Supportive and palliative care for lung cancer patients

Lung cancer patients face poor survival and experience co-occurring chronic physical and psychological symptoms. These symptoms can result in significant burden, impaired physical and social function and poor quality of life. This paper provides a review of evidence based interventions that support best practice supportive and palliative care for patients with lung cancer. Specifically, interventions to manage dyspnoea, one of the most common symptoms experienced by this group, are discussed to illustrate the emerging evidence base in the field. The evidence base for the pharmacological management of dyspnoea report systemic opioids have the best available evidence to support their use. In particular, the evidence strongly supports systemic morphine preferably initiated and continued as a once daily sustained release preparation. Evidence supporting the use of a range of other adjunctive non-pharmacological interventions in managing the symptom is also emerging. Interventions to improve breathing efficiency that have been reported to be effective include pursed lip breathing, diaphragmatic breathing, positioning and pacing techniques. Psychosocial interventions seeking to reduce anxiety and distress can also improve the management of breathlessness although further studies are needed. In addition, evidence reviews have concluded that case management approaches and nurse led follow-up programs are effective in reducing breathlessness and psychological distress, providing a useful model for supporting implementation of evidence based symptom management strategies. Optimal outcomes from supportive and palliative care interventions thus require a multilevel approach, involving interventions at the patient, health professional and health service level.

Prognostic value of hTERT mRNA expression in surgical samples of lung cancer patients : the European Early Lung Cancer Project

Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.

Prognostic impact of vascular and lymphovascular invasion in early lung cancer

Background The prognostic significance of vascular and lymphatic invasion in non-small-cell lung cancer is under continuous debate. We analyzed the effect of tumor aggressiveness (lymphatic and/or vessel invasion) on survival and relapse in stage I and II non-small-cell lung cancer. Methods We retrospectively analyzed prospectively collected data of 457 patients with stage I and II non-small-cell lung cancer from 1998 to 2008. Specimens were analyzed for intratumoral vascular invasion and lymphovascular space invasion. Overall survival and disease-free survival were estimated using the Kaplan-Meier method, and differences were determined by the logrank test. Cox regression analysis was performed to identify independent risk factors. Results: The incidence of intratumoral vascular invasion was 23.4%, and this correlated significantly with grade of differentiation, visceral pleural involvement, lymphovascular space invasion, and N status. The incidence of lymphovascular space invasion was 5.5%, and this correlated significantly with grade of differentiation, lymph nodes involved, and intratumoral vascular invasion. On multivariate analyses, intratumoral vascular invasion proved to be an significant independent risk factor for overall survival but not for disease-free survival. Lymphovascular space invasion was associated significantly with early tumor recurrence but not with overall survival. Conclusions: Vascular and lymphatic invasion can serve as independent prognostic factors in completely resected nonsmall- cell lung cancer. Intratumoral vascular invasion and lymphovascular space invasion in early stage non-small-cell lung cancer are important factors in overall survival and early tumor recurrence. Further large scale studies with more recent patient cohorts and refined histological techniques are warranted.

IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.

Inflammation in lung carcinogenesis

It was Dvorak in 1986 that postulated 'tumours are wounds that do not heal' as they share common cellular and molecular mechanisms, which are active in both wounds and in cancer tissue. Inflammation is a crucial part of the innate immune system that protects against pathogens and initiates adaptive immunity. Acute inflammation is usually a rapid and self-limiting process, however it does not always resolve. This leads to the establishment of a chronic inflammatory state and provides the perfect environment for carcinogenesis. Inflammation and cancer have long had an association, going back as far as Virchow in 1863, when leucocytes were noted in neoplastic tissue. It has been estimated that approximately 25% of all malignancies are initiated or exacerbated by inflammation caused by infectious agents. Furthermore, inflammation is linked to all of the six hallmarks of cancer (evasion of apoptosis, insensitivity to anti-growth signals, unlimited replicative potential, angiogenesis, increase in survival factors and invasion and metastasis). It is thought that inflammation may play a critical role in lung carcinogenesis given that individuals with inflammatory lung conditions have an increased risk of lung cancer development. Cigarette smoking can also induce inflammation in the lung and smokers are at a higher risk of developing lung cancer than non-smokers. However, exposure to a number of environmental agents such as radon, have also been demonstrated as a causative factor in this disease. This chapter will focus on inflammation as a contributory factor in non small cell lung cancer (NSCLC), concentrating primarily on the pathological involvement of the pro-inflammatory cytokines, TNF-α, IL-1β, and the CXC (ELR+) chemokine family. Targeting of inflammatory mediators will also be discussed as a therapeutic strategy in this disease. © 2013 by Nova Science Publishers, Inc. All rights reserved.

Thromboxane synthase expression and correlation with VEGF and angiogenesis in non-small cell lung cancer

Background Thromboxane synthase (TXS) metabolizes prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with angiogenesis and poor outcome. TXS has been identified as a potential therapeutic target in NSCLC. This study examines a link between TXS expression, angiogenesis, and survival in NSCLC. Methods TXS and VEGF metabolite levels were measured in NSCLC serum samples (n=46) by EIA. TXB2 levels were correlated with VEGF. A 204-patient TMA was stained for TXS, VEGF, and CD-31 expression. Expression was correlated with a range of clinical parameters, including overall survival. TXS expression was correlated with VEGF and CD-31. Stable TXS clones were generated and the effect of overexpression on tumor growth and angiogenesis markers was examined in-vitro and in-vivo (xenograft mouse model). Results Serum TXB2 levels were correlated with VEGF (p<0.05). TXS and VEGF were expressed to a varying degree in NSCLC tissue. TXS was associated with VEGF (p<0.0001) and microvessel density (CD-31; p<0.05). TXS and VEGF expression levels were higher in adenocarcinoma (p<0.0001) and female patients (p<0.05). Stable overexpression of TXS increased VEGF secretion in-vitro. While no significant association with patient survival was observed for either TXS or VEGF in our patient cohort, TXS overexpression significantly (p<0.05) increased tumor growth in-vivo. TXS overexpression was also associated with higher levels of VEGF, microvessel density, and reduced apoptosis in xenograft tumors. Conclusion TXS promotes tumor growth in-vivo in NSCLC, an effect which is at least partly mediated through increased tumor angiogenesis.

High coexpression of both EGFR and IGF1R correlates with poor patient prognosis in resected non-small-cell lung cancer

Background Recent experimental and biomarker evidence indicates that the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor 1 (IGF1R) interact in the pathogenesis of malignant epithelial tumors, including lung cancer. This study examines the expression of both receptors and their prognostic significance in surgically resected non-small-cell lung cancer (NSCLC). Methods EGFR and IGF1R expression were evaluated in 184 patients with NSCLC (83 squamous cell carcinomas [SCCs], 83 adenocarcinomas [ADCs], and 18 other types) using immunohistochemical (IHC) analysis. Expression of both receptors was examined in matched fresh frozen normal and tumor tissues from 40 patients with NSCLC (20 SCCs and 20 ADCs) by Western blot analysis. Results High EGFR expression was detected in 51% of patients, and SCCs had higher EGFR expression than did non-SCCs (57.4% vs. 42.5%; P =.028). High IGF1R expression was observed in 53.8% of patients, with SCC having higher expression than non-SCC (62.6% vs. 37.3%; P =.0004). A significant association was shown between EGFR and IGF1R protein overexpression (P <.005). Patients with high expression of both receptors had a poorer overall survival (OS) (P =.04). Higher EGFR and IGF1R expression was detected in resected tumors relative to matched normal tissues (P =.0004 and P =.0009), with SCC having higher expression levels than ADC. Conclusion Our findings indicate a close interrelationship between EGFR and IGF1R. Coexpression of both receptors correlates with poor survival. This subset of patients may benefit from treatments cotargeting EGFR and IGF1R. © 2014 Elsevier Inc. All rights reserved.

Targeted therapies in non-small cell lung cancer

The majority of non-small cell lung cancer (NSCLC) patients present with advanced disease and with a 5 year survival rate of <15% for these patients, treatment outcomes are considered extremely disappointing. Standard chemotherapy regimens provide some improvement to ~40% of patients. However, intrinsic and acquired chemoresistance are a significant problem and hinder sustained long term benefits of such treatments. Advances in proteomic and genomic profiling have increased our understanding of the aberrant molecular mechanisms that are driving an individual's tumour. The increased sensitivity of these technologies has enabled molecular profiling at the stage of initial biopsy thus paving the way for a more personalised approach to the treatment of cancer patients. Improvements in diagnostics together with a wave of new targeted small molecule inhibitors and monoclonal antibodies have revolutionised the treatment of cancer. To date there are essentially three targeted agents approved for clinical use in NSCLC. The tyrosine kinase inhibitor (TKI) erlotinib, which targets the epidermal growth factor receptor (EGFR) TK domain, has proven to be an effective treatment strategy in patients who harbour activating mutations in the EGFR TK domain. Bevacizumab a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) can improve survival, response rates, and progression-free survival when used in combination with chemotherapy. Crizotinib, a small-molecule drug, inhibits the tyrosine kinase activity of the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion protein, resulting in decreased tumour cell growth, migration, and invasiveness in patients with locally advanced or metastatic NSCLC. The clinical relevance of several other targeted agents are under investigation in distinct molecular subsets of patients with key "driver" mutations including: KRAS, HER2, BRAF, MET, PIK3CA, AKT1,MAP2K1, ROS1 and RET. Often several pathways are activated simultaneously and crosstalk between pathways allows tumour cells to escape the inhibition of a single targeted agent. This chapter will explore the clinical development of currently available targeted therapies for NSCLC as well as those in clinical trials and will examine the synergy between cytotoxic therapies.

Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer

Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

Global analysis of serum microRNAs as potential biomarkers for lung adenocarcinoma

Early diagnosis and the ability to predict the most relevant treatment option for individuals is essential to improve clinical outcomes for non-small cell lung cancer (NSCLC) patients. Adenocarcinoma (ADC), a subtype of NSCLC, is the single biggest cancer killer and therefore an urgent need to identify minimally invasive biomarkers to enable early diagnosis. Recent studies, by ourselves and others, indicate that circulating miRNA s have potential as biomarkers. Here we applied global profiling approaches in serum from patients with ADC of the lung to explore if miRNA s have potential as diagnostic biomarkers. This study involved RNA isolation from 80 sera specimens including those from ADC patients (equal numbers of stages 1, 2, 3, and 4) and age- and gender-matched controls (n = 40 each). Six hundred and sixty-seven miRNA s were co-analyzed in these specimens using TaqMan low density arrays and qPCR validation using individual miRNA s. Overall, approximately 390 and 370 miRNA s were detected in ADC and control sera, respectively. A group of 6 miRNA s, miR-30c-1* (AU C = 0.74; P < 0.002), miR-616(AU C = 0.71; P = 0.001), miR-146b-3p (AU C = 0.82; P < 0.0001), miR-566 (AU C = 0.80; P < 0.0001), miR-550 (AU C = 0.72; P = 0.0006), and miR-939 (AU C = 0.82; P < 0.0001) was found to be present at substantially higher levels in ADC compared with control sera. Conversely, miR-339-5p and miR-656 were detected at substantially lower levels in ADC sera (co-analysis resulting in AU C = 0.6; P = 0.02). Differences in miRNA profile identified support circulating miRNA s having potential as diagnostic biomarkers for ADC. More extensive studies of ADC and control serum specimens are warranted to independently validate the potential clinical relevance of these miRNA s as minimally invasive biomarkers for ADC.

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

Psychological symptoms : a review of screening practices for patients with coronary heart disease (CHD)

Background/Aims: Coronary heart disease (CHD) and coronary events have been strongly linked to psychological symptoms in patients during hospitalisation and post-discharge. Within Australia CHD average length of stay is decreasing and symptoms often do not present until discharge. Early screening and treatment of psychological symptoms has been recommended to reduce mortality and identify anxiety and depression. This literature review was undertaken to evaluate and describe current screening practices to identify psychological symptoms in these patients.

Adenovirus species C is associated with chronic suppurative lung diseases in children

Background The role of human adenoviruses (HAdVs) in chronic respiratory disease pathogenesis is recognized. However, no studies have performed molecular sequencing of HAdVs from the lower airways of children with chronic endobronchial suppuration. We thus examined the major HAdV genotypes/species, and relationships to bacterial coinfection, in children with protracted bacterial bronchitis (PBB) and mild bronchiectasis (BE). Methods Bronchoalveolar lavage (BAL) samples of 245 children with PBB or mild (cylindrical) BE were included in this prospective cohort study. HAdVs were genotyped (when possible) in those whose BAL had HAdV detected (HAdV+). Presence of bacterial infection (defined as ≥104 colony-forming units/mL) was compared between BAL HAdV+ and HAdV negative (HAdV−) groups. Immune function tests were performed including blood lymphocyte subsets in a random subgroup. Results Species C HAdVs were identified in 23 of 24 (96%) HAdV+ children; 13 (57%) were HAdV-1 and 10 (43%) were HAdV-2. An HAdV+ BAL was significantly associated with bacterial coinfection with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae (odds ratio [OR], 3.27; 95% confidence interval, 1.38–7.75; P = .007) and negatively associated with Staphylococcus aureus infection (P = .03). Young age was related to increased rates of HAdV+. Blood CD16 and CD56 natural killer cells were significantly more likely to be elevated in those with HAdV (80%) compared with those without (56.1%) (P = .027). Conclusions HAdV-C is the major HAdV species detected in the lower airways of children with PBB and BE. Younger age appears to be an important risk factor for HAdV+ of the lower airways and influences the likelihood of bacterial coinfection

2nd ESMO consensus conference on lung cancer : early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, earlystage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Second ESMO consensus conference on lung cancer : pathology and molecular biomarkers for non-small-cell lung cancer

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with nonsmall- cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.