P-83 A collaborative pathway for malignant pleural effusion

Inflammatory signaling networks between tumor cells and immune cells contribute to the development of malignant pleural effusion (MPE). B cells have been found in MPE; however, little is known about their roles there. In the present study, by using mouse MPE models, we noted that although the total B cells in MPE were decreased as compared with the corresponding blood and spleen, the percentage of activated naïve B cells expressing higher levels of CD80, CD86, myosin heavy chain-II, CD44, CD69, and programmed cell death-ligand 1 (PD-L1) molecules were increased in wild-type mouse MPE. Compared with wild-type mice, decreased T helper (TH)1 cells and increased TH17 cells were present in B cell-deficient mouse MPE, which paralleled to the reduced MPE volume and longer survival time. Adoptive transfer of activated naïve B cells into B cell-deficient mice was able to increase TH1 cells and decrease TH17 cells in MPE and shorten the survival of mice bearing MPE. Furthermore, we demonstrated that activated naïve B cells inhibited TH17-cell expansion via the PD-1/PD-L1 pathway and promoted naïve CD4+ T-cell differentiation into TH1/TH17 cells through secreting IL-27/IL-6 independent of the PD-1/PD-L1 pathway. Collectively, our data uncovered a mechanism by which naïve B cells promote MPE formation by regulating TH1/TH17 cell responses, making these B cells an attractive target for therapeutic intervention in the fight against cancer.

BackgroundMonocytes are involved in tumor growth and metastasis, but the distribution of monocyte phenotypes and their role in the development of malignant pleural effusion (MPE) remains unknown.MethodsA total of 94 MPE patients (76 diagnosed with adenocarcinoma lung cancer and 18 with squamous cell lung cancer) and 102 volunteers for health examination in Xiangya Hospital from December 2016 to December 2019 were included in the study.ResultsThe distribution of monocyte subtypes identified by the expression of CD14 and CD16 were analyzed by flow cytometry. The proportion of CD14++CD16+ intermediate monocytes were significantly increased in pleural effusion of MPE patients. The complement system components were assayed by immunohistochemistry and ELISA, and higher expression of the classical and alternative pathways were detected in malignant pleural tissue. Transwell assay further revealed that C5a enhanced the infiltration of intermediate monocytes into the pleural cavity by promoting CCL2 production in pleural mesothelial cells (PMCs). In addition, C5a promoted the secretion of IL‐1β by intermediate monocytes. Furthermore, C5a activated in intermediate monocytes and IL‐1β released after C5a stimulation by monocytes promoted the proliferation, migration, adhesion, and epithelial‐to‐mesenchymal transition (EMT) of tumor cells, and attenuated tumor cell apoptosis.ConclusionsC5a, activated by the classical and alternative pathways of the complement system, not only mediated the infiltration of intermediate monocytes by enhancing CCL2 production in PMCs but also induced IL‐1β release from the recruited monocytes in MPE. The consequence of C5a activation and the subsequent IL‐1β overexpression in intermediate monocytes contributed to MPE progression.

Advanced respiratory disease imposes a greater symptom burden than many cancers but not does have comparable recognition of the need for supportive and palliative care or the infrastructure for its systematic delivery. Consequently, many people with advanced respiratory disease (and those closest to them) have a poor quality of life, disabled by chronic breathlessness, fatigue and other symptoms. They are socially isolated by the consequences of long-term illness and are often financially impoverished. The past decade has seen an increasing realisation that care for this group must improve and that symptom management must be prioritised. Clinical guidelines recommend person-centred care, including access to supportive and palliative care as needed, as part of standard medical practice. Advanced lung disease clinics and specialist breathlessness services (pioneered within palliative care) are developing within respiratory medicine services but are provided inconsistently.This review covers the comprehensive assessment of the patient with advanced respiratory disease, the importance of supporting carers and the current best practice in the management of breathlessness, fatigue and cough. It also suggests ways to incorporate person-centred care into the general respiratory clinic, assisted by better liaison with specialist palliative and primary care. Emerging evidence shows that excellent symptom management leads to better clinical outcomes and reduces inappropriate use of emergency medical services.Key pointsPeople living with advanced respiratory disease and severe chronic breathlessness (and those closest to them) have a poor quality of life.Chronic breathlessness is a disabling symptom, and acute-on-chronic/episodic breathlessness is frightening to experience and observe.Chronic breathlessness imposes profound physical limitations and psychosocial burdens on those suffering from it or living with someone experiencing it.Fatigue and cough are two other cardinal symptoms of advanced respiratory disease, with very detrimental effects on quality of life.The impact of all these symptoms can be alleviated to a variable extent by a predominantly non-drug complex intervention.Many of the interventions are delivered primarily by allied health or nursing professionals.Doctors, nurses and other health professionals also need to play an active part in promoting quality of life as part of excellent medical care.A person-centred, psychologically informed approach is needed by all clinicians treating patients with advanced respiratory disease.Educational aimsTo give specialist respiratory clinicians practical clinical tools to help improve the quality of life of their patients with advanced respiratory disease and chronic breathlessness.To outline the evidence base for these interventions with reference to definitive sources.To highlight the importance of person-centred care in people with respiratory disease at all stages of illness.

Editorial introductions

PC-FACS

Background: EGFR/KRAS axis mutations are frequent in human malignantpleuraleffusions (MPE). Aims: To investigate the relationship between perturbations in the EGFR-KRAS axis and malignant pleural effusion development. Methods: Several mouse and human cancer cell lines were characterized for EGFR/KRAS status and for their MPE competence in appropriate hosts. EGFR/KRAS signalling was modulated in various cell lines via standard molecular techniques. MPE-associated inflammation was monitored by bioluminescence imaging, immunophenotyped by flow cytometry, and modulated by splenectomy and adoptive bone marrow transfer. EGFR/KRAS axis was targeted using gefitinib, deltarasin, and anti-CCL2 antibodies. Results: A causative relationship between Δ Kras and MPEwas established by showing that mouse and human cancer cell lines bearing Δ Kras are MPE competent and that activated Kras is capable of conferring MPE competency to human and mouse cells. Furthermore, Kras dependent downstream paracrine signaling to bone marrow activated a distinct GR1+/CD11B+ myeloid cell population, which is maturing in the spleen and is consequently recruited to the pleural cavity in a cancer-elaborated CCL2-dependent way. Splenectomy partially protects hosts from MPE. The pharmacological manipulation of Δ EGFR/ Δ KRAS axis with Gefitinib (targeting Δ EGFR ) or Deltarasin (targeting Δ KRAS ) and the antibody-mediated neutralization of CCL2 completely annihilate MPE formation and the recruitment of CD11b+/GR1+ cells to the pleura. Conclusions: Our work provides insights to MPE pathobiology and a multitude of strategies to target a currently untreatable terminal human condition. Funding: European Research Council Starting Independent Investigator Grant #260524.

The Optimal Treatment of Malignant Pleural Effusions A Continuing Dilemma

Background:Malignant pleural effusion (MPE) has varied survival and indicates advanced disease. LENT prognostic score is the first validated score used for MPE. This study assessed the role of LENT among palliative care cancer patients and assessed different patient, tumor, and treatment related factors that may affect survival.Methods:A retrospective study of advanced cancer patients with MPE, seen in palliative care outpatient clinic (2013–2015) until death, was done. LENT prognostic score could be calculated in 15 patients. Patient, tumor, and treatment related factors that affect survival were assessed.Results:The study included 48 patients (70.8% female; 29.2% male) with a median age of 53 years. Lung (41.7%) was the most common primary, and adenocarcinoma (44.7%) was the most common histology. The median overall survival (OS) was 14.5 months (interquartile range [IQR]: 5.25–32.75) and median survival time (ST) was 3 months (IQR: 1–7.75). ST was significantly low with poor Eastern Cooperative Oncology Group (ECOG) performance status (P = 0.002), bilateral effusion (P < 0.001), and with no oncological treatment after MPE diagnosis (P < 0.001). OS and ST were significantly low with lung primary (P = 0.006 and 0.02, respectively). Age, gender, breathlessness, tumor histology, lung metastasis, and interventions for MPE did not significantly affect survival. The median ST in the moderate and high risk LENT groups was 6 and 3 months, respectively (P = 0.16).Conclusion:ECOG performance status, bilateral effusion, and no oncological treatment after diagnosis of MPE were associated with poor ST. Lung primary was associated with shorter OS and ST. Small numbers precluded any definitive conclusion on the prognostic value of LENT in our group of patients, and hence larger studies are recommended.

The National Consensus Project's (NCP) Clinical Practice Guidelines for Quality Palliative Care, published in 2004, defined eight domains of care essential to palliative care clinical practice. The National Quality Forum's (NQF) 2006 document, A National Framework and Preferred Practices for Palliative and Hospice Care Quality: A Consensus Report, based on the NCP's Guidelines, identified 38 evidence-based preferred practices for palliative care. This article demonstrates how the Guidelines and Preferred Practices may be operationalized in practice, focusing specifically on Domain 4 of the Guidelines, “Social Aspects of Care.” Domain 4 incorporates many pertinent aspects of hospice and palliative care related to communication and care planning. In particular, emphasized is the inclusion of the patient and family in discussions about ongoing care and creation of care plans that respect the social community of patient and family.

Rebuttal From Dr Lee

Pulmonary rehabilitation is an interdisciplinary program of care for patients with chronic respiratory disorders, created individually and aimed at physical and social indicators and autonomy optimizing. Physical therapists in an interdisciplinary palliative care team are key to the success of pulmonary rehabilitation for palliative patients, focusing on the physical functioning.Objective — to review the data from literature references regarding the characteristics and usage frequency of pulmonary rehabilitation for patients with respiratory diseases who require palliative and hospice care, and to specify respiratory diseases in palliative care patients for which pulmonary rehabilitation is currently used. As a result of the literature review, it was established that pulmonary rehabilitation in patients with chronic respiratory diseases who require palliative and hospice care is aimed at improving pulmonary symptoms (shortness of breaths) and functional status, reducing the intensity of accompanying symptoms, even in the late stages of the disease, which ultimately contributes improving the quality of life and survival of patients, reducing the burden on those who care for them. But access to physical (pulmonary) rehabilitation for patients with chronic respiratory diseases who need palliative and hospice care, is currently not routine in practice and not used enough around the world, unfortunately. It was found that today pulmonary rehabilitation in palliative patients is used only for chronic obstructive pulmonary diseases, interstitial lung diseases, cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis and bronchiectasis. At the same time, the literature does not describe the use of physical therapy methods, including pulmonary rehabilitation, in patients with bronchial asthma who require palliative treatment. Pulmonary rehabilitation in patients with chronic respiratory diseases who require palliative and hospice care is a relevant and effective method of treatment, but needs wider implementation in the modern health care system.

Simple SummaryThe development of pleural effusion is a common debilitating occurrence during metastasized breast cancer. Malignant cells in pleural effusions originating from the primary tumor suggest the spread of the disease and can serve as a model for metastatic breast cancer. Hence, we established three-dimensional organoid lines from four patients with malignant pleural effusion. Patient-derived organoids were characterized by flow cytometry for individual target antigen expression profiles. Adapter CAR-T cells (AdCAR-T) and biotinylated monoclonal antibodies were evaluated to specifically target patient-derived organoids and assess responses in a personalized fashion. This study demonstrates the feasibility of precision immunotherapy utilizing AdCAR-T to target patient-individualized antigen patterns.A frequent symptom of metastasized breast cancer (BC) includes the development of malignant pleural effusion (MPE), which contains malignant cells derived from the primary tumor site. The poor prognosis of MPE in metastasized BC indicates the necessity for dependable precision oncology and the importance of models representing the heterogenous nature of metastatic BC. In this study, we cultured MPE-derived metastatic tumor cells from four advanced BC patients using organoid technology. We assessed the expression of tumor-associated antigens on MPE-derived organoid lines by flow cytometry (FC). Based on an individual antigen expression pattern, patient-derived organoids were treated with adapter CAR-T cells (AdCAR-T) and biotinylated monoclonal antibodies targeting CD276, HER2, EGFR, TROP2, or EpCAM. Co-culture assays revealed specific organoid lysis by AdCAR-T depending on individual antigen expression patterns. Our results demonstrate that MPE-derived organoids can serve as a reliable tool for assessing the efficacy of AdCAR-T on metastatic BC in a patient-individualized manner. This approach could potentially be applied in a preclinical setting to instruct therapy decisions. Further, our study demonstrates the feasibility of precision immunotherapy utilizing AdCAR-T to target patient-individualized antigen patterns.

Places of cancer death in Germany

Introduction Symptom burden, including breathlessness, in patients with advanced heart failure is very severe. How best to address these needs in a hospital population is not yet fully addressed. We describe a novel approach to proactive palliative care in this population. Method University Hospital Southampton has appointed a palliative care consultant with a third of his time dedicated to work proactively with the inpatient heart failure team. In the first year of the post, we have conducted a survey of the heart failure team to ascertain their confidence in management of breathlessness in advanced heart failure. Results At the time of writing, we had 16 responses (6 consultant, 4 registrar and 6 clinical nurse specialist). NYHA classification was universally used for breathlessness measurement. 45% had no non-pharmacological methods for management with 50% suggesting a fan and far fewer any other methods. Oral and intravenous diuretics were widely used whilst only one said they would use subcutaneous diuretic. 70% use opioids and 45% benzodiazepines. Very few (12.5%) felt confident in management with the majority feeling ‘somewhat confident’ (50%) or ‘not so confident’ (37.5%). In answer to the question ‘when would you consider referral to palliative care and how would you do this?’ the answers ranged from ‘don’t know’ to naming the specific palliative care consultant. The main themes centred on end of life care and symptoms beyond the managing team’s confidence. Conclusion and further work The cardiology team demonstrates confidence in managing breathlessness in the modalities they are used to (oral or IV diuretics) but appear to lack confidence in alternative routes or non-pharmacological methods. We will take the results of this survey to proactively target teaching to the cardiology teams, to increase their confidence in breathlessness management but also to raise the profile of palliative care within this patient population.

118 Background: Palliative care is emerging as an integral component of oncology care. There is growing evidence of its benefits but providers struggle with how to integrate specialist palliative services for the oncology population. The purpose of this study was to measure patients’ knowledge and perceptions, and their intention to seek palliative services. This study helps inform and guide oncology and palliative providers in their efforts to bridge the gap for oncology patients. Methods: The study used a cross-sectional design. A convenience sample of adult oncology patients using ambulatory cancer services at a community hospital was surveyed using the Knowledge of Care Options (KOCO) and Perceptions of Palliative Care Instrument (PPCI). Clinical information was abstracted from their health records retrospectively. Descriptive statistics were used to describe all variables. The association between knowledge, perceptions, and intention was analyzed using Pearson’s r correlation and multivariate regression analysis. Results: The majority of the 139 participants enrolled were female (61.9%), white (76.7%), and had good functional status with ECOG of 0 or 1 (87.1%). Mean age was 63.4 years. The mean KOCO score was 84.4% although several items scored less than 70%. Overall intention to seek palliative care was low at 2.53 on a seven point scale; a majority of patients indicated that they were unlikely to seek palliative care. There was a positive correlation between overall perception and intention to seek palliative care in the next three months (r = 0.212, p = 0.02).In addition, patients with higher scores on perceived needs for palliative care were more likely to report an intention to seek palliative care (r = 0.308, p = 0.001). Conclusions: There remains a knowledge deficit about palliative care in the oncology population. Participants did not experience negative emotional or cognitive reactions in response to information about palliative care. Perceived needs were associated with intention to seek palliative care services. Routine screening for needs and effective educational strategies are needed to better integrate palliative and oncology care.