Intrapleural Administration Research Articles

Efficacy of medical thoracoscopy combined with fibrinolytic therapy in the treatment of complicated parapneumonic effusions and empyema

ObjectiveThis study aimed to evaluate the clinical efficacy, safety, and feasibility of medical thoracoscopy combined with fibrinolytic therapy for the treatment of complicated parapneumonic effusions and empyema, with a focus on therapeutic outcomes and recovery duration.MethodsA retrospective cohort study was conducted involving 108 patients treated at Zhongshan Hospital, Xiamen University, between January 2015 and May 2024. Patients were categorized into two groups: the medical thoracoscopy group (n = 33) and the traditional treatment group (n = 75). The thoracoscopy group underwent thoracoscopic adhesiolysis and loculation breakdown, followed by intrapleural urokinase administration. The traditional treatment group received pleural catheter drainage combined with urokinase therapy. Primary outcomes included changes in inflammatory markers (white blood cell count, C-reactive protein, and procalcitonin), imaging outcomes (resolution of pleural effusion, pulmonary inflammation, and the incidence of pleural thickening at three months), pulmonary function assessed by forced vital capacity (FVC), and in-hospital mortality. Secondary outcomes encompassed the duration of postoperative fever, drainage time, intravenous antibiotic use, complication rates, initial treatment failure, length of hospital stay, and hospitalization costs.ResultsBoth groups demonstrated significant reductions in inflammatory markers post-treatment (P < 0.05). Pleural effusion resolution, pulmonary inflammation reduction, and the incidence of pleural thickening at three months were comparable between the groups (P > 0.05). Improvements in FVC were observed in both groups, with significantly greater gains in the thoracoscopy group (P < 0.05). No in-hospital mortality was reported. Compared to the traditional treatment group, the thoracoscopy group exhibited significantly lower postoperative inflammatory marker levels (P < 0.05), alongside shorter durations of postoperative fever, pleural drainage, intravenous antibiotic use, and hospital stay (all P < 0.05). The thoracoscopy group also had a significantly lower initial treatment failure rate (P < 0.05). Complication rates and hospitalization costs were comparable between the groups (P > 0.05).ConclusionsMedical thoracoscopy combined with fibrinolytic therapy offers significant advantages in the management of complicated parapneumonic effusions and empyema. This approach effectively enhances inflammation control, improves pulmonary function, and accelerates recovery time without compromising safety or increasing costs, underscoring its potential for broader clinical application.

Mild Magnetothermal Immunotherapy for Malignant Pleural Effusion.

Malignant pleural effusion (MPE) is one of the most difficult complications of cancer to cure, usually indicating poor prognosis in late-stage cancer patients. Due to the presence of a large number of tumor-associated immune cells with the tumor promoting phenotype in MPE and pleural tumors, current clinical therapy offers limited effectiveness. Here, a mild magnetothermal regulation strategy is proposed based on a magnetic nanocatlytic nanoplatform ZCMF@PEG-AF (ZCMF-AF)constructed by surface-modifying anti-F4/80 antibody (AF) on ZnCoFe2O4@ZnMnFe2O4 magnetic nanoparticles (ZCMF) to target and polarize tumor-associated macrophages. Under alternating magnetic field-induced hyperthermia (41-42°C), ZCMF-AF exhibits in situ nanocatalytic production of hydroxyl radicals via released iron ions under acidic cellular environment, which induces repolarization from the immunosuppressed M2 phenotype to the M1 phenotype. More importantly, the tumor cell damage induced by M1 macrophages and magnetic hyperthermia promote the maturation of dendritic cells, which subsequently awakens cytotoxic T lymphocytes to combat tumor cells. The integrated innate and adaptive immunity activations based on ZCMF-AF nano-immunomedicine through intrapleural administration elicit substantially regulated immune microenvironment of MPE and pleural tumors. Moreover, the interpleural magnetic nanoparticle-based immunotherapy effectively reduced the MPE volume and inhibited tumor growth in the pleural cavity, significantly prolonging the survival of the MPE-bearing mice.

Quality Improvement Initiatives for Pleural Infection Managed with Intrapleural Therapy.

Rationale Pleural infection is associated with significant mortality and its management is complex. Little attention has been given to care process metrics such as management delays, pleural drainage practices, and adequacy of intrapleural therapy administration despite their potential impact on outcomes. Audits revealed gaps in those care processes in our institution. Objectives To assess the impact of quality improvement initiatives on pleural effusion management in adults. Methods We performed a retrospective comparison of patients treated with intrapleural therapy for pleural infection at the McGill University Health Centre before (April 2013-April 2016, N=109) and after interventions (June 2020-June 2021, N=44). Interventions included a pleural drainage policy and order set, an intrapleural therapy protocol and pre-printed order, implementation of intrapleural therapy administration by nurses, local pleural infection guideline development, and an online learning module for physicians. Major outcomes (length of stay, mortality, surgical treatment) and care process metrics (management delays, pleural drainage practices, intrapleural therapy administration) were compared between the two periods. Results After implementation of the interventions, in-hospital mortality and length of stay were unchanged, but surgical management went from 14% to 0% (p=0,01). Delays in drain insertion and intrapleural therapy initiation were not significantly different. Insertion of drains smaller than 12Fr decreased from 51% to 7% (p<0,001). Drain blockage decreased from 20% to 2% (p=0,004). Additional drain insertions went from 62% to 48% (p=0,12). After interventions, 70% of intrapleural therapy doses were given by nurses, the intrapleural therapy protocol was more often adequately followed, less doses were missed, and less extended therapy was prescribed. Complications related to drain insertion and intrapleural therapy were similar between the two periods. Conclusions Following the implementation of multifaceted quality improvement interventions for pleural infection including involvement of nurses in pleural drain flushing and intrapleural therapy, improvements were observed in intrapleural therapy administration, chest drainage practices, and need for surgery. However, length of stay, mortality, and management delays were unchanged.

Reduction in the need for surgery and mortality after early administration of fibrinolytics following empyema drainage.

Although intrapleural administration of fibrinolytics is an important treatment option for the management of empyema, the addition of fibrinolytics failed to reduce the need for surgery and mortality in previous randomized controlled trials. This study aimed to investigate the effects of administrating fibrinolytics in the early phase (within 3 days of chest tube insertion) of empyema compared with late administration or no administration. We used the Japanese Diagnosis Procedure Combination Inpatient Database to identify patients aged ≥16 years who were hospitalized and underwent chest tube drainage for empyema. A 1:2 propensity score matching and stabilized inverse probability of treatment weighting were conducted. Among the 16265 eligible patients, 3082 and 13183 patients were categorized into the early and control group, respectively. The proportion of patients who underwent surgery was significantly lower in the early fibrinolytics group than in the control group; the odds ratio (95% confidence interval) was 0.69 (0.54-0.88) in the propensity score matching (P = 0.003) and 0.64 (0.50-0.80) in the stabilized inverse probability of treatment weighting analysis (P < 0.001). All-cause 30-day in-hospital mortality, length of hospital stay, duration of chest tube drainage, and total hospitalization costs were also more favourable in the early fibrinolytics group. The early administration of fibrinolytics may reduce the need for surgery and death in adult patients with empyema.

Phase 2 study to evaluate the novel mitochondrial PRX3 inhibitor, RSO-021, as an intrapleural monotherapy and in combination with IV paclitaxel in patients with malignant pleural effusion due to mesothelioma or another advanced solid tumor.

TPS8124 Background: Tumor cells generate elevated levels of reactive oxygen species (ROS), leading to increased expression and activity of critical ROS scavenging pathways. Peroxiredoxin 3 (PRX3) is the principal peroxide scavenging enzyme in mitochondria. RSO–021 is a novel small molecule PRX3 inhibitor that inactivates PRX3 through direct covalent adduction of active site cysteine residues, in turn inducing oxidative stress that is incompatible with tumor cell survival. Preclinical studies of RSO-021 show that it selectively inhibits mitochondrial PRX3 in vitro and is highly effective in a variety of tumor models, including mesothelioma and many solid tumors. RSO-021 has completed phase 1 evaluation in patients with advanced mesothelioma or solid tumors with predominant pleural disease and malignant pleural effusions. The phase 1 data supported weekly intrapleural dosing of RSO-021 at the 90 mg dose level, with acceptable safety and early signals of efficacy. Some patients were able to receive &gt;30 weeks of treatment. Pre- and post-dose primary prophylaxis for local inflammatory reactions to intrapleural injection was instituted during dose escalation, using corticosteroids, NSAIDS and paracetamol. It also became clear that RSO-021 should not be administered to patients with a dry pleural tap, due to risk of extravasation. Methods: The objectives of this open-label, multi-center, 4-arm phase 2 study (MITOPE) are to confirm the efficacy, safety, tolerability, and pharmacology of weekly intrapleural RSO-021 administration. Exploratory endpoints include target engagement as well as biomarkers of response and inflammation. The study explores 2 different RSO-021 doses (90 mg/wk and 45 mg/wk) per FDA Project Optimus, both as monotherapy and in combination with IV paclitaxel 175 mg/m2 every 3 weeks at until progression or limiting toxicity. Each arm at each dose has a 2-stage Simon design (12-21 patients) requiring 1 response to trigger stage 2 (null/target response rate 3%/20% and type I/type II error 0.05/0.8) for a maximum of 168 patients in the trial. Three of the 4 study arms are investigating the antitumor activity of RSO-021 monotherapy (arms 1-3) and the fourth is assessing the paclitaxel combination. Eligibility (by arm) requires: newly diagnosed treatment-naïve mesothelioma with pleural effusion; mesothelioma with pleural effusion that progressed on ≥1 standard of care (SoC) regimen; solid tumor with predominant pleural/lung disease and effusion that progressed on ≥1 SoC regimen; and breast, epithelial ovarian or non-small cell lung cancer with predominant pleural/lung disease and effusion that progressed on ≥1 SoC regimen. The first patient was treated in 4Q2023 and the trial is actively recruiting to all 4 arms at 9 UK sites. Additional sites are planned. Clinical trial information: NCT05278975 .

Engineered lactococcus lactis intrapleural therapy promotes regression of malignant pleural effusion by enhancing antitumor immunity

Intrapleural immunotherapies have emerged as a prominent field in treating malignant pleural effusion (MPE). Among these, bacteria-based intrapleural therapy has exerted an anti-MPE effect by immuno-stimulating or cytotoxic properties. We previously engineered a probiotic Lactococcus lactis (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 and co-stimulator OX40 ligands. FOLactis activates tumor antigen-specific immune responses and displays systemic antitumor efficacy via intratumoral delivery. However, no available lesions exist in the pleural cavity of patients with MPE for intratumoral administration. Therefore, we further optimize FOLactis to treat MPE through intrapleural injection. Intrapleural administration of FOLactis (I-Pl FOLactis) not only distinctly suppresses MPE and pleural tumor nodules, but also significantly extends noticeable survival in MPE-bearing murine models. The proportion of CD103+ dendritic cells (DCs) in tumor-draining lymph nodes increases three-fold in FOLactis group, compared to the wild-type bacteria group. The enhanced DCs recruitment promotes the infiltration of effector memory T and CD8+ T cells, as well as the activation of NK cells and the polarization of macrophages to M1. Programmed death 1 blockade antibody combination further enhances the antitumor efficacy of I-Pl FOLactis. In summary, we first develop an innovative intrapleural strategy based on FOLactis, exhibiting remarkable efficacy and favorable biosafety profiles. These findings suggest prospective clinical translation of engineered probiotics for managing MPE through direct administration into the pleural cavity.

Abstract C027: RSO-021, a first-in-class covalent inhibitor of mitochondrial PRX3: From bench to bedside

Abstract RSO-021 is a first-in-class mitochondrial peroxiredoxin 3 (PRX3) covalent small molecule inhibitor. The safety and tolerability of RSO-021 are currently being tested in the phase 1-2 MITOPE clinical trial in patients with malignant pleural effusion (MPE) arising from malignant mesothelioma or metastatic cancer to the lungs (NCT05278975). Altered redox status, resulting in elevated cellular hydrogen peroxide (H2O2) levels, drives the growth and proliferation of mesothelioma and other solid tumors. PRX3, the primary mitochondrial H2O2 scavenging enzyme, supports tumor cell escape from oxidative stress and aggressive tumor growth. RSO-021 attacks active site cysteine residues in PRX3 covalently to inactivate the enzyme, resulting in elevated H2O2 levels in the mitochondria incompatible with tumor cell survival. RSO-021 showed potent PRX3 inactivation and anti-tumor activity in pre-clinical cell and mouse models of mesothelioma with good tolerability supporting its clinical development. The MITOPE trial (NCT05278975) is an open-label, non-randomized, multicenter, translational phase 1-2 dose-escalation and expansion study designed to determine the safety, tolerability, dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of RSO-021 after intrapleural administration after complete drainage in patients with MPE due to mesothelioma or other metastatic disease. RSO-021 is administered locally as a pleural infusion through an indwelling catheter as a single dose on Day 1, 8 and 15 of each 3-week cycle. Safety is assessed at the end of the 21-day DLT period and efficacy every 6 weeks. PK and PD are assessed on pleural fluid, biopsies and with systemic sampling. RSO-021 is administered until disease progression, unacceptable toxicity, withdrawal of consent or study termination. Currently, MITOPE is actively recruiting patients in 4 open UK sites, with additional 9 sites on-boarding shortly. The dose escalation phase of the trial has 13 patients dosed at either 90, 120 or 180 mg flat dose levels and is anticipated to complete recruitment by the end of 2023. The trial will then continue to recruit patients as part of the dose expansion phase of the trial, which is exploring specific indications, including newly-diagnosed and previously-treated MM with MPE, as well as combination with systemic therapy in patients with refractory solid tumors and MPE. Citation Format: Dean A. Fennell, Sean Dulloo, Peter Szlosarek, Fiona Thistlethwaite, Simon Lord, Najib M Rahman, Brian Cunniff, Joanna Dzialo, Charlotte Poile, Rakesh Panchal, Jarrett Duncan, Pip Graham, Alice Bexon, George N. Naumov, James Spicer. RSO-021, a first-in-class covalent inhibitor of mitochondrial PRX3: From bench to bedside [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C027.

A case report on intrapleural administration of antibiotic in tuberculous empyema

A case report on intrapleural administration of antibiotic in tuberculous empyema

Pleural inflammatory response, mesothelin content and DNA damage in mice at one-year after intra-pleural carbon nanotube administration

Many in vitro and in vivo studies have shown that exposure to carbon nanotubes (CNTs) is associated with inflammation, oxidative stress and genotoxicity, although there is a paucity of studies on these effects in the pleural cavity. In the present study, we investigated adverse outcomes of pleural exposure to multi-walled CNTs (MWCNT-7, NM-401 and NM-403) and single-walled CNTs (NM-411). Female C57BL/6 mice were exposed to 0.2 or 5 µg of CNTs by intra-pleural injection and sacrificed one-year post-exposure. Exposure to long and straight types of MWCNTs (i.e. MWCNT-7 and NM-401) was associated with decreased number of macrophages and increased number of neutrophils and eosinophils in pleural lavage fluid. Increased protein content in the pleural lavage fluid was also observed in mice exposed to MWCNT-7 and NM-401. The concentration of mesothelin was increased in mice exposed to MWCNT-7 and NM-411. Levels of DNA strand breaks and DNA oxidation damage, measured by the comet assay, were unaltered in cells from pleural scrape. Extra-pleural effects were seen in CNT exposed mice, including enlarged and pigmented mediastinal lymph nodes (all four types of CNTs), pericardial plaques (MWCNT-7 and NM-401), macroscopic abnormalities on the liver (MWCNT-7) and ovaries/uterus (NM-411). In conclusion, the results demonstrate that intra-pleural exposure to long and straight MWCNTs is associated with adverse outcomes. Certain observations such as increased content of mesothelin in pleural lavage fluid and ovarian/uterine abnormalities in mice exposed to NM-411 suggests that exposure to SWCNTs may also be associated with some adverse outcomes.

Sequential intrapleural administration of fibrinolytic drugs and dornase alfa for empyema management. Treatment protocol based on its physicochemical stability

ObjectiveIntrapleural administration of fibrinolytics and dornase alfa has been shown in randomized studies to be able to reduce both the need for surgical debridement of empyema and the average hospital stay. However, its application in clinical practice is limited, probably due to the lack of protocols that simplify its administration. The present study aims to analyze the physicochemical stability of the simultaneous urokinase and dornase alfa administration for the subsequent development of a clinical practice use protocol. MethodIn vitro stability test of urokinase, dornase alfa and a combination of both. Its stability was evaluated as (i) absence of particles, (ii) color variation and (iii) pH changes at times 0, 30 minutes, 1, 2 and 4 hours at 37 °C. Each sample was prepared and analyzed in triplicate. ResultsIndividual solutions of urokinase and dornase alfa showed slight changes in pH, finding no changes in either color or presence of suspended particles. The urokinase and dornase alfa combination was not stable after 2 hours, when turbidity emerged due to flocculation and phase separation. After 4 hours, precipitate formation was found. A protocol for clinical use was developed based on urokinase and dornase alfa sequential administration, since it was not possible to guarantee the physicochemical stability of the simultaneous administration of both drugs. ConclusionsThe physicochemical stability data obtained does not allow to ensure a simultaneous administration of both drugs in a safe and effective way, thus a sequential administration protocol is proposed.

Intrapleural Streptokinase in Management of Multiloculated Pleural Effusion as a Complication of Frequent Relapse Nephrotic Syndrome - A Case Report

Treatment of pleural effusion with intrapleural administration of fibrinolytic drugs has proven to be efficient and secure. Patients with pleural effusion who receive streptokinase instillations in conjunction with chest tube draining avoid surgery and have better outcomes. Its application in multiloculated pleural effusion, which develops as a nephrotic syndrome consequence, has only occasionally been documented. We describe a case of multiloculated pleural effusion that did not react to conventional chest tube drainage but resolved completely and dramatically in response to intrapleural streptokinase.

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

IntroductionAidi injection (Aidi), a traditional Chinese medicine injection, is often practiced to control malignant pleural effusion (MPE). ObjectivesWe 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. MethodologyAll 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. ResultsAll 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. ConclusionsCurrent 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.

Anti-PD1 does not improve pyroptosis induced by γδ T cells but promotes tumor regression in a pleural mesothelioma mouse model.

Mesothelioma is an aggressive tumor in the pleural cavity that is difficult to treat. Diagnosis is usually late with minimal treatment options available for the patients and with unfavorable outcomes. However, recent advances in immunotherapy using γδ T cells may have potential against mesothelioma, given its ample tumoricidal and tumor-migratory properties could allow its infiltration to the widespread tumor mass. Thus, we hypothesize that Vδ2 T cells can perform cytotoxic activities against mesothelioma especially when combined with immune checkpoint blocker against PD-1. Human Vδ2 T cells were expanded from peripheral blood mononuclear cells using Tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) plus IL-2 for 13 days, before used to test for cytotoxicity against mesothelioma cell lines. Mesothelioma-bearing mice was established by Intrapleural administration of mesothelioma cell lines to test for the efficacy of Vδ2 T cells plus anti-PD-1 antibody combination treatment. Pyroptosis was evaluated by cell morphology, western blot analysis, and ELISA experiments. Flow cytometry was used to examine expression of BTN2A1, BTN3A1, PD-L1, PD-L2 on mesothelioma cell lines. Immunofluorescence staining was performed to detect Vδ2 T cells post adoptive transfer and characteristics of pyroptosis in ex vivo mesothelioma tissue sections. Indeed, our data demonstrated that Vδ2 T cells killing mesothelioma can be enhanced by anti-PD-1 antibody in vitro, especially for high PD-1 expressing cells, and in vivo in the intrapleural mesothelioma mice model established by us. Adoptive transfer of Vδ2 T cells into these mice leads to tumor regression by 30-40% compared to control. Immunofluorescence of the tumor section confirmed infiltration of Vδ2 T cells into the tumor, especially to cells with BTN2A1 expression (a Vδ2 T cell activating molecule) despite PD-L1 co-localization. Interestingly, these cells co-expressed cleaved gasdermin D, suggesting that pyroptosis was induced by Vδ2 T cells. This was verified by Vδ2 T/mesothelioma co-culture experiments demonstrating membrane ballooning morphology, increased cleaved caspase-3 and gasdermin E, and upregulated IL-1β and IL-18. Vδ2 T cells plus anti-PD1 exhibited cytotoxicity against mesothelioma in vivo. However, we found no advantage for anti-PD-1 against PD-1 high expressing Vδ2 T cells in promoting pyroptosis. Taken together, our work demonstrated that Vδ2 T cells combined with anti-PD-1 antibody can be developed as a potential combination immunotherapy for mesothelioma.

The intrapleural administration with thymic peptides in malignant pleural effusion: A clustered systematic review and meta-analysis

BackgroundThymic peptides (TPs) are often used to control malignant pleural effusion (MPE). So, we performed a clustered systematic review and meta-analysis to clarify the treatment regimens of TPs for MPE, demonstrate their clinical effectiveness and safety, and reveal the indications and optimal usage for a desired effectiveness. Materials and methodsWe collected all trials of TPs for MPE from Chinese and English databases (from inception until May 2021). After evaluating their bias risk, we pooled the data from each regimen using the meta-analysis or descriptive analysis, and summarized the evidence quality using the Grading of Recommendation Assessment, Development and Evaluation approach (GRADE). ResultsThirty-four trials were clustered into TPs for MPE from lung cancer or miscellaneous tumors. The TPs combined with chemical agents were mainly used in MPE from lung cancer. All five regimens, only thymosin with oxaliplatin (L-OHP) significantly improved the complete response (CR) [2.40 (1.84 to 3.13)], quality of life [2.04 (1.20 to 3.48)], 0.5- and 1-year overall survival (OS) rate [5.75 (3.02 to 10.92) and 5.29, (1.71 to 16.36)]. It also up-regulated the T lymphocyte levels, and reduced the pleurodesis failure, disease progression and adverse events. In patients with moderate to large volume, Karnofsky Performance Status score ≥ 50 or anticipated survival time ≥ 3 months, the thymosin (300 mg/time, one time/week and lasting two to eight times) with oxaliplatin (100 mg/m2) achieved a desired response. Most results were moderate quality. ConclusionsThe current evidences indicate that the TPs are important pleurodesis agents, which combination with chemical agents are mainly used in MPE from lung cancer. The thymosin with L-OHP is a main regimen, which shows a significant improvement in clinical responses, antitumor immunity, and with a reasonable security. The evidence also provides indications and optimal usage for achieving a desired effectiveness.

Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion.

Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.

Povidon-iodine applied for the treatment of chylothorax in children

Introduction. The aim of this study is to demonstrate the experience of non-surgical treatment of congenital and acquired chylothorax in children using povidone-iodine.Material and methods. The study presents results of treatment of 10 patients with chylothorax who had chemical pleurodesis with povidone-iodine. The study covered a time period from 2016 to 2020. The congenital character of the disease was registered in 2 patients, the acquired one - in 8 patients. The main indication for surgery was ineffective conservative therapy, including the withdrawal of feeding and the administration of preparation Octreotide. The procedure consisted of intrapleural injection of 4% povidone-iodine solution into the pleural cavity with the calculated dose of 1 ml/kg and solution exposure for 4 hours. Results. The interpleural administration of povidone-iodine was effective in all patients. Complications of chemical pleurodesis were observed in 2 patients and were associated with pulmonary edema on the injection side. Lymph outflow was stopped on average in 4 days. There was one adverse episode which developed because of the lung malformation incompatible with life. Conclusions. Intrapleural administration of povidone-iodine is an effective treatment of chylothorax in children.

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)

IntroductionThis 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...

Intrapleural interleukin-2–expressing oncolytic virotherapy enhances acute antitumor effects and T-cell receptor diversity in malignant pleural disease

ObjectiveThe mainstay of treatment for patients with malignant pleural disease is fluid drainage and systemic therapy. A tumor-specific oncolytic virus or T-cell–activating interleukin-2 immunotherapy may provide an opportunity for local control. We previously developed a vaccinia virus–expressing interleukin-2, an oncolytic virus that mediated tumor regression in preclinical peritoneal tumor models with expansion of tumor-infiltrating lymphocytes. We evaluated the antitumor efficacy and immune modulatory effects of vaccinia virus–expressing interleukin-2 in malignant pleural disease. MethodsA murine model of malignant pleural disease was established with percutaneous intrapleural deposition of the Lewis lung carcinoma cell line and monitored with bioluminescent imaging. After intrapleural or systemic administration of vaccinia viruses (vaccinia virus yellow fluorescent protein control, vaccinia virus–expressing interleukin-2), systemic anti–programmed cell death-1 antibody, or combination therapy (vaccinia virus–expressing interleukin-2 and anti–programmed cell death-1), tumor mass, immune cell infiltration, T-cell receptor diversity, and survival were assessed. ResultsIntrapleural vaccinia virus resulted in significant tumor regression compared with phosphate-buffered saline control (P < .05). Inclusion of the interleukin-2 transgene further increased intratumoral CD8+ T cells (P < .01) and programmed cell death-1 expression on CD8+ tumor-infiltrating lymphocytes (P < .001). Intrapleural vaccinia virus–expressing interleukin-2 was superior to systemic vaccinia virus–expressing interleukin-2, with reduced tumor burden (P < .0001) and improved survival (P < .05). Intrapleural vaccinia virus–expressing interleukin-2 alone or combined treatment with systemic anti–programmed cell death-1 reduced tumor burden (P < .01), improved survival (P < .01), and increased intratumoral αβ T-cell receptor diversity (P < .05) compared with systemic anti–programmed cell death-1 monotherapy. ConclusionsIntrapleural vaccinia virus–expressing interleukin-2 reduced tumor burden and enhanced survival in a murine malignant pleural disease model. Increased CD8+ tumor-infiltrating lymphocytes and αβ T-cell receptor diversity are associated with enhanced response. Clinical trials will enable assessment of intrapleural vaccinia virus–expressing interleukin-2 therapy in patients with malignant pleural disease.

Oncolytic herpesvirus therapy for mesothelioma – A phase I/IIa trial of intrapleural administration of HSV1716

ObjectivesMalignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM. Materials and methodsPatients with MPM received 1 × 107iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response. ResultsOf thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naïve. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks. ConclusionsIntrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.

COMPLEX BIOSTIMULATION OF INTRAPLEURAL ADHESIOGENESIS IN THORACAL SURGERY

The aim of the study is to determine the effectiveness of the use of platelet enriched plasma in the complex treatment of chest trauma and chronic pleural empyema.Materials and methods. The work was performed on 450 male rats, simulated with chest trauma (n=180) and chronic pleural empyema (n=270). In the experimental groups, biostimulation of adhesiogenesis as an intrapleural injection of 1 ml of platelet-enriched plasma was carried out; in the comparison group; the animals with pleural empyema were injected with 1 ml of doxycycline solution; in the negative control groups, the treatment was not carried out at all. Withdrawal from the experiment took place on the 10th, 20th, 30th days. The samples of intrapleural adhesions were fixed in 10% formalin, followed by histological tracing and preparation of micropreparations, staining with hematoxylin and eosin. The morphometric study included determination of the volume fraction (VF) of collagen and reticular fibers; fibrin; inflammatory cells; blood-stream (%).Results. An intrapleural administration of platelet-rich plasma is an effective way to stabilize the rib cage in chest injuries, and to eliminate residual cavities in chronic pleural empyema. When assessing the severity of the adhesions in chest trauma, it was found out that adhesions are most often visualized at the sites of rib fractures (from 13.3 to 40%). In pleural empyema, during the entire process of observation, the VF of collagen fibers forming adhesions was higher in the group with biological stimulation of adhesiogenesis than in the NCpe group and in the CG. In the PRP group, already at the initial stages of the experiment, this indicator was significantly lower than in the NC and CG (p&lt;0.05).Conclusion. Based on the data obtained, the effectiveness of the use of platelet-enriched plasma in thoracic surgery for the biological potentiation of adhesiogenesis has been proved in experimental chest injuries and chronic pleural empyema.