Virtual Library

Background:
Despite imaging advances, differentiating pleural malignancy (PM) from benign pleural disease (BPD) remains challenging, particularly early-stage Malignant Pleural Mesothelioma (MPM), which can look similar to benign asbestos-related pleural effusion (BAPE). We report the diagnostic performance of a novel Magnetic Resonance Imaging (MRI) biomarker of PM - Early Contrast Enhancement (ECE).

Methods:
24 patients with suspected PM were recruited prospectively (January 2013-November 2014). All underwent contrast-enhanced Computed Tomography (CT) scanning and Thoracoscopy. 3-T Pleural MRI was performed prior to Thoracoscopy (median 4 (IQR 4–8) days). Imaging methodology was developed using patients 1-6. In 18 patients, T1-weighted 3D-spoiled-gradient-echo sequences were acquired coronally at baseline, 40 and 80 seconds and 4.5, 9 and 13.5 minutes after intravenous Gadobutrol contrast. Mean signal intensity (SI) of parietal pleura at each time-point was derived from 15 regions of interest placed by two respiratory physicians. ECE on the resulting SI/time curve was defined objectively as an early peak (at/before 4.5 minutes) and/or late fall in mean SI (Figure 1). CT and MRI scans were assessed for morphological features of PM by two thoracic radiologists. All analyses were blinded. Diagnostic performance was assessed using contingency tables. Inter- and intra-observer agreement was assessed using Cohen’s kappa statistic. Figure 1



Results:
Median patient age was 73 (IQR 70–80) years. 75% (n=18) were asbestos-exposed. ECE was present in 10/11 patients with PM (MPM (10); lung cancer (1)). The false negative case had MPM. 1 MPM case was initially diagnosed with BAPE but reclassified as MPM after developing progressive PM, consistent with their initial MRI result (ECE present). ECE was absent in 6/7 patients with BPD (BAPE (4), fibrothorax (2), TB (1)). The false positive case had TB. Table 1 summarises diagnostic performance.

Table 1: Diagnostic performance and reproducibility of ECE, CT morphology and MRI morphology in pleural malignancy

	Sensitivity (%)	Specificity (%)	Negative Predictive Value (%)	Positive Predictive Value (%)	Inter-observer agreement	Intra-observer agreement
CT Morphology	90	50	80	69	0.753	Not done
MRI Morphology	91	71	83	83	0.727	Not done
MRI Early Contrast Enhancement	91	86	86	91	0.766	1.000

Conclusion:
ECE appears a sensitive and specific objective biomarker of PM, out-performing subjectively-defined CT and MR morphology. SI/time curves for ECE assessment can be generated reproducibly in patients with minimal pleural thickening, suggesting potential utility as a non-invasive biomarker for the early detection of MPM or low-volume metastatic PM.

Background:
There is no established diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein on the surface of many cell types that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 in patients with MPM.

Methods:
The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. Soluble CD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. To make a comparative review of the usefulness of sCD26, we determined serum and pleural fluid soluble mesothelin-related peptides (SMRP). SMRP was measured by the chemiluminescent enzyme immunoassay (CLEIA) based on 2-step sandwich method.

Results:
Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P=0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P=0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P=0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P=0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P=0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P=0.028). Median values of serum and pleural fluid SMRP in MPM patients were 0.43 and 15.37 mmol/l, respectively. Median value of pleural fluid SMRP in epithelioid MPM was 17.28 mmol/l. Median values of serum SMRP in SPE and pleural fluid SMRP in OPD were 0.90 and 0.43 mmol/l, respectively. Pleural fluid SMRP in MPM was significantly higher than in OPD (P=0.000) and serum SMRP in MPM was significantly higher than in SPE (P=0.000).

Conclusion:
Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM.

Background:
Identifying driver mutations assists with understanding molecular aspects of cancer and development of novel drugs. The genetics of malignant pleural mesothelioma (MPM) has primarily been to date described in terms of deletions of specific chromosomal regions with CDKN2A and NF2 most commonly mutated, and more recently, evidence for a role of BAP1. The current work suggests that activation of the Integrin Linked Kinase (ILK) pathway may be oncogenic in a subset of MPM.

Methods:
Whole-genome sequencing was accomplished for 10 tumor and matched normal genomic DNA samples using a Complete Genomics platform. Tumor and normal genomes were sequenced to at least 30-fold haploid coverage, with corresponding diploid coverage of at least 99.5%. Selected candidates single nucleotide variations (SNVs) were further characterized using PCR and Sanger sequencing to identify tumor-specific single nucleotide mutations. Potential driver genes were investigated in 147 additional MPM cases by targeted resequencing. Levels of transcripts were examined in an available expression data set (Affymetrix® Human Gene 1.1 ST Array). Association of mutation status and gene expression to clinicopathologic variables was explored statistically.

Results:
Among 146 single nucleotide variants (SNVs) mapping in amino acid coding regions of annotated exons and generating non-synonymous amino acid changes, 85 were confirmed to be tumor specific. Functional enrichments of genes affected by point mutations were performed utilizing Ingenuity Pathway Analysis to identify clusters of genes annotated in pathways potentially relevant to the biology of MPM. Mutations affecting genes involved in the Integrin Linked Kinase (ILK) pathway were the most significantly (p = 4.9e-5) enriched. Specifically, 5 of 10 sequenced MPM samples showed point mutations in at least one of 6 genes of this pathway (MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A). Re-sequencing analysis of 147 MPM tumors identified 40 SNVs in these genes among 31 MPM samples (21%). Thirty-five (88%) SNVs were present in both tumor and matching normal DNA samples. In 4 samples, tumor specific mutations were identified, 3 in MYH9 (1.4%) and 2 in RHOA (1.4%) both recently proposed as genes involved in tumorigenesis. Non-epithelioid tumors expressed significantly higher levels of MYH9 (p<0.001), RHOA (p<0.001), and MYH10 (p=0.001) compared to epithelioid tumors. RHOA was more highly expressed in men than women (p=0.001). The highest quartile of MYH9 and of RHOA expression was associated with higher gender-adjusted risk of death (HR=2.23 and HR=1.95, respectively) compared to the lower three quartiles (p<0.001) by multivariate analysis.

Conclusion:
Tumor specific mutations in MYH9 or RHOA were found in six of 157 (3.8%) MPM patients. Interestingly, both MYH9 (22q13.1) and RHOA (3p21.3) reside in two chromosomal regions frequently deleted in MPM. Additional analysis is in progress to investigate the role of ILK pathway activation in MPM. These observations suggest that a sub-class of MPM may respond to therapy targeting the ILK pathway.

Abstract not provided

Background:
Local tumor recurrence is very frequent after resection of malignant pleural mesothelioma (MPM). Intracavitary chemotherapy has been shown to be a promising approach to improve local tumor control. Here, we present the results of a phase-I-dose-escalation trial with intracavitary application of cisplatin-fibrin after surgical tumor resection.

Methods:
Altogether 12 patients (75% IMIG stage III-IV) were treated with 4 different dose levels of cisplatin (11, 22, 33 and 44mg/m[2] body surface area (BSA)). Eight patients of 22, 33 and 44mg/m[2] groups received previous induction treatment with intravenous cisplatin/pemetrexed. Cisplatin-fibrin was sprayed on the surface of chest wall, diaphragm, mediastinum and lung after pleurectomy/decortication (P/D). Blood was taken before surgery and at several time points after the treatment. Tissue sampling was conducted before and at 90 minutes after the administration. Cisplatin levels were measured by inductively coupled plasma sector field mass spectrometry.

Results:
Serum cisplatin kinetics and AUC0-120 are depicted in figure 1. Induction intravenous chemotherapy contributed to >50% of total serum cisplatin levels compared to cisplatin-fibrin (figure 1B). The median AUC0-24 of the 3 patients in the highest dose level (44mg/m[2]BSA) including predoses from induction chemotherapy reached 23h*µg/g, which is still below the suggested renal toxicity risk level, 25h*µg/g (Royer 2008). Our serum cisplatin AUC levels stayed far below levels reported after intrapleural perfusion (approx. 89h*µg/g (Ried 2013)). Local cisplatin concentration in tissues varied from 12-133 (median: 36.5µg/g) and did not seem to be dose dependent. No dose limiting toxicity due to cisplatin was observed. Major morbidity was observed in 4 patients (33%). 30day- and 90day-mortality was 0%. The median follow up after surgery was 11 months (range: 5-28 months). In 8 patients receiving 11, 22, 33 mg/m[2]BSA, relapse was detected after a median freedom from recurrence (FFR) of 8 months (95% confidence interval (CI): 1-14 months). In three patients with early IMIG stage (I and II), no sign of relapse was observed at 28, 8 and 6 months after the treatment (11, 44, 44 mg/m[2]BSA, respectively). The last patient (44mg/m[2]BSA) with IMIG stage III tumor currently shows no sign of recurrence at 5 months after surgery. Figure 1



Conclusion:
The administration of intracavitary cisplatin-fibrin as high as 44mg/m[2]BSA is safe after P/D, also in combination with induction chemotherapy. Tissue cisplatin concentration was high whereas no dose limiting toxicity due to systemic distribution was detected. A confirmation of the safety and efficacy of the highest dosage, 44 mg/m[2]BSA, in a phase II trial is warranted.

Background:
Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures (SOPs) to facilitate basic and translational research is very limited. MesobanK, funded by the British Lung Foundation and the Mick Knighton Mesothelioma Research Fund, is a UK based bioresource to collect fresh tissue, blood, pleural fluid and anonymised linked clinical data to strict SOPs from patients with malignant pleural mesothelioma.

Methods:
1) To construct a tissue microarray (TMA) from 1000 cases of formalin fixed paraffin embedded pleural mesothelioma tissue linked to a clinical data set. Each case will have several cores taken to allow for tumour heterogeneity. 2) To collect 300 cases of fresh pleural mesothelioma tissue (5 samples per case), blood (whole blood, serum, plasma and buffy coat) and pleural fluid (supernatant and cell pellet) linked to a clinical data set. Longer term follow up and survival data will be provided by the UK National Cancer Registration Service. 3) To develop at least 20 new fully characterised and annotated mesothelioma cell lines. Governance MesobanK abides by all relevant UK and EU legislation regarding the collection of tissue and data. Mesobank is a member of the UK Confederation of Cancer Biobanks. Prioritisation for access to samples will be based solely on scientific merit. The project is managed by a dedicated project manager and overseen by a Steering Committee; an independent Scientific Advisory Board reviews anonymised applications for samples.

Results:
All required ethical permissions have been obtained. A secure, web-based multi-user database has been constructed for data collection. As of April 2015, 730 of the 1000 cases for the TMA have been acquired from UK pathology departments and the first part of the TMA construction is underway at the Cancer Research UK Cambridge Institute. In the first year of operation, 100 prospective cases have been banked and quality control to assess tumour percentage and necrosis in each sample is underway. Figure 1 shows weight of sample versus tumour percentage from the QC of the first 144 samples. Twenty six new cell lines have been developed and are currently being characterised. Figure 1



Conclusion:
Procurement of formalin fixed tissue for the TMA and fresh biospecimens is progressing well and MesobanK is now open for investigators to apply for tissue samples. Enquiries about tissue availability should be directed to [email protected]. An application form is available at www.mesobank.com. A cost contribution model has been developed to support on-going funding of MesobanK.

Background:
Malignant pleural mesothelioma (MPM) is a devastating malignancy with still rising incidence worldwide. Its aggressive biological behavior and therapy resistance result in a median overall survival (OS) of 9 to 17 months only. Currently, platinum-based chemotherapy in combination with antifolate agents is the standard front-line therapy for MPM and to date no molecularly targeted therapeutic approaches have been approved in the clinics. Nintedanib is an indolinone derivative that has been demonstrated to efficiently inhibit the activity of VEGFR, PDGFR and FGFR tyrosine kinase isoforms and thus to be capable to suppress angiogenesis and tumor growth. Here, we report the antitumor activity of nintedanib in MPM.

Methods:
21 MPM cell lines were treated with nintedanib and SRB assays were performed to determine the IC50 values for each cell line. 4 sensitive cell models were selected for further in vitro analysis: BrdU, TUNEL and clonogenic assays were performed to investigate the impact of the drug on the proliferation, apoptosis and colony formation capacity of MPM cells, respectively. The migratory activity of MPM cells was analyzed with 2D videomicroscopy. The downstream signaling of the target receptors was investigated by Western blot analysis. Drug interactions with cisplatin were assessed in the p31 MPM cell line and in its cisplatin-resistant subline (p31cis) by using the CalcuSyn software. The in vivo anti-MPM activity of nintedanib was studied in an orthotopic human MPM xenograft model in SCID mice. Tumor-bearing animals were treated with 50 mg/kg nintedanib daily, per os (PO) or intraperitoneally (IP) and followed for survival.

Results:
Nintedanib exerted a growth inhibitory effect on MPM cell lines in both short- and long-term viability assays. The inhibition of proliferation was observed in all MPM cell models analyzed, whereas significant apoptosis induction was only found in half of them. Migratory activity strongly decreased upon nintedanib treatment. Down-regulation of Erk1/2 phosphorylation was evident within 10 min of treatment and was present even after 24h. Nintedanib, however, had no inhibitory effect on the activation of Akt or S6. Additive, but no synergistic effect on cell viability was detected in the p31 and p31cis MPM cells when nintedanib was combined with cisplatin. In vivo, survival of PO-treated animals showed favorable trend (vs. PO control, log-rank test, p=0.059). Nintedanib significantly prolonged the survival of mice when it was administered IP (vs. IP control, log-rank test, p=0.0008).

Conclusion:
Our data suggest that nintedanib exerts antitumor activity in MPM both in vitro and in vivo and thus may represent a promising novel therapeutic option in this malignancy.

Abstract not provided

Background:
Knowledge about how symptoms change following lung cancer surgery is important. Patients want information about the usual course of recovery including information about when they need to contact their clinician if symptoms persist. To our knowledge, only three studies have evaluated the occurrence of symptoms in patients prior to and following lung cancer surgery. The purpose of this study was to evaluate changes in symptom occurrence from the preoperative period to 1 year after surgery using a multidimensional symptom assessment scale (i.e., Memorial Symptom Assessment Scale (MSAS).

Methods:
Patients were recruited from three university hospitals in Norway. They completed a number of self-report questionnaires prior to and again at 1, 5, 9, and 12 months following surgery. The questionnaires provided information on demographic and clinical characteristics as well as on symptoms. Patients’ medical records were reviewed for disease and treatment information. Descriptive statistics were used to present demographic and clinical characteristics. Analysis of variance (ANOVA) was used to compare the total number of symptoms across the 5 assessments.

Results:
At 12 months after surgery, the sample consisted of 113 (58%) men and 81 (43%) women who had a mean age of 66 years (SD 8.1, range 30 to 86). Findings from the ANOVA demonstrated significant changes in total number of symptoms over time. Compared to the preoperative assessment ( =8.7 + 6.8), patients reported a higher number of symptoms at 1 month ( =12.4 + 6.3), 5 months ( =10.2 + 6.6), 9 months ( =9.3 + 7.0), and 12 months ( =10.6 + 7.2). Post hoc contrasts found no differences in the number of symptoms at the 5, 9, and 12 month assessments. The occurrence of the five of the most frequent symptoms (i.e., pain, lack of energy, shortness of breath (SOB), feeling drowsy, worrying) increased significantly from before to one month after surgery and then decreased at 5 months. At 5 and 12 months, 78% of the patients reported SOB. Lack of energy was reported by 70.8% and 66.5% of the patients at 5 and 12 months, respectively. Forty-seven percent of the patients reported worrying and 65% of the patients reported drowsiness at the 5 and 12 month assessments. Finally, the occurrence of pain decreased from 56% at 5 months to 49% at 12 months. Cough and difficulty sleeping persisted over the first five months of the study. From 5 months to 12 months, 51% continued to report difficulty sleeping. The occurrence of cough was reduced from 60% at 5 months to 54% at 12 months.

Conclusion:
Findings from this study suggest that patients experience a high number of symptoms for up to 12 months after lung cancer surgery. The reduction in symptom burden is relatively modest from 5 to 12 months. These findings can be used to educate patients about the course of postoperative recovery after lung surgery. In addition, clinicians need to assess for these symptoms and develop effective interventions to improve symptom management for this vulnerable group of patients.

Background:
Various approaches to immunotherapy have shown promise in the treatment of lung cancer. Checkpoint inhibitors have been used to enhance T-cell immune response against lung cancers. The inhibitors include drugs that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1). Immune checkpoint inhibitors promote t-cell proliferation allowing the immune system to recognize tumor antigens. If the t-cells become over active, they can attack healthy tissue, a process referred to as auto immunity. These adverse events (irAEs) differ from typical cytotoxic therapy side effects. Early identification and management of irAEs can help minimize advanced toxicities. An assessment algorithm was developed to help guide nurses and other health care providers in the assessment and management of irAEs.

Methods:
Immune checkpoint inhibitors are associated with immune related adverse events, referred to as irAEs. Immune checkpoint inhibitors promote t-cell proliferation allowing the immune system to recognize tumor antigens. However, if the t-cells become overactive, they can start to attack healthy tissue, a process referred to as auto-immunity. This process can occur in any organ of the body. Typically it occurs in systems that contain significant T cells. IrAEs are usually low grade. However, grade 3-4 toxicity has been noted in up to 15% of patients across studies. There have been treatment related deaths as a result of unidentified or managed side effects. There are variable patterns of presentation of irAEs. They may occur immediately after infusion or several months after treatment completion or discontinuation. The risk of irAEs may be increased with combination checkpoint therapy and combination with radiation therapy. The mechanism of the adverse event is immune mediated. Therefore, treatment may differ from the traditional management of the symptom. IrAEs are typically managed by drug discontinuation or administration of local or systemic corticosteroids. Hormone replacement may also be necessary for more advanced toxicities. Utilization of monitoring and treatment algorithms is essential for optimal control of irAEs.

Results:
An assessment algorithm was developed to help guide health care providers in the assessment, monitoring and management of immune related adverse events associated with immune checkpoint inhibitors.

Conclusion:
Patients and other healthcare providers must be educated about potential irAEs prior to treatment with checkpoint inhibitors. Members of the multidisciplinary team must be diligent in screening for the onset of irAEs during and after the completion of treatment. Early identification and treatment of irAEs can help minimize the risk for advanced toxicities and long term complications. In some cases, prompt management may allow for re-initiation of treatment.

Background:
The aim was to investigate the clinical effect and complication incidence of placing femoral venous catheters (FVCs) at different sites in patients with superior vena cava obstruction (SVCO). This study provides a basis for optimized vascular access in SVCO patients.

Methods:
Patients who underwent advanced lung cancer plus SVCO and received initial chemotherapy were treated in our hospital from July 2013 to January 2015. These patients were randomly divided into the observation and control groups. The observation group received “mid-thigh femoral venous catheters,” whereas the control group was treated with “groin femoral venous catheters.” The effect of catheter placement as well as the incidence of complications were compared between these two groups.

Results:
The bleeding scores (2.44±0.62 vs. 1.36±0.49), the retention time (195.08±39.19 days vs. 91.53±32.88 days), the patient comfort scores (4.20±0.87 vs. 1.35±0.91), and the pain scores (1.64±0.91 vs. 2.42±1.08) were all recorded and compared between the observation and control groups. The differences are statistically significant (P<0.001). Moreover, there are statistically significant differences in catheter-associated thrombosis (1.69% vs. 14.55%), catheter entry site infection (1.69% vs. 21.82%), and the incidence of total complications (11.86% vs. 45.45%) between the observation and control groups (P<0.05). However, the differences in both the one-time success rate of catheterization (98.32% vs. 98.18%) and the catheter occlusion (8.48% vs. 9.09%) are not significant between the observation and control groups (P>0.05).

Conclusion:
Compared to groin femoral venous catheters, mid-thigh femoral venous catheters have good catheter placement effect, low complication incidence rate, and little influence on patients’ degree of comfort; therefore, it is a suitable treatment for SVCO patients.

Abstract not provided

Background:
The role of the lung cancer nurse specialist (LCNS) varies across the UK, some working within teams and others as lone workers. Each LCNS brings strengths to the role and are individual in their approach. Over several years the National Lung Cancer Audit has highlighted the association between access to a LCNS and receipt of anti-cancer treatment. In 2013, 65.6% of patients who saw a LCNS received anti-cancer treatment, compared to 27.1% of those who did not see a LCNS[1]. A more detailed analysis has been carried out at Sheffield Hallam University Opening doors to treatment[2]. In the time-pressured setting of a MDT meeting it can be difficult to get your point across. This is where a real impact can be achieved in acting as patient advocate. A joint working initiative between Lilly Oncology and the National Lung Cancer Forum For nurses (NLCFN) has developed with the aim to help improve the contribution of the LCNS in the MDT meeting.

Methods:
LCNSs, particularly those new in post, were invited to apply for a place in the first UYV workshops on 6[th] and 7[th] October 2014 in London. Experienced professionals delivered the UYV programme including: - insights training - building confidence in order to effectively represent your patient in the MDT meeting - developing skills to manage challenging conversations - invaluable communication skills and strategies - greater understanding of Performance Status assessment A 12 week reflection period requiring submission of 3 reflective pieces of work followed the workshops. A mentor scheme was facilitated by 4 NLCFN committee members with teleconference calls organised by Lilly Oncology between the participants, their mentor and expert speakers. A final How you were heard closing workshop 19/01/2015, completed the training.

Results:
20 applications were received and all were offered and accepted a place. Formal evaluation of the workshops will be led by the Faculty of Health and Wellbeing, Sheffield Hallam University using mixed methods of data collection and analysis against: - the extent to which the LCNS feels more confident and competent to effectively influence patient outcomes at the MDT as a result of attending the workshop - the potential impact of using this model of training in comparison to other courses Initial feedback evaluation indicates that 100% of the delegates agreed that the programme was of value to their clinical practise and influenced how likely they are to contribute to the MDT. Emergent themes include perceived power relationships, confidence, self-efficacy and self-belief. Increased insight into own and others communication styles has been enlightening, with improved knowledge and confidence in assessing Performance Status. Post course online survey results are awaited which we are keen to share.

Conclusion:
This collaboration has proved very successful and repeat UYV Workshops for 2015 have been planned. Confidence / self-efficacy development for specialist practitioner roles and inter-professional working will be considered for future development. 1. http://www.hqip.org.uk/assets/NCAPOP-Library/NCAPOP-2014-15/HSCICNLCA-2014finalinteractivereport.pdf 2.http://www.shu.ac.uk/research/hsc/sites/shu.ac.uk/files/REVISED%20FINAL%20DRAFT%20GNC%20T%20LCNS%207%203%2014%20(2).pdf

Background:
Lung cancer is the most common smoking-related malignancy in the UK. Smoking cessation can improve survival, treatment efficacy and overall quality of life. The Lung Cancer Nurse Specialist (LCNS) is in a unique position to assess smoking history and the motivation/willingness of the patient to quit. The aim of this audit is to assess the effectiveness of the LCNS at assessing, actioning and documenting the smoking history and smoking cessation input of patients attending the Papworth Thoracic Oncology Service (PATHOS).

Methods:
A formic form was designed to include the audit criterion and aid data collection. Patients attending PATHOS from 01/09/2012 to 07/12/2012, with suspected or confirmed lung cancer, underwent a smoking assessment by one of 6 LCNSs.

Results:
Of 199 patients attending PATHOS 148 were suspected of having primary lung cancer. 118 (80%) had smoking audit forms completed by the LCNS. Of the 30 patients where no audit form was completed, 29 had smoking history recorded in nursing documentation and actioned as appropriate, 1 patient had no smoking history recorded. Expected audit standards of 100% were: All LCNSs (keyworkers) will have level 1 smoking cessation training - 83% (5/6) All patients assessed will have smoking assessment documented in holistic care plan - 80% (118/148) LCNS will discuss with all smokers the benefits of cessation and document - 100% (32/32) All smokers will be offered the NHS leaflet “It’s so much easier since I quit” or individualised Information Prescription and document in holistic assessment care plan - 97% (31/32) All smokers willing to consider quitting will be signposted to a smoking cessation service / GP clinic / National Helpline - 67% (18/27) Via audit forms received 16 (14%) patients never smoked, 70 (59%) ex-smokers, 32 (27%) current smokers. Of the current smokers the mean age to start smoking was 16.5 years. 21 (66%) smoked within 30 minutes of waking, 3 (9%) 31-60 minutes of waking and 8 (25%) after 60 minutes. 27 (84%) of smokers were willing to quit.

Conclusion:
Smoking cessation is an integral part of the LCNS role to help improve clinical outcomes and effectiveness. Meeting patients at various stages of the diagnosis and treatment pathway they are in a privileged position to affect change. Continued skill developments and improved understanding of smoking cessation strategies will increase their effectiveness. Recommendations: All LCNS to complete smoking cessation training level 1 and level 2 training within 1 year with annual update. Use: Ask / Assess / Advise / Assist / Arrange protocol to assist smoking cessation intervention. Nursing notes to include assessment of patient's progress in smoking cessation in order to monitor impact of intervention. Include smoking cessation advice as part of hospital Comissioning for Quality and Innovation (CQUIN).

Background:
Malignant Mesothelioma is a devastating disease associated with poor outcome and highly complex symptoms. The disease is frequently linked to past asbestos exposure, for many via occupational exposure. A Mesothelioma patient approached the lung cancer CNS expressing his wish to share his experience with others. Therafter, with the patient's consent, the content of this information continues to be used as an educational tool to enhance patient care.

Methods:
The format agreed was interview. Consent obtained. For maximum impact the interview was video recorded. It followed the patient story, told in his words from beginning to present: 1. Investigations and diagnosis 2. Treatment 3. The here and now It was very important to both authors that this be the patient’s story. Technical support used was recommended by Macmillan.

Results:
Diagnostic delays Angry cause occupational exposure. Imperitive doctors ask! Told Mesothelioma. No Cure. Devistated Prognosis 2 years: Chemotherapy recommended. ‘It was bad. If someone had said to me do you want to die, I would have said yes’. Lack of support group – all dying! Supportive lung nurses . Breathless – ‘Cannot walk anymore, have to take car’. ‘Unable to talk in groups, too breathless’. I’d rather put up with pain than take something stronger’ which takes away my quality of life. ‘Know things will get worse’. ‘I’m remote from my wife’. ‘I have a death sentence’. ‘I’m living it and at the end of it I’m gone’.

Conclusion:
A patient story is emotive and powerful. This story highlights in part the complexities associated with the Mesothelioma pathway. It also identifies various multifaceted difficulties patient’s face. This video is used as an educational tool for professionals in mesothelioma care within the UK.

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Abstract:
Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide, with a median survival that rarely exceeds 10–12 months in unselected patients with metastatic disease treated with conventional chemotherapy. In the last decade, identification of key genetic events driving tumor growth and metastatic spread led to the concept of oncogene-addiction. According to this model, the inhibition of certain molecular drivers by targeted agents could be effective in reducing tumor burden and improving patient survival. Several molecular alterations have been described in NSCLC, particularly in adenocarcinomas, especially, but not exclusively, in the never/ former smoker population. The most notable examples are the epidermal growth factor receptor (EGFR) activating mutations, mainly represented by deletion in exon 19 or the L858R substitution in exon 21, and the echinoderm microtubule protein like-4/anaplastic lymphoma kinase (EML4-ALK) translocation. Although only 12–15% of NSCLC tumors are EGFR mutated or ALK-rearrangement-positive, this translates into a considerable number of patients affected worldwide. In metastatic NSCLC, presence of EGFR activating mutations confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib. Indeed, nine large randomized trials comparing an EGFR-TKI versus standard platinum based chemotherapy have clearly demonstrated the superiority of the target agent in prolonging progression-free survival (PFS), improving response rate (RR) along with a more favorable safety profile. Similarly, in presence of EML4-ALK translocation, the ALK inhibitor crizotinib produces higher RR and longer PFS when compared to standard chemotherapy, both in first and second line setting. Unfortunately, no patient with metastatic oncogene-addicted NSCLC can achieve a definitive cure and after a median time of 8–12 months, all patients eventually develop acquired resistance to targeted therapy. So far, several studies of tumor samples obtained at the time of treatment failure have identified different potential mechanisms responsible for acquired resistance to targeted agents. In the majority of cases resistance is the consequence of a biological event occurring in the target (target-dependent acquired resistance), whereas in other cases acquired resistance is the consequence of the activation of other pathways (target-independent acquired resistance). As for EGFR mutant NSCLCs the emergence of the secondary T790M mutation in the tyrosine kinase domain of EGFR account for up to 60% of erlotinib or gefitinib failure, investigations have focused on the potential efficacy of a new class of drugs that could irreversibly inhibit T790M clones, with reduced activity against wild-type EGFR. This new class of agents includes several new drugs under clinical development, with rociletinib and AZD9291 to-date being the most promising. A large phase I-II study evaluated the efficacy of rociletinib in patients with EGFR mutations who progressed during previous treatment with an EGFR inhibitor. In patients with centrally confirmed T790M-positive tumors, RR was approximately 60% with a median PFS that exceeded 1 year. However, also patients whose tumors were T790M-negative gained some benefits from rociletinib with a RR of 29% and median PFS of approximately 6 months. In a phase I trial conducted in patients who failed first- or second-generation EGFR-TKI, AZD9291 produced a RR of 50%. Importantly, RR was 61% in patients harboring a T790M mutation, whereas in T790M-negative cases RR was 21% with a median PFS of only 3 months. Results of ongoing trials with rociletinib and AZD9291 will better clarify the role of third generation EGFR-TKIs in the treatment algorithm of EGFR mutant NSCLC. Similarly, for the vast majority of ALK positive NSCLCs, resistance is mediated by an ALK dominant mechanism, such as mutations in the kinase domain of ALK gene or ALK fusion gene amplification. So far, a number of mutations have been identified and they seem to confer different sensitivities to second-generation ALK inhibitors. In addition, there are an increasing number of patients for which disease progression occurs only in the central nervous system (CNS), supporting the hypothesis of an inadequate CNS drug penetration. Several novel and more potent second-generation ALK inhibitors are currently under investigations in clinical trials. Among them, ceritinib and alectinib gained the FDA breakthrough therapy designation for ALK-positive NSCLC due to the encouraging results that emerged from a phase I-II trials. Beyond EGFR mutations and ALK translocation, novel biomarkers have been linked with adenocarcinoma histology, including ROS1 fusion gene, MET amplification or mutations, BRAF and HER2 mutations, for which many targeted drugs are currently under investigation. ROS1 rearrangements and MET amplification represent two additional molecular aberrations candidate as predictors for crizotinib sensitivity. Indeed, results from expansion cohorts of the PROFILE 1001 phase I suggested the potential efficacy of crizotinib in lung cancer patients with ROS1 translocation or MET amplification. Another promising target is BRAF mutation, a rare event occurring in 1% to 3% of adenocarcinoma patients, including those with a history of smoking. Recently, combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib emerged as a suitable strategy in patients with BRAF mutant NSCLC. Dual BRAF/MEK axis inhibition translated into a RR of 63% with an acceptable toxicity profile. In conclusion, targeted agents are rapidly changing the natural history of NSCLC, with several new agents entering onto clinical practice. In the next few years, the major challenge will be to define the optimal sequence of targeted agents as well as their combination with novel strategies including immunotherapy.

Abstract:
Thymic malignancies represent a heterogeneous group of rare thoracic cancers [1, 2]. The histopathological classification distinguishes thymomas from thymic carcinomas. Thymomas are further subdivided into different types (so-called A, AB, B1, B2, and B3) based upon the atypia of tumor cells, the relative proportion of the associated non-tumoral lymphocytic component, and resemblance to the normal thymic architecture [3]. Thymic carcinomas are similar to their extra-thymic counterpart, the most frequent subtype being squamous cell carcinoma. The diagnosis of any thymic epithelial tumour relies on making the differential diagnosis with other anterior mediastinal tumours and non-malignant thymic lesions. Thymic epithelial tumours are routinely staged according to the Masaoka-Koga staging system, which is correlated with overall survival. Masaoka-Koga staging is a surgical pathology system that is assessable only after surgical resection of the tumour [4]. Recently, the International Association for the Study of Lung Cancer (IASLC) Staging Prognostic Factors Committee, together with the International Thymic Malignancy Interest Group (ITMIG), proposed a Tumour-Node-Metastasis (TNM)-based staging system for thymic malignancies, based on overall survival analyses of a retrospective international database of more than 10,000 cases [5]. The TNM-based approach has the advantage of being more appropriate both for thymoma and thymic carcinomas, which present with a higher propensity towards nodal and distant metastatic invasion. The management of thymic epithelial tumours is a paradigm of multidisciplinary collaboration. Systematic immunological check-up is recommended when a diagnosis of thymic epithelial tumour is suspected, including complete blood cells count with reticulocytes and serum protein electrophoresis, as well as anti-acetylcholine receptor and antinuclear antibodies tests. This is to make the diagnosis of the most frequent immune disorders associated with thymoma, the most frequent being myasthenia gravis, that may impact any therapeutic intervention, including surgery, radiotherapy, and chemotherapy. The treatment strategy is based on the resectability of the tumour [6]. The assessment of resectability is mostly based on the surgeon’s expertise; it is recommended to discuss indications for surgery in a multidisciplinary tumour board setting. The new TNM staging may even better help to formalize resectability: T1-3 level of invasion refers to structures amenable to surgical resection, when T4 level of invasion includes unresectable structures. If complete resection is deemed to be achievable upfront, as it is the case in Masaoka-Koga stage I/II and some stage III tumours, surgery represents the first step of the treatment, possibly followed by postoperative radiotherapy, and for carcinomas, chemotherapy. Standard approach is median sternotomy; minimally-invasive surgery is an option for presumed stage I and possibly stage II tumours in the hands of appropriately-trained thoracic surgeons. Current practices for postoperative radiotherapy are highly variable and there is paucity of prospective, multicentre evidence. The global trend over the past years has been towards a less frequent use of postoperative radiotherapy in thymoma, and to keep it in reserve for high-risk cases. This is based on recent reports from large databases, as well as pooled analyses of retrospective studies, indicating: 1) the absence of survival benefit after radiotherapy in stage I thymoma, or after R0/1 resection of stage II-III thymoma; 2) a similar rate of recurrence in patients who received postoperative radiotherapy or not after complete resection of thymoma; and 3) a recurrence-free and overall survival benefit with postoperative radiotherapy after resection of thymic carcinoma. If complete resection is deemed not to be achievable upfront on the basis of imaging studies, as it is frequently the case in Masaoka-Koga stage III/IVA tumours, a biopsy should be taken, followed by primary/induction chemotherapy as part of a curative-intent sequential strategy that integrates subsequent surgery or radiotherapy. Patients not eligible for local treatment receive palliative chemotherapy only. Cisplatin-based combination regimens should be administered; combinations of cisplatin, adriamycin and cyclophosphamide, and cisplatin and etoposide, are the recommended options [7]. Primary chemoradiotherapy with platin and etoposide is an option for thymic carcinomas. Innovative options may include KIT sequencing in the setting of potential access to specific inhibitors, particularly clinical trials; sunitinib may represent an off-label option as second-line treatment for thymic carcinomas, independently from KIT status, through antiangiogenic effects [8]. mTOR is emerging as a potential target in thymic epithelial tumours, following tumour responses observed in phase I-II trials. Ongoing trials are assessing immune checkpoint inhibitors for refractory thymic carcinoma. No prospective data are available to build recommendations about post-treatment oncological follow-up of patients. Follow-up may be continued for 10-15 years given the possible occurrence of late recurrences. Clinicians should be aware of the possible late onset of new autoimmune disorders. REFERENCES 1. Girard N, Mornex F, Van Houtte P, Cordier JF, van Schil P. Thymoma: a focus on current therapeutic management. J Thorac Oncol 2009;4:119-126. 2. Girard N, Ruffini E, Marx A, Faivre-Finn C, Peters S; ESMO Guidelines Committee. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; in press 3. Marx A, Ströbel P, Badve SS, et al. ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting. J Thorac Oncol. 2014;9:596-611. 4. Detterbeck F, Nicholson AG, Kondo K, et al. The Masaoka-Koga Stage Classification for Thymic Malignancies: Clarification and Definition of Terms. J Thoracic Oncol 2011; 6:S1710-6. 5. Detterbeck FC, Stratton K, Giroux D, et al; Staging and Prognostic Factors Committee; Members of the Advisory Boards; Participating Institutions of the Thymic Domain. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014;9:S65-72. 6. Detterbeck FC, Moran C, Huang J, et al. Which Way is Up? Policies and Procedures for Surgeons and Pathologists Regarding Resection Specimens of Thymic Malignancy. J Thoracic Oncol 2011;6:S1730-1738. 7. Girard M, Lal R, Wakelee H, et al. Chemotherapy definitions and policies for thymic malignancies. J Thorac Oncol 2011;6: S1749-1755. 8. Rajan A, Girard N, Marx A. State of the art of genetic alterations in thymic epithelial tumors. J Thorac Oncol 2014;9:S131-136

Abstract not provided

Abstract:
Lung cancer represents the major causes of cancer death in the industrialized countries. Non-small cell lung cancer (NSCLC) accounts for nearly 80% of all lung cancer cases. While in the early stages I and II surgery has been accepted as the major curative therapy, most of patients with NSCLC and major airway and vascular obstruction have an IIIB disease and rarely can be cured by local treatment modalities like surgery or radiotherapy alone. T4 tumors may include the mediastinal organs such as the vena cava, pulmonary artery, thoracic aorta, left atrium, carina and trachea. However the extend of the disease is usually made by radiological methods as computed tomography (CT), magnetic resonance imaging (MRT) or fusioned positron emission tomography and CT-scan (PET-CT) and the correlation between radiologic and pathologic findings is very low. Combined resection of the lung and major vessels or central airways for lung cancer remains challenging in terms of technical aspects and prognosis, because the local advanced disease comprises different subgroups with distinguishable clinical problems and necessary treatment decisions. In the surgical treatment of lung cancer invading the superior vena cava (SVC), the pattern of invasion was considered to be a significant prognostic factor. Patients who underwent partial SVC resection had a significantly higher probability of survival and there was a trend towards later recurrence in patients who had induction treatment. Also survival of patients with N2 disease was significantly worse than those with localized N0/N1 nodal status (1). For combined resection of thoracic aorta and primary lung cancer only studies with small number of cases are reported. The most patients received an adventitia resection or a patch graft repair of the defect in the aortic wall. For a smaller group total replacement of the descending aorta with an artificial vessel was reported, recent report indicated the placement of endoluminal prosthesis 1-3 weeks before surgery. Operative deaths occur in 0-24%, the 5 year survival ranged between 17% and 50%. Survival was only depended on mediastinal nodal involvement (2). Direct invasion of the left atrium (LA) has generally a significantly worse prognosis than patients with great vessels invasion. Patients who undergo LA resection have higher mortality and morbidity rates compared with those who had pneumonectomy alone. Median survival rate is 10 months, the 5-yearsurvival 14-16%. Palliative incomplete resection of T4 disease has not shown any survival benefit (3). Patients with localized invasion of the carina or/and distal trachea may be able to be completely resected despite their T4 classification. Extraluminal extension of the tumor found in CT-scan was associated with unresectability. In general, patients benefit from surgery, when a radical resection and systematic lymph node dissection can be achieved with low morbidity and mortality (4). For inoperable patients, palliative treatment with laser desobliteration, stent implantation or photodynamic therapy can be added to the standard chemoradiotherapy. Surgery in the treatment of lung cancer invading the great vessels, LA and major airways may improve survival only in selected patients. Induction treatment and new drugs may increase the number of potential candidates for surgery and improve survival. Preoperative every possible effort should be made to achieve an adequate evaluation of N-status. Complete resection is important and patient’s functional status must be compatible with the extent of resection and reconstruction. Literature Suzuki K, Asamura H, Watanabe S et al. Combined resection of superior vena cava for lung carcinoma: prognostic significance of patterns of superior vena cava invasion. Ann Thorac Surg 2004; 78:1184-9 Shiraishi T, Shirakusa T, Miyoshi T, et al. Extended resection of T4 lung cancer with invasion of the aorta; is it justified? Thorac Cardiovasc Surg 2005,53:375-9 Fukuse T, Wada H, Hitomi S. Extended operation for non-small cell lung cancer invading great vessels and left atrium. Eur J Cardiothorac Surg 1997; 11:664-9 Yildizeli B, Dartevelle PG, Fadel E, et al. Results of primary surgery with T4 non-small cell lung cancer during a 25-year period in a single center: the benefit is worth the risk. Ann Thorac Surg 2008, 86:1065-75

Abstract:
With the improvement of treatment efficacy, quality of life and sexual functioning after cancer treatment have become very important. Sexual well-being may be altered by both the diagnosis and the treatment of cancer. This in turn can have a deleterious impact on quality of life. Sexual dysfunction in cancer patients may result from biological, psychological and social factors (1). Biological factors such as anatomic alterations (rectum or penile amputation), physiological changes (hormonal status) and secondary effect of medical intervention may preclude normal sexual functioning even when sex desire is intact. Side effects of chemotherapy such as nausea, vomiting, fatigue, hair loss can result in adverse effects on sexuality together with disfiguring surgery (mastectomy, colostomy). Negative emotional states such as anxiety, depression, anger may also disrupt sexual activity (1). Disturbances of body image can contribute to the development of sexual dysfunction as well. Radiotherapy and radical prostatectomy are the most effective treatments for prostate cancer. Erectile dysfunction is reported in 6-80% after external-beam radiotherapy and 2-61% after brachytherapy. Erectile dysfunction after surgery is reported in 40-70% after nerve-sparing techniques and 100% in non-nerve-sparing techniques, and it occurs immediately after surgery. Ejaculation problems and libido decrease occur in up to 80%. Vascular, neurogenic and psychogenic factors are all important etiologic factors (1-3). Similar data are reported after treatment of bladder and colorectal cancer in males. Testicular cancer affects young men in their fertile and sexually active life. Retrograde ejaculation, erectile dysfunction, loss of libido, decreased orgasm and body image impairment are often reported after treatment (1,4). Surgery and radiotherapy for gynaecological cancer can alter vaginal sensation and may cause stenosis leading to painful penetration (1,3,5). These treatments lead to ovarian suppression, with vaginal discharge, dryness, dyspareunia and a loss of sexual interest. Only 50% of the females is still sexually active after cancer treatment (1). There is often fear of pain and of urine or faeces incontinence during sexual activity. Similar complaints are reported after treatment of colo-rectal and anal cancer in women. There is no data on the effects of treatment for lung cancer on sexual functioning. Though it is to be expected that these patients, both males and females, can report sexual dysfunction as a result of chemotherapy, social and psychological factors (distress, depression). For several reasons sexual counseling has not become a routine part of oncology care in most hospitals (6). There is a time constraint: in busy oncology clinics, where the outpatient visit is focused on addressing prognosis and treatment, physicians do not have time to assess quality of life. Another barrier is the discomfort physicians, and patients, have to discuss sexuality. The great majority of oncology professionals are scared to address sexuality and the great majority of sexological professionals are scared by cancer (7). Sexual counseling should be routinely provided in an oncology clinic having a health care professional (physician, or oncology nurse specialist) to evaluate and discuss quality of life matters, including sexual dysfunction, and possible treatments. In most cases patients do not require extensive medical or psychological treatments, but they need information about the impact of cancer treatment on sexuality (6). Patients, and partners, are often uninformed about the anatomy of sexual organs, therefore they have to be counseled on the effects that treatment has on the sexual organs. Several questionnaires are available to evaluate sexual functioning in both males and females (1). Recently a specific questionnaire on sexual functioning after treatment of cancer has been developed in the USA, but has not been validated yet in other countries (8). The 3rd International Consultation on Sexual Medicine appointed for the first time in 2009 a Committee on chronic illness (including cancer) and sexual medicine. The recommendations of that committee are very useful in helping to develop research programs in oncology and sexual medicine (9). Sexual dysfunction is often unrecognized, underestimated and untreated. Cancer affects quantity and quality of life. The challenge for physicians and other health care professionals is to address both components with compassion (7). References 1. Sadovsky R, Basson R, Krychman M, et al. Cancer and sexual problems. J Sex Med 2010;7:349-373. 2. Incrocci L, Slob AK, Levendag PC. Sexual (dys)function following radiotherapy for prostate cancer: a review. Int J Radiat Oncol Biol Phys 2002;52:681-693. 3. Incrocci L, Jensen PT. Pelvic radiotherapy and sexual function in men and women. J Sex Med 2013;10 Suppl 1:53-64. 4. Wortel RC, Ghidey WA, Incrocci L. Orchiectomy and radiotherapy for stage I-II testicular seminoma: a prospective evaluation of short-term effects on body image and sexual function. J Sex Med 2015;12:210-218. 5. Jensen PT, Groenvold M, Klee MC, et al. Longitudinal study of sexual function and vaginal changes after radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2003;56:937-949. 6. Schover LR. Counseling cancer patients about changes in sexual function. Oncology 1999;11:1585-1591. 7. Incrocci L. Talking about sex to oncologists and cancer to sexologists. J Sex Med 2011;12:3251-3253. 8. Flynn KE, Lin L, Cyranowski JM, et al. Development of the NIH PROMIS® Sexual Function and Satisfaction measures in patients with cancer. J Sex Med 2013;10 Suppl 1:43-52. 9. Montorsi F, Adaikan G, Becher E, et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2010;7:3572-3588.

Abstract:
Approximately 30-40% of patients with advanced lung cancer develop bone metastases, but as the newer therapies are extending survival, the chance of developing bone metastases increases. Bone metastases cause skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia – all of which can have debilitating consequences (including pain) affecting patients' health-related quality of life (HR-QOL) and performance status (PS)[1]. Bone metastases are the most common cause of cancer-associated pain in patients with advanced malignancies[2]. Poor PS prevents the patients from receiving further lines of treatments available today. SREs are associated with increased economic costs. In one clinical trial, the median time to first SRE was only 5 months[3]. Early detection of bone metastases can prevent SREs and avoid inappropriate implementation of major surgery or chemoradiation therapy. With the new generation bisphosphonate zoledronic acid or denosumab (anti-RANKL activity), one can reduce the number of patients who experience SREs, decrease the annual incidence of SREs, and delay the median time-to-first SRE[3]. These agents are effective even after the onset of SREs. They are well tolerated, with manageable side effects. The biochemical markers of bone metabolism especially N-telopeptide of type I collagen (NTX) and bone specific alkaline phosphatase (BALP) can be both prognostic and predictive markers for the patients with bone metastases from NSCLC[4-6]. Anticancer activity of zoledronic acid and denosumab further supports their use as soon as bone metastases are diagnosed in patients with non-small cell lung cancer (NSCLC). Further trials will inform us about the efficacy of these agents for prevention of bone metastases and even about possible effects on visceral metastases, with a significant impact on overall survival[7, 8]. These trials will be discussed, as well as the explanation for the longer survival on the bone-targeted agents. The new targeted agents which are being investigated will be mentioned too[9, 10]. References 1. Coleman RE (1997). Skeletal complications of malignancy. Cancer 80 (suppl.): 1588- 1594 2. Mercadante S (1997). Malignant bone pain: pathophysiology and treatment. Pain 69: 1-18. 3. Rosen LS, Gordon D, Tchekmedyian S, et al (2003). Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial – the Zoledronic Acid Lung Cancer and other Solid Tumors Study Group. J Clin Oncol 21: 3150-3157. 4. Coleman RE, Major P, Lipton A, et al (2005). Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonatezoledronic acid. J Clin Oncol 23: 4925-4935. 5. Lipton A, Cook R, Saad F, et al (2008). Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 113: 193-201. 6. Hirsh V, Major PP, Lipton A, et al (2008). Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol 3: 228-236. 7. Luo FR, Camuso A, McGlinchey K, et al (2005). Evaluation of anti-osteoclastic activity of the novel, oral multi-targeted kinase inhibitor Dasatinib (BMS- 354825). AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, November 14-18, 2005, Philadelphia, PA, p173 [Abstract B178]. 8. Borgstein NG, Yang Y, Condon CH, et al (2008). ACE-011, a soluble activin receptor type IIA IgG-Fc fusion protein decreases follicle stimulating hormone and increases bone- specific alkaline phosphatase, a marker of bone formation in postmenopausal healthy women. Cancer Research 69 (2 Suppl): Abstract 1160. 9. Hellerstedt BA, Edelman G, Vogelzang NJ, et al (2012). Activitiy of cabozantinib (XL 184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 30(suppl): Abstract 7514. 10. Parker C, Nilsson S, Heinrich D, et al (2013). Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New Engl J of Med 369(3): 213-223.