyzed as primary outcome. Quality-of-life (QOL) score was recorded as secondary outcome using the questionnaire 30 (QLQ-C30) of the European Organization for Research and Treatment of Cancer (EORTC). The efficacy and safety of the two treatments were compared. RESULTS: Total 135 patients were recruited and randomized in this study, with 67 patients in the study group and 68 patients in the control group. The ORR in the study group (80.70%) was significantly higher than that in the control group (31.03%, p < 0.001). However, neither changes of QOL scores, nor incidence rates of adverse events were significantly different between the two groups (p = 0.076 and 0.197, respectively). CONCLUSION: Efficacy of HITHOC or HIPEC is superior to that of conventional modality for the treatment of malignant effusion with comparable side effects.

Efficacy of hyperthermic intrathoracic chemotherapy for initially diagnosed lung cancer with symptomatic malignant pleural effusion.

Initially diagnosed malignant pleural effusion (MPE) has different systematic treatments, and defining the best drainage regimen according to the responsiveness of MPE to different systematic treatments is important. This study compared the efficacy of hyperthermic intrathoracic chemotherapy (HITHOC) and pleural catheter drainage (IPCD) for initially diagnosed lung cancer with symptomatic MPE. We retrospectively reviewed the medical records of initially diagnosed lung cancer patients with symptomatic MPE between January 2018 and May 2022. The patients were treated with IPCD or HITHOC for local control of MPE after diagnosis. Systematic regimens were conducted during 1 month according to guidelines after local treatment. Intrathoracic MPE progression-free survival (iPFS) and overall survival (OS) were calculated, Univariate and multivariable Cox-regression were used to identify factors associated with iPFS and OS. A total of 33 patients were evaluated; 10 (30.3%) patients received IPCD, and 23 (69.7%) patients received HITHOC. No difference in the MPE control rate at 1 month was found between the IPCD group (90%) and HITHOC group (95.7%). However, this control rate was significantly higher in the HITHOC group (69.6%) than in the IPCD group (30%) at 3 months (P = 0.035). Multivariate analysis showed that receiving tyrosine kinase inhibitors (TKIs) or chemotherapy was a significant protective factor for iPFS (HR = 0.376, 95% CI 0.214-0.659, P = 0.007) and OS (HR = 0.321, 95% CI 0.174-0.594, P < 0.001). According to subgroup analysis, among patients treated with TKIs, those who received HITHOC had longer iPFS and OS than those who received IPCD (P = 0.011 and P = 0.002, respectively), but this difference was not found in the palliative care subgroup. Moreover, no patients treated with chemotherapy showed reaccumulation of MPE. Systematic TKIs or chemotherapy prolonged iPFS and OS for those initially diagnosed with lung cancer with symptomatic MPE. HITHOC prolonged iPFS and OS for those treated with systematic TKIs.

The evidence framework of traditional Chinese medicine injection (Aidi injection) in controlling malignant pleural effusion: A clustered systematic review and meta-analysis.

INTRODUCTION: Aidi injection (Aidi), a traditional Chinese medicine injection, is often practiced to control malignant pleural effusion (MPE). OBJECTIVES: We performed a registered systematic review and meta-analysis (PROSPERO: CRD42022337611) to clarify the clinical role of Aidi in MPE, reveal optimal combinations of Aidi and chemical agents, their indications, therapeutic route and usage, and demonstrate their clinical effectiveness and safety. METHODOLOGY: All randomized controlled trials (RCTs) about Aidi in controlling MPE were collected from Chinese and English databases (up to October 2022). We clustered them into multiple homogenous regimens, evaluated the risk-of-bias at outcome level using a RoB 2, extracted and pooled the data using meta-analysis or descriptive analysis, and finally summarized their evidence quality. RESULTS: All 56 studies were clustered into intrapleural administration with Aidi alone or plus chemical agents, and intravenous administration with Aidi for MPE. Intrapleural administration with Aidi alone displayed similar clinical responses on Cisplatin (DDP) alone. Only administration with Aidi plus DDP significantly improved complete response and quality of life, and displayed a low pleurodesis failure, disease progression, hematotoxicity, gastrointestinal and hepatorenal toxicity. For patients with moderate to massive effusion, Karnofsky Performance Status score ≥ 50 or anticipated survival time ≥3 months, Aidi (50 ml to 80 ml each time, one time each week and three to eight times) plus DDP (20 to 30 mg, 40 to 50 mg, or 60 to 80 mg each time) significantly improved clinical responses. Most results had moderate to low quality. CONCLUSIONS: Current evidences indicate that Aidi, a pleurodesis agent, plays an interesting clinical role in controlling MPE. Aidi plus DDP perfusion is a most commonly used regimen, which shows a significant improvement in clinical responses. These findings also provide an indication and possible optimal usage for rational drug use.

Hyperthermic intrathoracic chemotherapy for the treatment of malignant pleural effusion caused by breast and ovarian cancer: A systematic literature review and pooled analysis.

OBJECTIVES: Breast and ovarian cancer account for over 30% of malignant pleural effusions (MPEs). Treatment of the metastatic disease requires control of the MPE. Even though primarily symptomatic, the treatment of the MPE can potentially affect the oncological course of the disease. The aim of this review is to analyze the effectiveness of intrathoracic chemotherapy in the treatment of MPE caused by breast and ovarian cancer. METHODS: A systematic literature research was conducted up until May 2021. Studies published in English on patients undergoing either surgical or interventional intrapleural chemotherapy were included. RESULTS: Thirteen studies with a total of 497 patients were included. Analysis was performed on 169 patients with MPE due to breast cancer and eight patients with MPE secondary to ovarian cancer. The pooled success rates of intrathoracic chemotherapy for controlling the MPE were 59.1% and 87.5%, respectively. A survival analysis was not possible with the available data. The overall toxicity of the treatment was low. CONCLUSIONS: Intrathoracic chemotherapy achieves symptomatic control of the MPE in 59.1% of patients with metastatic breast cancer and 87.5% of patients with metastatic ovarian cancer. This is inferior to other forms of surgical pleurodesis. Data from small case series and studies on intraperitoneal chemotherapy show promising results. However, formal oncological studies on the use of intrathoracic chemotherapy for metastatic breast or ovarian cancer are lacking. Further prospective pilot studies are needed to assess the therapeutic oncological effects of this treatment.

Study protocol of a phase 1 clinical trial establishing the safety of intrapleural administration of liposomal curcumin: curcumin as a palliative treatment for malignant pleural effusion (IPAL-MPE).

INTRODUCTION: This is a phase 1, open-label, single-centre, uncontrolled, dose-escalation study to evaluate the feasibility, tolerability and pharmacokinetic profiles of a single dose of liposomal curcumin, administered via an existing tunnelled indwelling pleural catheter (TIPC) directly to the tumour site in individuals with diagnoses of malignant pleural effusion. Primarily, we aim to determine a maximum tolerated dose of liposomal curcumin administered via this method. METHODS AND ANALYSIS: We will use a 3+3 expanded cohort for predefined dose-escalation levels or until a predefined number of dose-limiting toxicities are reached. Participants will be administered a single dose of liposomal curcumin (LipoCurc, SignPath Pharma) via their existing TIPC as a sequential enrolling case series with the following dose cohorts: 100, 200 and 300 mg/m2. Primary endpoints are determination of the maximum tolerated dose within the predetermined dose range, and determination of the feasibility of intrapleural administration of liposomal curcumin via an existing TIPC. Secondary endpoints include determination of the safety and tolerability of intrapleural administration of liposomal curcumin, median overall survival, effects on quality of life and on feelings of breathlessness, and the pharmacokinetics and concentrations of curcumin from the plasma and the pleural fluid. Important inclusion criteria include age ≥18 years, an existing TIPC, a pleural biopsy or pleural fluid cytology-proven diagnosis of malignant pleural effusion and for whom no antitumour therapy of proven benefit is available or has been previously declined, eastern cooperative group performance status <2. ETHICS AND DISSEMINATION: The study protocol has been approved by the Southern Adelaide Local Health Network Human Research Ethics Committee (HREC) (approval number: HREC/20/SAC/11). Study results will be published in peer-reviewed journals, and presented at conferences, in field of medical oncology and respiratory medicine. TRIAL REGISTRATION NUMBER: ACTRN12620001216909. PROTOCOL VERSION NUMBER: V.1.0.

Toxicity reduction and water expelling effect preservation of Shizaotang after its toxic members processing with vinegar on rats with malignant pleural effusions.

ETHNOPHARMACOLOGICAL RELEVANCE: Shizaotang (SZT), consisted of Euphorbia kansui S.L.Liou ex S.B.Ho (EK), Euphorbia pekinensis Rupr. (EP), Daphne genkwa Sieb. et Zucc. (DG，fried) and Ziziphus jujuba Mill. (ZJ), is usually used for treating malignant pleural effusions (MPE), but the toxicity of EK and EP limits its clinical safe application. It was reported that vinegar processing can reduce the toxicity of EK and EP. Whether EK and EP processing with vinegar can cause the reduced toxicity and retained pharmacological effects of SZT, it still remains unknown. AIM OF THE STUDY: We aimed to evaluate whether using vinegar processed EK and EP would reduce toxicity and preserve water expelling effect of SZT. MATERIALS AND METHODS: Network pharmacology and qualitative analysis of SZT/VSZT were used to construct compound-target-pathway network of their effects and toxicity. Pleural fluid weight, urine volume, uric electrolyte, pH, pro-inflammatory cytokines in pleural fluid, serum Renin-Angiotensin-Aldosterone System (RAAS), anti-diuretic hormone (ADH) and intestinal aquaporin 8 (AQP8) protein were used to evaluate the effect mechanisms involved in rats experiments. And liver damage, oxidative damage and HE staining (liver, stomach, and intestine) were used to determine the toxicity. RESULTS: Network pharmacology analysis reviewed inflammation-related pathways of the effect and toxicity of SZT/VSZT: VEGF-PI3K-AKT pathway inhibited MPE by changing the vasopermeability; PI3K-Akt/Mitogen-activated protein kinase (MAPK)/TNF-NF-κB signaling pathway inhibited MPE by up-regulating expression of AQP8 protein. In vivo experiments displayed that SZT/VSZT could reduce pleural fluid, increase urine volume, lower pro-inflammatory cytokines levels and up-regulate AQP8 protein expression significantly (P < 0.05, P < 0.01). In addition, disorders on electrolyte (Na+, K+ and Cl-) and pH were ameliorated (P < 0.05, P < 0.01). The levels of RAAS and ADH were significantly dose-dependently called back (P < 0.01). These findings were partly consistent with the results of network pharmacology analysis. Results of toxicity experiments demonstrated that SZT and VSZT exhibited certain toxicity on normal rats, and VSZT had lower toxicity than that of SZT. Interestingly, SZT and VSZT exerted alleviation effect to the liver damage and oxidative damage on model rats. CONCLUSION: SZT/VSZT improved MPE by regulating associated inflammation pathways. Besides, compared to SZT, VSZT showed lower toxicity and equivalent expelling MPE effect. This study may provide scientific basis for guiding the clinical application of SZT.

In vitro cell culture of patient derived malignant pleural and peritoneal effusions for personalised drug screening.

BACKGROUND: Malignant serous effusion (MSE) denotes a manifestation of metastatic disease with typical high concentrations of both cancer and immune cells, making them an ideal resource for in vitro cytologic studies. Hence, the aim of the study was to investigate the features of 2D and 3D MSE culture systems as well as their feasibilities for in vitro drug screening. METHODS: Pleural and peritoneal effusions from 8 patients were collected and processed for 2D monolayer and 3D hanging drop cell culture into GravityPLUS™ plates. Representative markers for cell components, proliferation rate and tumour classification were investigated by immunohistochemistry, followed by absolute quantification using a digitalised image analysis approach. Further, we implemented another 3D cell culture model based on a low attachment method for in vitro drug sensitivity testing of carboplatin, pemetrexed and pembrolizumab for 5 patients. RESULTS: Monolayer cell culture was favourable for the growth of mesothelial cells, while hanging drop culture in GravityPLUS™ plates showed better ability for preserving cancer cells, inducing positive diagnostic markers expression and restraining the growth of mesothelial cells. For in vitro drug testing, MSE from five patients presented various drug sensitivities, and one case showed strong response to PD-1 checkpoint inhibition (pembrolizumab). For some patients, the application of combinatorial drugs had better therapeutic responses compared to monotherapy. CONCLUSIONS: Digitalised quantification of data offers a better understanding of different MSE culture models. More importantly, the proposed platforms are practical and amenable for performing in vitro chemo-/immunotherapeutic drug testing by using routine cytologic MSE in a personalised manner. Next to cell blocks, our work demonstrates the prognostic and predictive value of cytologic effusion samples.

Chinese medicine Xiaoshui decoction inhibits malignant pleural effusion in mice and mediates tumor-associated macrophage polarization by activating autophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoshui decoction (XSD) is a traditional Chinese medicine compound prescription that has been shown to reinforce the spleen and remove the fluid retention, while being widely used in the treatment of malignant pleural effusion (MPE). We previously reported that XSD alleviates symptoms and improves the quality of life in patients with MPE; however, the mechanism employed by XSD on MPE has not yet been elucidated. AIM OF THE STUDY: To investigate the role and mechanism of XSD in inhibiting the development of MPE, and in regulating macrophage polarization in vitro and in vivo. MATERIALS AND METHODS: A murine MPE model was used to study the effect of XSD on MPE. Mice with MPE were randomly allocated to a control group and XSD-low-dose (1.144 g/mL), XSD-middle-dose (2.288 g/mL), XSD-high-dose (4.576 g/mL), or cisplatin groups. RAW264.7 cells were induced to form tumor-associated macrophages (TAMs) as well as M1 and M2 macrophages using different conditioned media in vitro. RESULTS: XSD effectively inhibited MPE formation, reduced pleural permeability and angiogenesis, and prolonged mice survival. Particularly, XSD treatment induced the polarization of TAMs to the M1 phenotype in MPE. Moreover, in-vitro XSD remarkably promoted the expansion of M1 macrophages and reduced M2 macrophages by enhancing autophagy. CONCLUSIONS: XSD inhibits MPE development and regulates macrophage polarization by activating autophagy, indicating that XSD may serve as a novel option for integrative MPE therapies.

Effect of thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin in treating pleural effusion in patients with advanced non-small cell lung cancer.

PURPOSE: To explore the efficacy and safety of thoracic hyperthermia perfusion with recombinant human endostatin plus nedaplatin in the treatment of pleural effusion in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion, and among them, 61 received thoracic hyperthermic perfusion with recombinant human endostatin (ES) plus nedaplatin (Endostatin group), while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone (Cisplatin group). The short-term efficacy, changes in the pleural effusion and serum immunological indicators before and after treatment, quality of life, and incidence of adverse reactions were compared between the two groups of patients. Finally, the progression of pleural effusion in patients were followed up and recorded. RESULTS: After treatment, the overall response rate of patients in Endostatin group was considerably higher than that in Cisplatin group (p=0.030). At 2 weeks after treatment, the level of alanine transferase (ALT) rose notably, while that of carcinoembryonic antigen (CEA) declined dramatically in both groups of patients, and the patients in Endostatin group had markedly lower levels of ALT and CEA than those in Cisplatin group (p=0.007, p=0.003). After treatment, the Karnofsky Performance status (KPS) score of patients was prominently raised in the two groups, and Endostatin group exhibited considerably higher KPS scores than Cisplatin group (p=0.045). The incidence rates of nausea and vomiting as well as diarrhea in Endostatin group were prominently lower than those in Cisplatin group (p=0.039, p=0.048). According to the follow-up results, the median time to the progression of pleural effusion in Endostatin group was markedly longer than that in Cisplatin group (p=0.008). CONCLUSIONS: Compared with the thoracic hyperthermic perfusion with cisplatin alone, the thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin showed dramatically potential efficacy, decrease of the incidence rate of adverse reactions in the digestive system, improvement of quality of life of patients, and prolongation of progression of pleural effusion.

Low-Frequency Sonophoresis of Chinese Medicine Formula Improves Efficacy of Malignant Pleural Effusion Treatment.

OBJECTIVE: To evaluate whether low-frequency ultrasound-facilitated transdermal delivery of a Chinese medicine (CM) formula could improve the efficacy of intrapleural administration of interleukin-2 (IL-2) in treatment of malignant pleural effusion (MPE). METHODS: A total of 110 eligible participants were randomized into the low-frequency sonophoresis (LFS) of CM (LSF/CM) group (55 cases) and the control group (55 cases) by simple randomization using a random number table. The control group was treated with an intrapleural administration of IL-2; and the LFS/CM group was treated with LFS of a CM gel formulation, combined with the same IL-2 injection as in the control group. The CM formula consisted of Semen Lepidii, Semen Sinapis, Ramulus Cinnamomi, Poriacocos, Herba Lycopi, and Radix Paeoniae Rubra. After 2-week treatment, the therapeutic outcome was determined by the change of the amount of MPE, which was evaluated by B-scan ultrasound and/or chest X-ray, and the change of quality of life (QOL) scores, which were evaluated by the Eastern Cooperative Oncology Group (ECOG) performance status. RESULTS: A significantly higher objective remission rate (ORR) was obtained with intrapleural IL-2 plus LFS/CM than IL-2 treatment alone (P=0.049). In addition, more patients in the LFS/CM group than in the control group had an improved QOL score (P=0.048), and no patients in the LFS/CM group had a reduced QOL. CONCLUSION: LFS of CM formulation could effectively alleviate MPE and improve the QOL of cancer patients.

Efficacy and safety of Viscum album extract (Helixor-M) to treat malignant pleural effusion in patients with lung cancer.

PURPOSE: Manifestations of malignant pleural effusions (MPEs) are alleviated by local therapies as well as by systemic treatment. After 2009, when commercial use of talc was discontinued in Korea, we have used Helixor-M, which is derived from the European mistletoe (Viscum album), as an alternative sclerosing agent for pleurodesis. We aimed to evaluate the efficacy and safety of Helixor-M for controlling MPE. METHODS: Between 2009 and 2015, we consecutively enrolled 52 patients with lung cancer, who underwent pleurodesis to treat MPE and were analyzed retrospectively. On day 1, 100 mg of Helixor-M was instilled via pleural catheter. If the procedure was not effective, it was repeated every other day up to five times, and the dose increased each time by 100 mg. The primary study outcome was reappearance of pleural effusion at 1 month after the last pleurodesis procedure. RESULTS: The median age of patient was 63 years, and 77% of the 52 patients were male. About 85% of pleural effusions were found to be malignant by cytogenetic analysis. Forty-two (81%) patients were evaluable for recurrence of MPE. The 1-month recurrence rate was 48% (20/42). Among the 20 patients who developed recurrent MPE, 6 required therapeutic thoracentesis. Thirteen (25%) patients experienced procedure-related pain requiring medication. Eight (15%) had fever > 38 °C. CONCLUSIONS: Our results suggest that a pleurodesis with Helixor-M was an effective and tolerable procedure for controlling MPE in lung cancer patients.

Evaluation of the efficacy and safety of elemene in treating malignant pleural effusion caused by tumors: A PRISMA guided meta-analysis.

OBJECTIVE: Elemene is widely used to treat malignant pleural effusion in China. This meta-analysis aimed to evaluate the efficacy and safety of elemene in treating malignant pleural effusion. METHODS: Electronic databases including Pubmed, the Cochrane Library, Embase and Chinese biomedical literature database were searched until March 2017. Clinical controlled trials (CCTs) assessing the efficacy and safety of elemene in the treatment of malignant pleural effusion were included. The quality of the included studies was evaluated using the quality evaluation criteria of the Cochrane Handbook version 5.1.0. RESULTS: A total of 46 CCTs were included, with 2992 patients. Results of meta-analysis showed that elemene significantly improved the overall response rate (ORR) in controlling malignant pleural effusion (risk ratio [RR] = 1.16; 95% CI: 1.08-1.23; P < .05). Subgroup results showed that the ORR of elemene in the treatment of lung cancer patients with malignant pleural effusion (RR = 1.20, 95% CI: 1.07-1.34; P < .05) was higher than that of other cancers (RR = 1.14, 95% CI: 1.05-1.23; P < .05). Meanwhile, elemene did not significantly increase the incidences of chest pain and fever (P > .05). CONCLUSION: Elemene is suggested to have the ability of improving the treatment outcome of malignant pleural effusion with acceptable safety.

Evaluation of efficacy and safety for Brucea javanica oil emulsion in the control of the malignant pleural effusions via thoracic perfusion.

BACKGROUND: Brucea javanica oil emulsion (BJOE) is traditional Chinese medicine with implicated anti-tumor activity, which has been used for treating lung cancer in China. The aim of this investigation was to evaluate the effects and safety of intrapleural injection of BJOE in treating malignant pleural effusion (MPE). METHODS: The randomised controlled trials (RCTs) on the effects and safety of BJOE in treating MPE were searched from electronic medical database including MEDLINE, SCI, EMBASE, Cochrance Library and CNKI. A total of 14 RCTs with 1085 patients were involved in this meta-analysis. RESULTS: The overall response rate (ORR) of traditional chemotherapy drugs plus BJOE was higher than that of traditional chemotherapy drugs alone (p = 0.001; odds ratio = 1.39). Meanwhile, the combination of BJOE and traditional chemotherapy drugs improved the quality of life (QOL) of patients with MPE (p < 0.001; odds ratio = 1.56) compared with traditional chemotherapy drugs alone. Moreover, the participation of BJOE reduced the myelotoxicity and digestive reactions caused by traditional chemotherapy drugs (p < 0.05). CONCLUSIONS: The efficacy and safety of traditional chemotherapy drugs plus BJOE was superior to traditional chemotherapy drugs alone via intrapleural injection in controlling MPE, which suggested that BJOE can be used to treat MPE.

Comparative metabolomics analysis for the compatibility and incompatibility of kansui and licorice with different ratios by UHPLC-QTOF/MS and multivariate data analysis.

Kansui, the root of Euphorbia kansui T.N. Liou ex T.P. Wang (Euphorbiaceae), is a well-known poisonous traditional Chinese medicine (TCM). However, many monographs of TCM indicated that it cannot be co-used with licorice, as kansui-licorice is a typical "eighteen incompatible" medicaments. Our previous studies have indicated that kansui was effective in treating malignant pleural effusion (MPE), and the efficacy could be weakened by the co-use of licorice, even causing serious toxicity at the given ratio. Nevertheless, the actual mechanisms of their dosage-toxicity-efficacy relationship need to be well clarified. The present study aimed to investigate the effect of individual and combined use of kansui and licorice on MPE rats, and explain the underlying mechanisms from a metabolomic perspective. Urine samples were analyzed by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Partial least-squares discriminate analysis (PLS-DA) models were built to evaluate the interaction between kansui and licorice. Seven potential biomarkers contribute to the separation of model group and control group were tentatively identified. And selenoamino acid metabolism and nicotinate and nicotinamide metabolism with the impact-value 0.31 and 0.24, respectively, were filtered out as the most important metabolic pathways. Kansui and kansui-licorice at a ratio of 4:1 can treat MPE rats by adjusting abnormal metabolic pathways to the normal state, while it may have opposite result with kansui-licorice 1:4. The different influences to the two metabolic pathways may partially explain the dosage-toxicity-efficacy relationship of kansui-licorice with different ratios. The results could offer valuable insights into the compatibility property changes for the two herbs.

Pharmacokinetic evaluation of intrapleural perfusion with hyperthermic chemotherapy using cisplatin in patients with malignant pleural effusion.

OBJECTIVES: Malignant pleural effusion (MPE) has a poor prognosis. Most patients are treated with tube thoracostomy and sclerotherapy, although its success rate is around 64%. We have investigated intrapleural perfusion with hyperthermic chemotherapy (IPHC) using cisplatin in a study with a pharmacokinetic evaluation. METHODS: Patients with MPE, performance status of 0-1, possibility of good lung expansion and Cr<1.2mg/dL were treated with IPHC. The circuit was filled with 2000mL of normal saline containing cisplatin at a dose of 80mg/m2. Under video-assisted thoracoscopic surgery, the thoracic cavity was filled and perfused at a speed of approximately 1L/min at a temperature of 43°C for 1h. Perfusion solution and plasma samples were periodically collected, and concentrations of protein-unbound (free) platinum, which was the active derivative of cisplatin, and total platinum were determined by flameless atomic absorption spectrometry. RESULTS: Twenty patients with MPE (8 lung cancers, 7 mesotheliomas, and 5 others) were enrolled in this study. Rate of free platinum concentration relative to total platinum concentration in perfusion solution after 1hr IPHC at 43°C was 61.1±12.9%. Area under curve (AUC) of free platinum in the pleural space was calculated to be 26.3µg/mLxh, resulting in complete control of pleural effusion for 3 months after IHPC in all cases (95% confidence interval: 83-100%). While, absorption rate of total platinum from the pleural space was 33.8±17.0% (27.4±13.6mg/m2), and the maximum concentration of total platinum in serum was low, 0.66±0.31µg/mL, resulting in controllable side effects; grade 1 renal toxicity: 6 patients, grade 1 emesis: 7 patients. CONCLUSIONS: IPHC with cisplatin showed favorable pharmacokinetic profiles for an optional treatment to control malignant pleural effusion.

A Randomized Controlled Study to Observe the Efficacy of External Treatment With a Traditional Chinese Medicine Herbal Ointment on Malignant Plural Effusion: Outcome Report and Design Review.

BACKGROUND: Malignant pleural effusion (MPE) is a common complication in most malignancies. Despite its frequent occurrence, current knowledge of MPE remains limited and the effect of the management is still unsatisfying. Traditional Chinese medicine (TCM) external treatment has unique advantages, such as quicker efficacy and fewer side effects. OBJECTIVE: To observe the effects and safety of Kang'ai Xiaoshui ointment (TCM herbal ointment) in MPE. DESIGN: This was a placebo-controlled double-blinded randomized study. A total of 80 patients were enrolled, of which 72 were randomized to receive Kang'ai Xiaoshui ointment or placebo at an allocation ratio of 1:1. Kang'ai Xiaoshui ointment or placebo was applied on the thorax wall for 8 hours daily. The intervention lasted 2 weeks. Kang'ai Xiaoshui ointment consisted of Astragalus membranaces （）, Semen pharbitidis （）, Cassia twig （）, Pericarpium arecae （）, Curcuma zedoary （）, Borneol （), and other substances. In both groups, diuresis and drainages were used as needed. Outcomes covered the quantity of pleural effusion evaluation, TCM Symptom Scale, Karnofsky Performance Scale, and safety indicators such as routine blood test, blood biochemistry test, and response table of skin irritation. RESULTS: Of 72 patients randomized to receive Kang'ai Xiaoshui ointment or placebo along with symptomatic treatment, the response rate was documented as 42.4% for the treatment group and 25.0% for the placebo group ( P = .138). As for the TCM symptom scale, the treatment group showed improvement in chest distress ( P = .003), fullness and distention ( P = .042), shortness of breath ( P < .001), no statistical significance in palpitation ( P = .237), and pain ( P = .063), whereas the placebo group did not show statistical significance in any of the 5 symptoms. Major adverse events related to the treatment, mainly skin irritation, were distributed equally. CONCLUSIONS: Kang'ai Xiaoshui ointment showed a potential of reducing MPE, and it could alleviate symptoms of dyspnea. Thus, it may be appropriate as a supplementary intervention for MPE. There were some flaws in the study design. A larger scale and better designed trial is advocated.

The dosage-toxicity-efficacy relationship of kansui and licorice in malignant pleural effusion rats based on factor analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: The root of Euphorbia kansui T.P. Wang (Euphorbiaceae), a well-known traditional Chinese medicine (TCM) with certain toxicity, is known as Gan sui (Chinese: ) or kansui. It has been used to treat edema, ascites, asthma, and etc. Licorice is the root of Glycyrrhiza uralensis Fisch. or Glycyrrhiza inflate Bat. or Glycyrrhiza glabra L., Leguminosae. It is a widely used herbal medicine native to southern Europe and parts of Asia as an herbal medicine and natural sweetener. Kansui cannot be co-used with licorice, which is recorded in "eighteen incompatible" medicaments in many monographs of TCM. AIM OF THE STUDY: The present study was conducted to investigate the dosage-toxicity-efficacy relationship of the co-use of kansui and licorice and to explore its regularity of the toxicity and efficacy change. MATERIALS AND METHODS: Malignant pleural effusion rats were used and randomly divided into the normal control group, model group, positive control group (furosemide), kansui group, licorice group, and kansui-licorice groups with different ratios (kansui: licorice: 4:1, 2:1, 1:1, 0.5:1, 0.25:1, 0.1:1). Each group was adopted simultaneously to investigate the characteristic of toxicity and effect by measuring the pleural fluid and urine volumes, serum biochemical indexes, and serum TNF-α, IL-2 and IFN-γ levels. The factor analytic approach was used to analyze the dosage-toxicity-efficacy relationship between kansui and licorice. RESULTS: Two common factors were extracted from 8 indexes concerning toxicity and 5 indexes concerning efficacy. And the total factors related to toxicity (Ft) and efficacy (Fe) were calculated. The curved line of Ft indicated that the toxicity was increased along with the dose increase in licorice. The curved line of Fe indicated that the efficacy was decreased along with the dose increase in licorice. The intersection of these two lines was between the ratios of 2:1 and 1:1, and was deemed the flex point of the dosage-toxicity-efficacy. CONCLUSIONS: Kansui demonstrated a certain efficacy in treating malignant pleural effusion, and the efficacy could be weakened by the co-use of licorice, even causing serious toxicity at the given ratio. The ratio between 2:1 and 1:1 (kansui: licorice) was deemed the flex point of the dosage-toxicity-efficacy of kansui and licorice. The results will be helpful for their better utilization and development.

A meta-analysis of elemene versus DDP intrapleural injection in the treatment of malignant pleural effusion caused by lung cancer.

OBJECTIVE: The objective of this study was to evaluate the clinical efficacy of elemene versus DDP intrapleural injection in the treatment of malignant pleural effusion caused by lung cancer by meta-analysis. MATERIALS AND METHODS: PubMed (1960 ~ 2016.4), EMBASE (1980 ~ 2016.4), and CNKI (1979 ~ 2016.4) databases were searched to identify the clinical studies of elemene intrapleural injection in the treatment of lung cancer malignant pleural effusion. The odds ratio (OR) was used to evaluate the clinical efficacy of elemene in the treatment of pleural effusion compared to cisplatin (DDP). RESULTS: Seven hundred and Thirty-two subjects with 14 studies were finally included in this meta-analysis. Meta-analysis demonstrated that the objective response rate in elemene group was much higher than that in DDP group (OR = 1.34, 95% confidence interval: 1.07 ~ 1.69, P < 0.05). The Begg's funnel plot and Egger's line regression test showed no statistical publication bias. CONCLUSION: High clinical efficacy of elemene in the treatment of lung cancer malignant pleural effusion was found compared to DDP.

[Dosage-toxicity-efficacy relationship of Kansui Radix in malignant pleural effusion models based on Walker 256 analysis].

To investigate the dosage-toxicity-efficacy relationship of Kansui Radix, explore its regularity of the toxicity and efficacy change, and provide scientific basis for its clinical rational application, the malignant pleural effusion models were used to observe the effect of Kansui Radix with larger dose range (0.045-1.620 g•kg•d⁻¹ for Kansui Radix) on biochemical indexes and hydrothorax volume in experimental animals. Factor analysis method was also used to comprehensively assess the dosage-toxicity-efficacy relationship of Kansui Radix. The results showed that the rats in model group had larger hydrothorax volume, and ALT, AST, LDH, HBDH, IFN-γ, IL-2 and TNF-α levels were significantly increased (P<0.05), while TP and ALB levels were decreased (P<0.05) as compared with the blank group. After drug administration, various treatment groups decreased hydrothorax volume, IFN-γ, IL-2, TNF-α and increased TP and ALB levels as compared with model group, indicating certain therapeutic effect; and increased ALT, AST, LDH and HBDH levels, indicating certain liver and cardiac toxicity. In the factor analysis, two common factors were extracted from nine indexes, explaining 89.1% of the information. The analysis results suggested that there was no obvious toxicity in case of independent use of Kansui Radix within the dosage range set in pharmacopeia, while it would produce liver toxicity and cardiac toxicity upon 3 times of the dosage set in pharmacopeia, and the toxicity was increased with the increase of dose. At the same time, Kansui Radix can decrease the hydrothorax volume in malignant pleural effusion models and improve relevant physical indexes in a dose-dependent manner. Comprehensive analysis results of its toxic effect characteristics indicated that the upper-limit dose of Kansui Radix in pharmacopeia shall be regarded as the relatively optimal therapeutic dose.