Incurable Lung Research Articles

Pilot randomized trial of a transdisciplinary geriatric intervention for older adults with cancer.

11549 Background: Oncologists often struggle with managing the unique care needs of older adults with cancer. We sought to determine the feasibility of delivering a transdisciplinary geriatric intervention designed to address the geriatric (physical function & comorbidity) and palliative care (symptoms & prognostic understanding) needs of older adults with cancer. Methods: We randomly assigned patients age ≥65 with newly diagnosed incurable gastrointestinal (GI) or lung cancer to receive a transdisciplinary geriatric intervention or usual care. Intervention patients received two visits with a geriatrician who was trained to address patients’ palliative care needs in addition to conducting a geriatric assessment. We defined the intervention as feasible if > 70% of patients enrolled in the study and > 75% completed study visits and surveys. At baseline and week 12, we assessed patients’ quality of life (QOL, Functional Assessment of Cancer Therapy General), symptoms (Edmonton Symptom Assessment System), and communication confidence (Perceived Efficacy in Patient Physician Interactions). As this was a pilot study, we calculated mean change scores in outcomes and estimated intervention effect sizes (ES). Results: From 2/2017-6/2018, we randomized 62 patients (55.9% enrollment rate [most common reason for refusal was feeling too ill]; median age = 72.3 [range 65.2-91.8]; 45.2% female; cancer types: 56.5% GI, 43.5% lung). Among intervention patients, 82.1% attended the first visit and 76.2% attended both. Overall, 77.8% completed all study surveys. Compared to usual care, intervention patients had less decrement in QOL scores (-0.77 vs -3.84, ES = .21), greater reduction in the number of moderate/severe symptoms (-0.69 vs +1.04, ES = .58), and more improvement in communication confidence (+1.06 vs -0.80, ES = .38). Conclusions: In this trial of older adults with advanced cancer, more than half enrolled in the study and over 75% of those who enrolled completed all study visits and surveys. Our effect size estimates suggest that a transdisciplinary intervention targeting patients’ geriatric and palliative care needs may be a promising approach to improve patients’ QOL, symptom burden, and communication confidence. Clinical trial information: NCT02868112.

Protective effects of Rosavin on bleomycin-induced pulmonary fibrosis via suppressing fibrotic and inflammatory signaling pathways in mice

Idiopathic Pulmonary fibrosis (IPF) is diagnosed as a life-threatening, progressive and incurable lung disease characterized by accumulation of extracellular matrix and myofibroblasts, resulting in the function degradation and structural alterations in normal lung parenchyma. Notably, Pulmonary Fibrosis has been considering as a difficult problem in clinical with high mortality and effective treatment strategies. Rosavin, a benzylPropylene glycoside, is isolated from Rhodiola rosea L., exhibiting nootropic, anti-depressant, anti-cancer, anti-inflammatory and anti-oxidative activities. In this study, we attended to elucidate the pharmacological activity of Rosavin for treatment of pulmonary fibrosis induced by bleomycin in mice. The results indicated that Rosavin could significantly ameliorate the lung index and Pathological structure of mice with Pulmonary fibrosis by bleomycin-induced. Additionally, Rosavin could evidently decreased inflammatory cells infiltration in bronchoalveolar lavage fluid and pro-inflammatory cytokines expression in lung tissue specimens induced by bleomycin. Rosavin could down-regulate the expression of hydroxyproline and malondialdehyde and increased the activities of superoxide dismutase, glutathione peroxidase in lung tissue. The expression of Nrf2 were increased, and the expression of NF-κB p65, TGF-β1 and α-SMA were inhibited. The findings revealed the protective effects and the primary mechanism of rosavin on bleomycin-induced pulmonary fibrosis, which provided a scientific foundation for Rosavin as a promising candidate for Pulmonary fibrosis treatment.

Profiling long non-coding RNA changes in silica-induced pulmonary fibrosis in rat

Silicosis is a kind of chronic and incurable lung fibrotic disease with pathogenesis and molecular mechanisms largely unknown. Mounting evidence suggests that long non-coding RNAs (lncRNAs) are involved in the pathogenesis of silicosis. However, how many lncRNAs involved in the pulmonary fibrosis remains to be elucidated. In this study, Wistar rats were exposed to silicon dioxide by an improved tracheal intubation method. Rats in the control group were treated with normal saline solution. Results showed that 28 days after exposure, there were significant differences in body weight and lung coefficient of rats treated with silica compared with control rats. The formation of lung fibrosis in silica-induced rats was confirmed by histologic examination. We then investigated the lncRNAs expression changes in lung tissues of silica-exposed rats and compared that with the rats in the control group using microarray. The results indicated that silica exposure leads to altered expression profile in 682 lncRNAs (300 upregulated and 382 downregulated). Seventy-three ceRNA pairs were acquired by predicted analysis. Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses were used to predict the biological pathway and functional classification of lncRNAs. The results showed that silica exposure affected 13 lncRNAs pathways. The functional classification mainly involved in protein binding, cell shape and extracellular exosome. This study indicated that alteration of lncRNAs may play a role in silica-induced pulmonary fibrosis through regulation of expressions of functional genes in lungs of rat. Our results provide more insights into the mechanism of silicosis.

The Need to Prioritize and Re-prioritize Palliative Care Options: Smoking Cessation as a Case-in-Point.

Palliative care in cancer patients requires a continuous reprioritization of effort. This review describes the need for this reprioritization and uses smoking cessation as a case-in-point. The treatment of patients with metastatic non-small cell lung cancer has changed dramatically in the past few years. Interestingly, patients who had previously smoked now have an improved prognosis-for a variety of reasons. This review discusses this last observation in detail and raises the question of how forcefully we should advise smoking cessation in patients with incurable metastatic non-small cell lung cancer.

Palliative thoracic radiotherapy near the end of life in lung cancer: A population-based analysis

ObjectivesPalliative thoracic radiotherapy (RT) can improve quality of life for patients with advanced lung cancer, but treatment can be associated with acute toxicity and symptomatic relief may take several weeks. The optimal fractionation schedule is not known. Delivery of RT near the end of life (EOL) is an emerging indicator of poor quality care. The aim of this study was to determine utilization of palliative thoracic RT in the last 4 weeks of life, and factors associated with its use, in patients with incurable lung cancer in a population-based healthcare system. Materials and methodsAll patients with lung cancer in British Columbia treated with palliative thoracic RT in 2014 and 2015 were identified. Associations between starting a course of palliative thoracic RT within 4 weeks of death and patient/treatment characteristics were assessed using univariate and multivariate logistic regression analysis. Results1676 courses of palliative thoracic RT were delivered to 1584 lung cancer patients. Median survival was 20 weeks. 12% of palliative thoracic RT courses were delivered in the last 4 weeks of life, with short fractionation schedules and simple RT planning techniques used more frequently near EOL. Of RT courses delivered in the last 4 weeks of life 89% were courses of 1 – 5 fractions, 75% were completed as prescribed and 94% involved simple 1–2 field RT techniques. Receipt of RT in the last 4 weeks of life was associated with male gender, younger age, poor performance status, metastatic disease, small cell carcinoma histology and no prior chemotherapy. ConclusionFurther study and standardization of quality indicators for palliative RT utilization near EOL is required. Whilst clarification occurs, physicians should consider the prognosis of patients with incurable lung cancer and the realistic expectation of benefit from palliative thoracic RT when considering treatment indications and fractionation schedules.

Needs with Regard to Decision Support Systems for Treating Patients with Incurable Non-small Cell Lung Cancer

Treatment decision-making for patients with incurable non-small cell lung cancer (NSCLC) is complex due to the rapidly increasing number of treatments and discovery of new biomarkers. Decision support systems (DSS) could assist thoracic oncologists (TO) weighing of the pros and cons of treatments in order to arrive at an evidence-based and personalized treatment advice. Our aim is to inventory (1) TO’s needs with regard to DSS in the treatment of incurable (stage IIIB/IV) NSCLC patients, and (2) preferences regarding the development of future tools in this field. We disseminated an online inventory questionnaire among all members of the Section of Oncology within the Society of Physicians in Chest Medicine and Tuberculosis. Telephone interviews were conducted to better contextualize the findings from the questionnaire. In total, 58 TO completed the questionnaire and expressed a need for new DSS. They reported that it is important for tools to include genetic and immune markers, to be sufficiently validated, regularly updated, and time-efficient. Also, future DSS should incorporate multiple treatment options, integrate estimates of toxicity, quality of life and cost-effectiveness of treatments, enhance communication between caregivers and patients, and use IT solutions for a clear interface and continuous updating of tools. With this inventory among Dutch TO, we summarized the need for new DSS to aid treatment decision-making for patients with incurable NSCLC. To meet the expressed needs, substantial additional efforts will be required by DSS developers, above already existing tools.

Time-lapse Imaging of Alveologenesis in Mouse Precision-cut Lung Slices.

Alveoli are the gas-exchange units of lung. The process of alveolar development, alveologenesis, is regulated by a complex network of signaling pathways that act on various cell types including alveolar type I and II epithelial cells, fibroblasts and the vascular endothelium. Dysregulated alveologenesis results in bronchopulmonary dysplasia in neonates and in adults, disrupted alveolar regeneration is associated with chronic lung diseases including COPD and pulmonary fibrosis. Therefore, visualizing alveologenesis is critical to understand lung homeostasis and for the development of effective therapies for incurable lung diseases. We have developed a technique to visualize alveologenesis in real-time using a combination of widefield microscopy and image deconvolution of precision-cut lung slices. Here, we describe this live imaging technique in step-by-step detail. This time-lapse imaging technique can be used to capture the dynamics of individual cells within tissue slices over a long time period (up to 16 h), with minimal loss of fluorescence or cell toxicity.

Relationship between perceptions of treatment goals and psychological distress in patients with advanced cancer.

44 Background: Several studies have demonstrated discordance between how patients perceive their goal of treatment versus how they perceive their oncologist’s goal. Studies evaluating the extent and risk factors of this discordance are lacking. Methods: We conducted a cross-sectional study of 559 patients with incurable lung, gastrointestinal, breast, and brain cancers. We used the Perception of Treatment and Prognosis Questionnaire to assess patients’ perceptions of both their treatment goal and their oncologist’s goal and categorized responses: 1) patients who reported that both their goal and their oncologist’s goal was concordant (either to cure or not to cure); and 2) patients who reported discordant perceptions of their goal versus their oncologist’s goal. We assessed patients’ psychological distress using the Hospital-Anxiety-and-Depression-Scale and used linear regression to assess the relationship between patients’ perceptions of their treatment goal and psychological outcomes. Results: 61.7% of patients reported that both their goal and their oncologist’s goal was non-curative; 19.3% reported that both their goal and their oncologist’s goal was to cure their cancer; and 19.0% reported discordance between their goal and their perception of the oncologist’s goal. Older age (OR = 0.98, P = 0.01), non-Hispanic ethnicity (OR = 0.31, P = 0.049), and higher education (OR = 0.62, P = 0.042) were associated with lower likelihood of reporting discordant goals. Patients with discordant perceptions of their goal and their oncologist’s goal reported higher anxiety (B = 1.56, P = 0.003) compared to those who reported that both their goal and their oncologist’s goal was curative. Patients who reported both their goal and the oncologist’s goal was non-curative had higher depression symptoms (B = 1.06, P = 0.013) compared to those who reported that both their goal and the oncologists’ goal was curative. Conclusions: One-fifth of patients with advanced cancer report discrepancies between their perceptions of their own and their oncologists’ treatment goal which is associated with psychological distress. Tools are needed to identify patients at risk of cognitive dissonance about their prognosis.

Communication Differences between Oncologists and Palliative Care Clinicians: A Qualitative Analysis of Early, Integrated Palliative Care in Patients with Advanced Cancer.

Growing evidence demonstrates the benefits of early, integrated palliative care (PC) for patients with advanced cancer and their caregivers. Yet, data are lacking on the communication patterns within this model of care. The goals of this study were to describe the content of patient-clinician discussions among patients receiving PC and to compare differences in discussion content between oncologists and PC clinicians. We conducted a qualitative observational analysis. We included patients with incurable lung and esophageal cancer enrolled in a randomized trial of early, integrated PC versus usual oncology care. We analyzed 68 audio-recorded clinic visits (34 oncologist visits; 34 PC clinician visits) immediately after patients' (N = 19) first and second cancer progressions. We examined themes of clinician communication, comparing the content and frequency of discussions between oncologists and PC clinicians. Although both oncology and PC clinicians discussed symptom management, medical understanding, and treatment decision making with patients at nearly all postprogression visits, PC clinicians tended to assess patient understanding of the treatment process and prognosis more often than oncologists. PC clinicians addressed patient coping, caregiver experiences and needs, and advance care planning more frequently than oncologists. PC clinicians play a distinct, complementary role to oncologists in providing care for patients with advanced cancer and their caregivers. PC clinicians tend to assess and elaborate on patient understanding of prognosis and treatment and emphasize effective coping, caregiver needs, and advance care planning. These results illuminate the communication elements by which early, integrated PC may improve patient and caregiver outcomes.

P2.15-14 Survivorship of Advanced Lung Cancer Patients with Psychiatric Disorders and Malnutrition Risk

Advanced lung cancer (aLC) is often accompanied by anxiety and/or depression and malnutrition risk. The above stated burdens have a huge influence on patients’ lives during the disease trajectory. Aim of this study was to assess the influence of depression and/or anxiety and malnutrition risk on overall survival (OS) in advanced lung cancer patients. This prospective trial was conducted at the Institute for Pulmonary Diseases of Vojvodina, Serbia. Patients with advanced lung cancer were included in this study regardless of lung cancer type and therapy regimen. Patients rated themselves on the Hospital Anxiety and Depression Scale (HADS). Malnutrition universal screening tool (MUST) was used for assessment of malnutrition risk. Univariate and multivariate analysis was performed in order to correlate the data. Out of total 134 patients, 76.9% were male and 23.1% female. Majority of patients were current smokers (58.2%), average age 61, with ECOG performance status 1 (79.9%) and diagnosed lung adenocarcinoma (48.5%). A psychiatric disorder was confirmed in 41.8% of patients (anxiety in 3.0%, depression in 19.4%, combined disorder in 19.4%). Malnutrition risk was observed in 35.0% of patients (low risk in 13.4%, high risk in 21.6%). Malnutrition risk was significantly related to education level (p=0.010) and age (p=0.040). Median OS of included patients was 17.8 months. We observed a significant relation between OS and psychiatric disorder (p=0.029) and OS and malnutrition risk (p=0.001). Median OS of patients without psychiatric disorders was 20.3, with depression 12.2 and with combined psychiatric disorders 13.9 months. Median OS of patients with low malnutrition risk was 20.6, for medium risk 12.3 and for high risk 13.2 months. Median OS of patients with any psychiatric disorder accompanied by increased malnutrition risk was 5.9 months (p=0.000). One-year survival was 71.7% in patients without burdens, 73.5% in patients with psychiatric disorder, 64.0% in patients with malnutrition risk and in 36.4% (p=0.018) in patients with combined burdens. Five-year survival was 5.7%, all these patients were without disorders. Depression and/or anxiety and malnutrition risk are present in large number of aLC patients and have great influence on not only quality of life but also overall survival. Effort should be done to implement easy-to-use screening tools in daily routine for early recognition of patients’ burdens and concerns which can improve comprehensive care of incurable lung cancer.

Opioid Dose and Survival of Patients with Incurable Nonsmall Cell Lung Cancer: A Prospective Cohort Study.

Preclinical studies show that opioids promote angiogenesis, tumor progression, and metastasis, resulting in shorter survival. To explore whether opioids are associated with the overall survival (OS) of patients with incurable nonsmall cell lung cancer (NSCLC). Prospective cohort study of patients with NSCLC. We investigated patients newly diagnosed with advanced or post-operative recurrent NSCLC between April 2013 and December 2015 at a single institute. We evaluated OS, opioid requirements, opioid doses, pain levels, and prognostic factors of advanced NSCLC. The effects of variables on survival were analyzed using univariable and multivariable models. Patients were stratified according to oral morphine equivalents (OMEs)/day (<60 or ≥60 mg) to assess the association between opioid dose and OS. We analyzed 150 patients, including 64 who received opioid treatment during follow-up. The median OS was 242 days in the opioid group and 627 days in the no-opioid group (log-rank p < 0.001). Multivariable models revealed that the opioid requirement was an independent predictor of shorter OS, after adjustment for prognostic variables, including sex, histology, stage, history of systemic chemotherapy, and performance status (hazard ratio 1.73, 95% confidence interval 1.137-2.631). There was no significant difference in OS between patients who received ≥60 mg OME/day for 250 days versus <60 OME/day for 242 days. The opioid dose does not shorten the survival of patients with advanced NSCLC. The opioid requirement is associated with shorter survival when opioids are administered any time during the clinical course, independent of the influence of other key factors.

Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease.

Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that afflicts millions of people worldwide, and it is the fourth leading cause of death. Systemic comorbidities affecting the heart, skeletal muscle, bone, and metabolism are major contributors to morbidity and mortality. Given the surprising finding in large prospective clinical biomarker studies that peripheral white blood cell count is more closely associated with disease than inflammatory biomarkers, we probed the role of blood growth factors. Using the SHIP-1-deficient COPD mouse model, which manifests a syndrome of destructive lung disease and a complex of comorbid pathologies, we have identified a critical and unexpected role for granulocyte-CSF (G-CSF) in linking these conditions. Deletion of G-CSF greatly reduced airway inflammation and lung tissue destruction, and attenuated systemic inflammation, right heart hypertrophy, loss of fat reserves, and bone osteoporosis. In human clinical translational studies, bronchoalveolar lavage fluid of patients with COPD demonstrated elevated G-CSF levels. These studies suggest that G-CSF may play a central and unforeseen pathogenic role in COPD and its complex comorbidities, and identify G-CSF and its regulators as potential therapeutic targets.

Palliative radiation and fractionation in medicare patients with incurable non-small cell lung cancer

PurposePalliative radiation therapy (RT) can improve quality of life but also incurs time and financial costs. The aim of this study was to evaluate factors associated with use and intensity of palliative RT for incurable non-small cell lung cancer (NSCLC). Methods and materialsThis was a retrospective analysis of Medicare's Surveillance, Epidemiology and End Results data. We identified patients who were diagnosed with incurable (American Joint Committee on Cancer 6th edition stage IIIB with malignant effusion or stage IV) NSCLC between 2004 and 2011. Univariable and multivariable logistic regressions were used to identify factors associated with the receipt of palliative RT and the use of >10 fractions during the first course of radiation. Among patients who were treated with radiation, freestanding versus hospital-based center information was collected on the basis of the location of the RT delivery claim. ResultsAmong 55,258 patients with incurable NSCLC, 38% (21,053 patients) received palliative RT during the first year after diagnosis. Among patients who received RT, 56% (11,717 patients) received >10 fractions. On multivariable analysis, factors associated with greater RT use included younger age group (overall P < .01), lower modified Charlson comorbidity score (overall P < .01), female sex (odds ratio [OR]: 1.1; P < .01), marital status (OR: 1.1; P < .01), and chemotherapy use (OR: 3.6; P < .01). Predictors for >10 fractions were chemotherapy use (OR: 1.7; P < .01) and treatment at a freestanding versus hospital-based facility (58% vs 43%; OR: 1.7; P < .01). ConclusionsMore than a third of patients diagnosed with incurable lung cancer receive palliative RT and 56% received >10 fractions. The use of RT varied by region and patient characteristics, and patients treated at freestanding RT centers were more likely to receive >10 fractions. Further research into factors that influence treatment decisions including potential financial incentives may contribute to the high value and strategic utilization of palliative RT.

Treatment of infected lungs by ex vivo perfusion with high dose antibiotics and autotransplantation: A pilot study in pigs.

The emergence of multi-drug resistant bacteria threatens to end the era of antibiotics. Drug resistant bacteria have evolved mechanisms to overcome antibiotics at therapeutic doses and further dose increases are not possible due to systemic toxicity. Here we present a pilot study of ex vivo lung perfusion (EVLP) with high dose antibiotic therapy followed by autotransplantation as a new therapy of last resort for otherwise incurable multidrug resistant lung infections. Severe Pseudomonas aeruginosa pneumonia was induced in the lower left lungs (LLL) of 18 Mini-Lewe pigs. Animals in the control group (n = 6) did not receive colistin. Animals in the conventional treatment group (n = 6) received intravenous application of 2 mg/kg body weight colistin daily. Animals in the EVLP group (n = 6) had their LLL explanted and perfused ex vivo with a perfusion solution containing 200 μg/ml colistin. After two hours of ex vivo treatment, autotransplantation of the LLL was performed. All animals were followed for 4 days following the initiation of treatment. In the control and conventional treatment groups, the infection-related mortality rate after five days was 66.7%. In the EVLP group, there was one infection-related mortality and one procedure-related mortality, for an overall mortality rate of 33.3%. Moreover, the clinical symptoms of infection were less severe in the EVLP group than the other groups. Ex vivo lung perfusion with very high dose antibiotics presents a new therapeutic option of last resort for otherwise incurable multidrug resistant pneumonia without toxic side effects on other organs.

Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation

ABSTRACTIrreversible destruction of bronchi and alveoli can lead to multiple incurable lung diseases. Identifying lung stem/progenitor cells with regenerative capacity and utilizing them to reconstruct functional tissue is one of the biggest hopes to reverse the damage and cure such diseases. Here we showed that a rare population of SOX9+ basal cells (BCs) located at airway epithelium rugae can regenerate adult human lung. Human SOX9+ BCs can be readily isolated by bronchoscopic brushing and indefinitely expanded in feeder-free condition. Expanded human SOX9+ BCs can give rise to alveolar and bronchiolar epithelium after being transplanted into injured mouse lung, with air-blood exchange system reconstructed and recipient’s lung function improved. Manipulation of lung microenvironment with Pirfenidone to suppress TGF-β signaling could further boost the transplantation efficiency. Moreover, we conducted the first autologous SOX9+ BCs transplantation clinical trial in two bronchiectasis patients. Lung tissue repair and pulmonary function enhancement was observed in patients 3–12 months after cell transplantation. Altogether our current work indicated that functional adult human lung structure can be reconstituted by orthotopic transplantation of tissue-specific stem/progenitor cells, which could be translated into a mature regenerative therapeutic strategy in near future.

Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis.

Silicosis is an incurable lung disease affecting millions of workers in hazardous occupations. It is caused by chronic exposure to the dust that contains free crystalline silica. Silica-induced lung damage occurs by several main mechanisms including cell death by apoptosis, fibrosis and production of cytokines. However, the signal pathways involved in these mechanisms are not fully characterized. In this study, the toll-like receptor 4 (TLR4)-related signal pathway was examined in silica-treated U937-differentiated macrophages. The expression level of TLR4 was measured by both quantitative PCR and Western blot. Confirmation of the involvement of MyD88/TIRAP and NFκB p65 cascade was performed by Western blot. The secretion of cytokines IL-1β, IL-6, IL-10 and TNFα was measured by enzyme-linked immunosorbent assay. Our results showed that TLR4 and related MyD88/TIRAP pathway was associated with silica-exposure in U937-differentiated macrophages. Protein expression of TLR4, MyD88 and TIRAP was upregulated when the U937-differentiated macrophages were exposed to silica. However, the upregulation was attenuated when TLR4 inhibitor, TAK-242 was present. At different incubation times of silica exposure, it was found that NFκB p65 cascade was activated at 10-60 minutes. Release of cytokines IL-1β, IL-6, IL-10 and TNFα was induced by silica exposure and the induction of IL-1β, IL-6 and TNFα was suppressed by the addition of TAK-242. In conclusion, our study demonstrated that TLR4 and related MyD88/TIRAP pathway was involved in silica-induced inflammation in U937-differentiated macrophages. Downstream NFκB p65 cascade was activated within 1 hour when the U937-differentiated macrophages were exposed to silica. The better understanding of early stage of silica-induced inflammatory process may help to develop earlier diagnosis of silicosis.

NLRP3 inflammasome inhibition attenuates silica-induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells

Silicosis is an incurable and progressive lung disease characterized by chronic inflammation and fibroblasts accumulation. Studies have indicated a vital role for epithelial-mesenchymal transition (EMT) in fibroblasts accumulation. NLRP3 inflammasome is a critical mediator of inflammation in response to a wide range of stimuli (including silica particles), and plays an important role in many respiratory diseases. However, whether NLRP3 inflammasome regulates silica-induced EMT remains unknown. Our results showed that silica induced EMT in human bronchial epithelial cells (16HBE cells) in a dose- and time-dependent manner. Meanwhile, silica persistently activated NLRP3 inflammasome as indicated by continuously elevated extracellular levels of interleukin-1β (IL-1β) and IL-18. NLRP3 inflammasome inhibition by short hairpin RNA (shRNA)-mediated knockdown of NLRP3, selective inhibitor MCC950, and caspase-1 inhibitor Z-YVAD-FMK attenuated silica-induced EMT. Western blot analysis indicated that TAK1-MAPK-Snail/NF-κB pathway involved NLRP3 inflammasome-mediated EMT. Moreover, pirfenidone, a commercially and clinically available drug approved for treating idiopathic pulmonary fibrosis (IPF), effectively suppressed silica-induced EMT of 16HBE cells in line with NLRP3 inflammasome inhibition. Collectively, our results indicate that NLRP3 inflammasome is a promising target for blocking or retarding EMT-mediated fibrosis in pulmonary silicosis. On basis of this mechanism, pirfenidone might be a potential drug for the treatment of silicosis.

Effects of Early Integrated Palliative Care on Caregivers of Patients with Lung and Gastrointestinal Cancer: A Randomized Clinical Trial.

The family and friends (caregivers) of patients with advanced cancer often experience tremendous distress. Although early integrated palliative care (PC) has been shown to improve patient-reported quality of life (QOL) and mood, its effects on caregivers' outcomes is currently unknown. We conducted a randomized trial of early PC integrated with oncology care versus oncology care alone for patients who were newly diagnosed with incurable lung and noncolorectal gastrointestinal cancers and their caregivers. The early PC intervention focused on addressing the needs of both patients and their caregivers. Eligible caregivers were family or friends who would likely accompany patients to clinic visits. The intervention entailed at least monthly patient visits with PC from the time of diagnosis. Caregivers were encouraged, but not required, to attend the palliative care visits. We used the Hospital Anxiety and Depression Scale (HADS) and Medical Health Outcomes Survey Short-Form to assess caregiver mood and QOL. Two hundred seventy-five caregivers (intervention n = 137; control n = 138) of the 350 patients participated. The intervention led to improvement in caregivers' total distress (HADS-total adjusted mean difference = -1.45, 95% confidence interval [CI] -2.76 to -0.15, p = .029), depression subscale (HADS-depression adjusted mean difference = -0.71, 95% CI -1.38 to -0.05, p = .036), but not anxiety subscale or QOL at week 12. There were no differences in caregivers' outcomes at week 24. A terminal decline analysis showed significant intervention effects on caregivers' total distress (HADS-total), with effects on both the anxiety and depression subscales at 3 and 6 months before patient death. Early involvement of PC for patients with newly diagnosed lung and gastrointestinal cancers leads to improvement in caregivers' psychological symptoms. This work demonstrates that the benefits of early, integrated PC models in oncology care extend beyond patient outcomes and positively impact the experience of caregivers. Early involvement of palliative care for patients with newly diagnosed lung and gastrointestinal cancers leads to improvement in caregivers' psychological symptoms. The findings of this trial demonstrate that the benefits of the early, integrated palliative care model in oncology care extend beyond patient outcomes and positively impact the experience of caregivers. These findings contribute novel data to the growing evidence base supporting the benefits of integrating palliative care earlier in the course of disease for patients with advanced cancer and their caregivers.

Role of Patient Coping Strategies in Understanding the Effects of Early Palliative Care on Quality of Life and Mood.

Purpose The early integration of oncology and palliative care (EIPC) improves quality of life (QOL) and mood for patients with advanced cancer. However, the mechanisms by which EIPC benefits these outcomes remain unclear. We therefore examined whether EIPC improved patients' coping strategies and if changes in coping accounted for intervention effects on QOL and depressive symptoms. Patients and Methods For this secondary analysis of an EIPC trial, we examined data from 350 patients with newly diagnosed incurable lung or GI cancer. Participants completed assessments of QOL (Functional Assessment of Cancer Therapy-General), depressive symptoms (Patient Health Questionnaire-9), and coping (Brief COPE) at baseline and 24 weeks. We used linear regression to test intervention effects on use of coping strategies and mediation regression models with bias-corrected bootstrapping to examine whether improvements in coping mediated the effects of early palliative care on patient-reported outcomes. Results Compared with usual oncology care, EIPC significantly increased patient use of approach-oriented coping strategies ( B = 1.09; SE = 0.44; P = .01) and slightly reduced use of avoidant strategies ( B = -0.44; SE = 0.23; P = .06) from baseline to 24 weeks. Also, the increased use of approach-oriented coping and reduction in avoidant coping were associated with higher QOL and lower depressive symptoms at 24 weeks. The positive changes in approach-oriented coping, but not avoidant coping, significantly mediated the effects of EIPC on QOL (indirect effect, 1.27; 95% CI, 0.33 to 2.86) and depressive symptoms (indirect effect, -0.39; 95% CI, -0.87 to -0.08). Conclusion Patients with incurable cancer who received EIPC showed increased use of approach-oriented coping, which was associated with higher QOL and reduced depressive symptoms. Palliative care may improve these outcomes by providing patients with the skills to cope effectively with life-threatening illness.

The positive effects of early integrated palliative care on patient coping strategies, quality of life, and depression.

92 Background: In a recent trial, early integrated palliative care (PC) improved quality of life (QOL) and reduced depressive symptoms in patients with newly-diagnosed incurable lung and gastrointestinal (GI) cancer. The mechanisms by which PC benefits these outcomes are unclear. We examined whether early integrated PC improved patients’ coping strategies and the degree to which changes in coping mediated intervention effects on QOL and depressive symptoms. Methods: From 5/2011 to 7/2015, we enrolled 350 patients with newly diagnosed incurable lung or non-colorectal GI cancer in a randomized trial of early PC integrated with oncology care vs. oncology care alone at Massachusetts General Hospital. Patients completed self-report measures of QOL (Functional Assessment of Cancer Therapy-General), depressive symptoms (Patient Health Questionnaire-9), and use of active and avoidant coping strategies (Brief Cope) at baseline, 12, and 24 weeks. Linear regression was used to assess the effects of the early PC intervention on active and avoidant coping strategies. A multiple mediation regression was modeled to examine whether changes in use of coping strategies mediated intervention effects on QOL and depressive symptoms. Results: Compared to oncology care, early integrated PC improved patients’ use of active coping ( B= 1.09, SE= 0.44, p= .01, 95% CI: 0.23, 1.96) and slightly reduced use of avoidant coping strategies ( B= -0.44, SE= 0.23, p= .06, 95% CI:-0.90, 0.02). Improvements in 24-week QOL in patients assigned to PC were mediated by increased use of active coping strategies (indirect effect = 1.27, 95% CI: 0.31, 2.86), but not by decreased use of avoidant coping. Similarly, PC-related reductions in 24-week depressive symptoms were mediated by increased use of active coping strategies (indirect effect = -0.39, 95% CI:-0.89, -0.08) but not by decreased use of avoidant coping. Conclusions: Patients with newly diagnosed incurable cancer who received early integrated PC showed increased use of active coping strategies, which was associated with improved QOL and depressive symptoms. PC may improve QOL and mood by providing patients with the skills to cope effectively with life-threatening illness. Clinical trial information: NCT01401907.