Virtual Library

Background
The updating of written clincial practice guidelines regularly is difficult and expensive. New evidence in cancer treatment is published frequently. Guideline booklets are difficult to disseminate widely and stakeholder feedback is mainly pre-publication. To enable lung cancer guidelines to be rapidly updated and widely disseminated and therefore more likely to be utilised, Cancer Council Australia developed a web-based wiki platform for guidelines and is evaluating its impact.

Methods
The initial methodology paralled the steps in published written guideline development but these were integrated with the wiki capability. An expert group, whose competing interests were documented, were identified, the key clinical questions and search strategies were developed for each question and literature searches recorded on the wiki. An online literature screening and critical appraisal process was developed. This provides data on which papers were used to form the guidelines and why papers were either selected or rejected depending on their quality. Evidence-based recommendations were formulated and evidence tables automatically generated. The wiki was closed in that only the invited experts could write or change a guideline but any stakeholder could comment on the guidelines at any time and the writing group would review and respond to comments. The initial vesion of the guidelines were distributed for targetted review by expert groups. We used web analytics to monitor usage. The writers remain engaged to appraise new papers and update the guideline rapidly as necessary. All previous versions could be accessed.

Results
Evaluation of the lung caner treatment guidelines developed on the wiki, showed that 22 authors had identified 67 clinical questions covering treatment of all stages of lung cancer. The literature search and screening process resulted in 2035 potentially relevant articles being forwarded for detailed methodological evaluation with another 571 added through snowballing and other methods. To fine-tune the initial draft content, the working party used the wiki to exchange 156 internal comments in 9 weeks. When the guidelines were released for the initial 30-day public consultation period, 1055 users visited lung cancer content pages. The majority of users (487) accessed the guidelines directly as a result of targeted emails, while 387 found the site by Google searches. Most respondents were from Australia (799) and New Zealand (60) with the United States (47) having the largest user group of respondents from the other countries who visited the site. A survey of the usability of the site indicated widespread acceptance. The average time on a content page was 1:27minutes. The landing page was the most popular content page with 3426 page views and an exit rate of 18.85%, which indicates that the landing page served as an important tool for visitors to navigate the guidelines. To date there were 38 external comments which occasioned 31 edits by the working party.

Conclusion
Adopting a platform built on MediaWiki, and moving to electronic guidelines has allowed rapid updates as new evidence becomes available and wider dissemination than print formats. The next strategy to boost uptake is to write Qstream education modules to accompany the guidelines.

Background
The “CLiC” Study seeks to characterise cough and identify its predictors using subjective and objective cough assessment tools, including the recently validated Manchester Cough in Lung Cancer Scale (MCLCS). Results will enable the identification of robust endpoints and therapeutic targets for novel antitussive interventional trials.

Methods
Patients with lung cancer (LC) and complaining of cough were recruited irrespective of stage and treatment, from two cancer centres. Demographic and clinical data were collected. Patients completed the MCLCS, Cough Severity Diary (CSD), cough severity Visual Analogue Scale (VAS) and the Brief Reflux Inventory (BRI, a validated 5-item questionnaire assessing gastro-oesophageal reflux disease (GORD)). The oncology specific European Organization for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 with the module (LC13), (including item 31: "In the past week, how often did you cough?") was also completed. Cough was graded according to Common Toxicity Criteria for Adverse Events (CTCAEv4.0). A sample size of 178 patients was required for analysis of 160 (based on Peduzzi J Clin Epidem 1996) for 10 participants per correlate per outcome in binary logistic regression, assuming a 10% attrition rate, the prevalence of severe cough to be 50% and 8 cough predictors.

Results
We recruited 179 patients (Oct'11-Nov'12). The median age was 65 yrs (range 25-83 years), with 53% patients male. The majority (79%) had non small cell lung cancer (NSCLC) and advanced stage disease (>IIIA 60%). In total, 36% were receiving cancer therapy at entry. Overall, 60% felt their cough warranted treatment. Having ensured validity of the cough assessment tools, the mean cough severity score (VAS) (n=171) was 43.4mm (SD 29.6). The mean cough-specific QoL score (MCLCS) was 25.3 (SD 8.8, with a range 1-50, high scores representing worse QoL).

Table showing association between cough predictors and cough severity (VAS) and cough specific QoL (MCLCS) scores on univariate analysis[*]
	Cough Severity (VAS)	Cough Specific QoL (MCLCS)	Comment
Age (≤70yrs vs >70yrs)	p=0.365#	p=0.834#
Gender	p=0.048#	p=0.171#	women worse cough severity
Smoking Status (current, ex, never)	p=0.191##	p=0.356##
Performance Status (WHO PS 0-3)	p<0.0001##	p<0.0001##	poorer PS worse cough severity poorer PS worse cough related QoL
Histology (NSCLC vs SCLC)	p=0.348#	p=0.274#
Stage (early vs advanced)	p=0.358#	p=0.301#
Tumour Location (central vs peripheral)	p=0.486#	p=0.040#	central tumours poorer cough related QoL
COPD (Chronic Obstructive Pulmonary Disease) (self-reported)	p=0.578#	p=0.128#
LRTI (Lower Respiratory Tract Infection) (self-reported)	p=0.022#	p=0.044#	LRTI worse cough severity LRTI worse cough related QoL
Asthma (self-reported)	p=0.021#	p=0.054#	asthma worse cough severity
GORD (BRI questionnaire)	p<0.0001#	p<0.0001#	GORD worse cough severity GORD worse cough related QoL
Nausea (EORTC QLQ C30)	p=0.004##	p=0.017##	Increased nausea worse cough severity. Increased nausea worse cough related QoL
Oral Steroids	p=0.434#	p=0.017#	On steroids worse cough related QoL
Over the Counter Antitussives	p=0.011#	p=0.067#	On antitussives worse cough severity
Opiates	p=0.497#	p=0.018#	On opiates worse cough related QoL
*Not all analysed cough predictors shown # Mann-Whitney-U Test ## Kruskal-Wallis Test

Conclusion
This is the largest single study to use validated cough-specific assessment tools in LC to characterise and assess potential influences on cough. LC patients have a severe cough, with comparable VAS scores to those of patients presenting to specialist chronic cough clinics. New antitussive therapies are needed. Key predictors of cough severity and reduced cough-specific QoL are performance status (PS), nausea and GORD. Preclinical research suggests that the neurokinin-1 pathway may mediate the vagal cough reflex pathway. Our results further support this hypothesis and imply that the neurokinin-1 pathway may be a relevant therapeutic target. The association with GORD may be explained by the shared vagal innervation of the airway and upper gastrointestinal tract.

Background
Cough is a common lung cancer (LC) symptom, yet effective therapies are lacking. The development and testing of novel therapies relies upon appropriate tools for the assessment of cough. CLiC is the first study to evaluate two new tools 1) objective ambulatory cough monitoring (ACM) from acoustic recordings (VitaloJAK™) and 2) the Manchester Cough in Lung Cancer Scale (MCLCS) quality of life (QoL) questionnaire. These provide complementary assessments of cough frequency and its impact upon the patient.

Methods
Patients with LC and complaining of cough were recruited, irrespective of stage or treatment, from two cancer centres. Demographic and clinical data were collected. All patients completed the MCLCS, Cough Severity Diary (CSD) and cough severity Visual Analogue Scale (VAS). The European Organization for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ) C30 with the module (LC13), (including item 31: "In the past week, how often did you cough?") was also completed. The Common Toxicity Criteria for Adverse Events (CTCAEv4.0) was used to grade cough. A subgroup underwent ACM and MCLCS on Days 0&60.

Results
We recruited 179 patients (Oct'11-Nov'12): median age 65yrs (range 25-83 years), 53% male. Majority (79%) had non small cell lung cancer, 60% advanced stage (>IIIA), 36% were on cancer therapy.

Table showing correlations between subjective cough assessment tools
	EORTC QLQ C30 cough item 31	CTCAE Cough Grading	MCLCS Manchester Cough LC Scale	CSD Cough Severity Diary
VAS Cough Severity	0.54**§ n=171	0.50**§ n=170	0.67**§ n=163	0.70**¥ n=84
EORTC QLQC-30 cough item Q31		0.45**§ n=173	0.57**§ n=165	0.52**§ n=85)
CTCAE Cough Grading			0.56**§ n=164	0.59**§ n=85
MCLCS Manchester Cough LC Scale				0.76**¥ n=82
** p<0.0001 ¥high correlation §moderate correlation

Table showing correlations between objective ACM and subjective cough tools
	VAS Cough Severity	MCLCS Manchester Cough LC Scale	Log Cough/hr Asleep	Log Cough/hr Awake	Log Cough/hr 24-hour
VAS Cough Severity		0.73** n=37	0.33* n=37	0.61** n=37	0.57** n=37
MCLCS Manchester Cough LC Scale			0.24 n=35	0.51* n=35	0.44* n=35
Log Cough/hr Asleep				0.52** n=35	0.62** n=35
Log Cough/hr Awake					0.97** n=37
** p<0.0001 * p<0.05

Intra-class correlations demonstrated good repeatability over time between Days 0&60 for cough frequency (24hour: r=0.77, p<0.0001, awake: r=0.79, p<0.0001, sleep: r=0.66, p=0.004) and MCLCS: r=067,p<0.001 .The median cough scores/hour were 14.1(24hour: range 0.7-156), 18.5 (awake: range 1-233) and 6.0 (asleep: range 0-110).

Conclusion
We have demonstrated moderate to strong correlations between established measures of cough and two novel assessment tools, suggesting the validity of MCLCS and ACM. Their good repeatability suggests they have excellent potential for the assessment of novel treatments in future intervention studies for LC-related cough. In contrast, standard oncology tools are blunt and poorly discriminate cough.

Background
Patients with newly diagnosed advanced lung cancer may experience severe impacts on their quality of life (QOL). However, relatively few studies have examined the longitudinal patterns of QOL and their relationship to patients’ symptoms during the first 12 months of cancer diagnosis. Thus, the purposes of this study were to (1) examine the overall pattern and the potential sub-patterns (if any) of QOL in these patients during the first 12 months of cancer diagnosis; and (2) identify those important characteristics of each QOL sub-pattern and their relationship to patients’ symptoms.

Methods
This is a 12-month prospective longitudinal study. Newly diagnosed advanced lung cancer patients (Stage IIIB & IV) were eligible to be recruited and followed for 12 months on 5 time points (Pre-treatment, 1, 3, 6 and 12 months since treatments). The overall QOL was measured by the overall QOL item in the EORTC QLQ-C30 (0-100 scoring, higher is better). The QOL patterns and factors related to the patterns were analyzed by Latent Class Growth Analysis (LCGA). Potential factors (independent variables) used to predict the overall QOL change and each QOL sub-pattern (dependent variables) included: physical function, selected symptoms, emotion distress, self-efficacy (on coping with cancer) and important demographic and treatment related variables.

Results
A total of 200 subjects completed the 5 follow-up assessments. Generally, patients had moderate level of QOL across the 12 months. There were three QOL sub-patterns were identified. In the pattern I (around 50% of subjects), patients reported moderate to relatively good levels of QOL (scoring around 70-80) across the 12 months. In the pattern II (around 45% of subjects), patients reported moderate levels of QOL (scoring around 50-70 QOL). In the pattern III (<10% subjects), patients reported poor level of QOL (scoring around 40 or less). Overall, symptoms including fatigue, pain, lack of appetite and dyspnea were significantly related to the changes of QOL. Other factors also included psychological distress, uncertainty and self-efficacy (level of confidence) in coping well with lung cancer.

Conclusion
The results provide a relatively comprehensive picture about the overall QOL and the sub-patterns of QOL for those newly diagnosed advanced lung cancer patients. The results further support the giving timing and tailoring interventions are needed to better improve lung cancer patients’ QOL. (Acknowledgement: National Health Research Institute,NHRI,Taiwan).

Abstract not provided

Background
Breathlessness in patients with lung cancer is common symptom affecting 50-70% of patients, rising to 90% for those with advanced lung cancer. Managing breathlessness is complex, treatment options are limited and treatments are sometimes unsuccessful. Inspiratory muscle training (IMT) is a non-pharmacological method that has shown positive results in Chronic Obstructive Pulmonary Disease and mixed results in other respiratory illnesses. As this treatment method has never been tested in patients with lung cancer, the aim of the current study was to assess how feasible this treatment is in the lung cancer population and explore changes in outcome variables, before launching a larger randomized trial.

Methods
Pilot feasibility randomized trial in patients with lung cancer having stable disease. The experimental group received training using a pressure threshold device (commercially available from Phillips Respironics). Patients were instructed to do 5 sessions weekly for 12 weeks for a total of 30mins per day, divided over 2 sessions. Patients in the control group received standard care and received the treatment at the end of their trial participation. Outcome measures were completed at baseline and monthly for 3 months, and included: physiological parameters (FEV1,FVC); perceived severity of breathlessness in six 10-point VAS assessing average breathlessness over past 24 hours, worst breathlessness over past 24hrs, breathlessness now, distress from breathlessness, ability to cope with breathlessness and satisfaction with breathlessness management; modified Borg scale; quality of life using the short form-Chronic Respiratory Disease Questionnaire (with subscales on dyspnea, fatigue; emotional function and mastery of breathlessness); Hospital Anxiety & Depression Scale, and safety.

Results
46 patients (M=37, F=9) at a mean age of 69.5 years old and a mean of 16 months post-diagnosis who were not currently receiving chemotherapy/radiotherapy were recruited from 3 centres in the UK and Cyprus. Seventy-percent had NSCLC and advanced disease. There were no changes in FEV1 and FVC levels between groups. There were time by intervention interaction effects in average breathlessness and worst breathlessness in past 24hrs (p<0.01) with the intervention arm showing stable breathlessness and the control group deteriorating, but no between-group differences. Statistical and clinically important differences were seen with regards to ability to cope with breathlessness (p=0.02), satisfaction with breathlessness management (p=0.024), fatigue (p=0.007), emotional function (p=0.006), breathlessness mastery (p=0.031), anxiety (p=0.027) and depression (p=0.048). The m-Borg difference between the 2 groups at 3 months was 0.80, which is borderline clinically significant but not statistically significant. Changes were more evident in the 3-month assessment. IMT was safe with only a small number of patients complaining of muscle fatigue and dizziness.

Conclusion
This trial shows the IMT is feasible and safe in patients with lung cancer with significant benefits particularly in their ability to cope with breathlessness and emotional distress. The details of this trial allow us to refine the treatment protocol and findings guarantee a fully-powered larger trial (N should be around 196 with m-Borg as primary outcome).

Background
Central airway obstruction is seen in around 30% of patients with primary lung cancer. This is often a life-threatening presentation of the disease due to imminent airway loss and therefore requires urgent intervention. Direct bronchoscopic techniques including airway stenting can offer an immediate improvement in symptoms and quality of life, in addition to providing time for further treatment modalities. Here we report outcomes from a large single centre five year experience of tracheobronchial stent insertion for palliation of advanced primary lung cancer.

Methods
A retrospective review of all patients undergoing tracheobronchial stent insertion between January 2007 and January 2012 was performed. Patients undergoing stent insertion for benign or secondary malignant disease were excluded. A total of 70 patients underwent 80 stenting procedures with an average age of 66 years. Patient notes were used to collect patient demographic, disease and stenting data. Outcomes included post-procedure length of stay, complications, need for further intervention and overall survival.

Results
Disease was identified within the trachea in 18 cases, bilaterally within the bronchi in 10 cases and in the left or right bronchus in 23 and 28 cases respectively. Expandable, nitinol stents were used for all patients with either a proximal or distal release system. Uncovered stents (57), covered stents (20) or a mixture of the two (3) were placed. The average length of stay was 2.5 days (range 0-17); however, 69% of patients were discharged on the same day or on day one following the procedure. There were no cases of stent migration identified. The most common complication was retained secretions requiring repeat bronchoscopy which occurred in 5 cases. One patient required telescopic insertion of a second stent due to malposition of the first. Median survival was 2.6 months with a 20% one-year survival. There were 4 in hospital deaths.

Conclusion
Central airway obstruction secondary to primary lung cancer can cause disabling dyspnoea and impending suffocation. Interventional bronchoscopic techniques, in particular airway stenting, can provide immediate relief of these symptoms. The survival data here reflects the advanced stage of disease in this patient group and, although unlikely to improve survival, airway stenting can offer the opportunity for further adjuvant treatment in some cases. More importantly perhaps, 91% of patients were discharged home following the procedure allowing an improved in quality of life. In our experience, tracheobronchial stent insertion can be used effectively to achieve these outcomes with minimal complications and a short hospital admission. Figure 1

Background
Tracheobronchial stent insertion is safe and effective in managing central airway obstruction in advanced lung carcinoma. Airway stenting offers both immediate relief of severe dyspnoea and time for adjuvant therapy. It is commonly used in specialist thoracic centres with a variety of stent models employed. A large number of centres still use fluoroscopic guidance for stent positioning, leading to increased radiation exposure for both patients and staff. The aim of this study was to compare outcomes in patients undergoing stent insertion with or without radiological guidance.

Methods
70 patients were identified who underwent a total of 79 stent procedures. The cohort was divided into two groups based on whether stents were inserted under radiological guidance or direct vision at bronchoscopy. Retrospective analysis of notes was performed to collect data with regards to stenting strategy and post-operative course. The primary outcomes were length of stay, complications, repeat procedure and survival.

Results
Of the 79 stent procedures, 41 were with radiological guidance (group 1) and 38 were under direct vision only (group 2). There was an equal distribution with regards to the position of the stents (Table 1). Both techniques were well tolerated with minimal complications and no stent migration. Post-procedure length of stay was 2.73 days in group 1 and 2.26 days in group 2, with no significant statistical difference seen (p=0.93). There was also no difference in need for further stent intervention. A comparison of survival is shown in Figure 1. Figure 1 Figure 2

Conclusion
Airway stenting is a vital technique in the management of impending central airways obstruction. Although traditionally carried out under radiological guidance, we found no differences in complications, need for repeat procedure or survival when using direct vision. This not only saves radiation exposure to patients and staff, but also improves the cost-effectiveness and logistics of planning these urgent cases.

Background
Amino-biphosphonates are third-generation bisphosphonates which act by inhibition of osteoclasts. We have presented at two previous ATS conferences (Dimitroulis I.A. et al 2009, 2011), the role of each amino-biphosphonate separately. We set out to investigate the superiority or inferiority of Ibandronic acid (Ibandronate) over Zoledronic acid (Zoledronate), in terms of efficacy in reducing bone pain, and complications in patients with skeletal metastases due to Lung Cancer.

Methods
Ninety six patients with Skeletal Metastases due to Lung Cancer were enrolled, and were randomized on a 1:1 basis to receive infusions of Ibandronate (50 pts) or Zoledronate (46 pts) intravenously, every 21 days. Infusion time for Zoledronate (4mg) was 15 minutes, and for Ibandronate (6mg) one hour. Patients (pts) were analysed for pain relief, skeletal-related events (SREs) and adverse events. All pts underwent dental and cardiac examination before enrollment, and completed blood tests every 21 days. Bone scan was performed every 6 months. Blood tests (including close monitoring of calcium levels and renal function) were performed before each amino-biphosphonate administration.

Results
Patients in both arms were well matched for their diagnosis, stage of disease, burden of skeletal disease, and performance status. Median follow-up was 24 months. At 24 months, mean increases in British Pain Inventory pain scores were lower with Zoledronate compared to Ibandronate (0.43 vs 0.89 [p=0.03]). Analgesic effect as defined by the 4 point analgesic scale was less with Zoledronate as compared to Ibandronate. Incidence of SREs was not significantly different between two arms (35% for Zoledronate vs 38% for Ibandronate [p=0.2]). Median time to the first SRE was not reached in either arm. At 18 months of median follow up, percentages of patients with skeletal-related events were 41% in the Zoledronate arm vs 45% in the Ibandronate arm (p=0.05). Zoledronate caused fever in six (12%) patients and hypocalcemia in one patient. Ibandronate caused hypocalcemia in one patient (2.2%). No cases of jaw osteonecrosis, atrial fibrillation or renal failure (all of them possible side-effects of amino-biphosphonates) were observed.

Conclusion
Zoledronate is the preferred amino-bisphosphonate for its shorter infusion time, availability and relative benefits. It is slightly better than Ibandronate in reducing bone pain and preventing skeletal-related events. The only possible drawback is that, locally, Zoledronate is 1.3 times more expensive than Ibandronate (according to the mean European Economic Community price).

Abstract not provided

Background
The median survival of patients with advanced stage malignant pleural mesothelioma (MPM) ranges between 9 and 12 months after diagnosis, regardless of the recent achievements with systemic therapies combining cisplatin and antifolates such as pemetrexed or raltitrexed. Since MPM is a relatively rare malignancy and early pre-neoplastic lesions are clinically difficult to be identified, the understanding of molecular pathogenesis including sequential accumulation of genetic/epigenetic alterations for MPM development has lagged behind other common malignancies. According to the COSMIC database the most frequently mutated genes in MPM include CDKN2A, NF2 and BAP1, followed by other 12 genes having been found mutated in a fraction of MPM cases (c-MET, VHL,WT1 among others). Clearly, a better and more systematic understanding of the role of genomic alterations in MPM is needed. In this retrospective study, a consecutive series of 123 formalin-fixed, paraffin embedded (FFPE) MPM tissue samples with clinical annotates, collected at two institutions, was retrospectively analyzed through Next-Generation Sequencing (NGS) technology to enhance knowledge about tumor-specific genomic profiling.

Methods
Genomic DNA was extracted by tumour microdissected FFPE samples for all 123 patients. Amplicons NGS libraries for 50 Oncogene included in Ion AmpliSeq™ Cancer Hotspot Panel (CHP) v.2 were generated as indicated by manufacturer, and sequenced in Personal Genome Machine IonTorrent. Variant Caller included in Torrent Suite Software was utilised to identify mutations in the samples, annotation was performed with Annovar software. Genomic analysis for BAP1 and NF2 (not included in the CHP) is separately ongoing.

Results
Of 123 advanced stage MPM patients, all treated with pemetrexed-based chemotherapy, 70% were males, current smokers 50%, median age 66.5 (range 36-82) years and histological subtypes were 96/22/5 epithelioid/biphasic/sarcomatous. With a cut off for allele frequency(AF)>=10% a total of 966 non-synonymous, 8 del-ins, 62 nonsense, 637 intronic, 204 regulatory and 1140 synonymous somatic sequence variations were detected in 107 patients already screened. Excluding synonymous mutations and irrespective of AF, the five most frequently altered genes were CSF1R (mut:154, pts:80), KDR (mut:148, pts:73), FLT3 (mut:132, pts:99), PIK3CA (mut:126, pts:60), TP53 (mut:111, pts:66). Evaluating mutations identified at least once, a correlation between HRAS and PIK3CA mutations and patient status (dead or alive) was observed (p=0.017 and p=0.039, respectively). Specifically, HRAS silent mutation p.H27H (rs12628) was responsible for the association (p=0.021) and occurred in 54% of 107 MPM compared to 30% of reported AF in available databases. PIK3CA p.I391M missense mutation (rs2230461; AF 24% in this series) was significantly associated to progression-disease (p=0.003). Among the other SNPs reported in at least 15 pts there are rs3729674(PIK3CA), rs1800863(RET), rs3822214(KIT), rs10006115(KDR), rs75580865(FLT3) and rs5030613(SMARCB1).

Conclusion
These extremely preliminary data indicate that NGS technology is feasible in FFPE MPM tissues and some of the detected genetic mutations are novel observations of potential prognostic and therapeutic interest.

Background
Following our publication (Cancer Immunol Immunother 2011) demonstrating the prognostic importance of chronic inflammatory cell infiltration in epithelioid malignant pleural mesothelioma (MPM), we investigated the prognostic significance of the immune microenvironment in the tumor nest and the tumor-associated stroma in epithelioid MPM.

Methods
A tissue microarray (TMA) was constructed from 170 epithelioid MPM cases, with 6 representative tumor cores and 3 representative stromal areas. Immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) and interleukin receptors (IL-7R and IL-12Rβ2) were performed. TMA slides were analyzed for immune cell infiltration of tumor and stroma (low vs high, divided by use of the median), as well as for immune marker expression (sum of intensity and distribution). Overall survival (OS) was estimated using Kaplan-Meier analysis, and log-rank tests and Cox proportional hazards models were used to analyze the association between each marker and OS.

Results
Analysis of single immune cell infiltration for all patients revealed that high tumor CD8+ T-cell infiltration, high CD20+ B-cell infiltration, and low tumor IL-7R expression correlated with higher OS (Figure). Combined tumor CD8+ and CD4+ cell infiltration significantly correlated with better OS (5-year OS, 36% [n=61] vs. 20% [n=96]; p=0.008). In a multivariate analysis including age, stage, lymph node metastases, lymphatic invasion, and vascular invasion, high CD8+ T-cell infiltration and low tumor IL-7R expression were independent predictors of OS (Table). Figure 1Figure 2

Conclusion
Tumor CD8+ T-cell infiltration and tumor IL-7R expression are independently associated with survival, which highlights the biologic and prognostic significance of the immune microenvironment for patients with epithelioid MPM.

Background
SS1P is a recombinant immunotoxin targeting the tumor differentiation antigen mesothelin, which is highly expressed in mesothelioma. Anti-tumor activity of SS1P was limited in phase I clinical trials due to development of neutralizing antibodies (NAbs) that limited treatment to one cycle. In immunocompetent mice P and C (P-C) can abrogate development of anti-SS1P NAbs. This pilot study was performed to determine the impact of P-C-based immune depletion on anti-SS1P NAb formation and to assess safety of P-C-SS1P.

Methods
Patients with progressive pleural or peritoneal mesothelioma who previously received platinum-based therapy were eligible. Up to 6 cycles of P 4 mg/m2 IV (cycle 1: days 1, 5, 9; cycle 2-6: day 1); C 200 mg PO (cycle 1: days 1-12; cycle 2-6: days 1-4) and SS1P IV (35 µg/kg, cycle 1: days 10, 12, 14; cycle 2-6: days 2, 4, 6) were administered (cycle 1 was 30 days and cycles 2-6 were 21 days) with restaging every 2 cycles in the absence of progressive disease and anti-SS1P NAbs.

Results
Eleven patients were enrolled. The median age was 52 years (range 43-68); male 7, female 4; pleural 9, peritoneal 2; median number of prior treatments was 3 (range 2-6). Three out of 10 evaluable patients had partial response with tumor regressions of 74%, 70% and 44% with complete resolution of metabolic activity in two patients and >70% reduction in the third (Table). The overall survival of these patients is 17+, 15+ and 18+ months. In addition, one patient with stable disease and one patient with progressive disease had dramatic response to post-SS1P chemotherapy using drugs to which they had not responded previously. All five patients who responded are alive with overall survival ranging from 11 to 18 months. The regimen of P-C delayed development of NAbs to SS1P, thereby allowing multiple cycles of therapy with SS1P. Only 2 of 10 (20%) patients developed anti-SS1P NAbs after one cycle compared to 88% of patients who received single agent SS1P in a previous study (p=0.0001), thus meeting the primary endpoint. The regimen of P-C-SS1P was safe and well tolerated and no patient developed opportunistic infections. Grade ≥ 3 adverse events were P-C related lymphopenia (100%), transaminitis (18%) and SS1P related back pain (9%), non-cardiac chest pain (18%) and fever (9%).

Pt	Overall Tumor Response[†]	Delayed Tumor Response[§]	Post Study Chemo.	Response to Post-SS1P Chemo.	Overall Survival (months)
1	PR (-44%)	Yes (7 m+)	-	-	18.2+
2	PR (-74%)	-	-	-	17.1+
3	SD	-	Yes	PR (-55%)*	15+
4	PR (-70%)	-	-	-	14.5+
5	SD	-	-	-	8.8
6	PD	-	-	-	6.2
7	PD	-	-	-	5.7
8	PD	Yes (4 m+)**	Yes	85% decrease in tumor [18]F-FDG uptake[¶]	10.6+
9	PD	-	-	-	4.2
10	SD	-	Yes	No	7.3
PR, partial response; SD, stable disease; PD, progressive disease; [18]F-FDG, Fluorodeoxyglucose; [†]In patients with tumor response the maximum percent decrease in tumor dimensions is shown; [§]Months from study initiation when response first observed; * PR to post-SS1P treatment with previously ineffective chemotherapy; **Patient 8 had initial PD, but at 4 months had 25% reduction in size of one of the target lesions and marked decrease of metabolic activity by PET; [¶]Patient 8 had 85% reduction in metabolic activity compared to baseline and SD by CT scan on post- SS1P chemotherapy.

Conclusion
SS1P and immune depletion with P-C results in significant and durable anti-tumor activity in heavily pre-treated chemotherapy refractory patients with mesothelioma.

Abstract not provided

Background
AMA is chimeric monoclonal antibody that binds to mesothelin, which is highly expressed in malignant mesothelioma and largely absent from normal tissue. In vitro studies indicate that AMA potentially has anti-tumor activity via antibody-dependent cellular cytotoxicity. AMA was studied in a Phase 2 mesothelioma trial.

Methods
This was a global, single arm, open label Phase 2 trial in 89 patients with previously untreated epithelial or mixed histology unresectable malignant pleural mesothelioma. Subjects received P/C every three weeks for 4 to 6 cycles combined with AMA 5mg/kg on days 1 and 8 of each 21 day cycle. All patients were fully supplemented with folate and B12 as per pemetrexed label requirements. Single agent AMA was then continued in the same schedule until disease progression. The primary endpoint was progression-free survival (PFS) at 6 months with a secondary end point of overall survival (OS).

Results
Median PFS was 6.1 months while median OS was 14.8 months. An evaluation of serum drug concentration relationship with clinical response noted that those subjects who achieved a median trough serum concentration of 32.9 µg/mL had an improved median PFS over those whose trough serum concentration was below the median (238 days vs 115 days, p<0.001). Similarly those subjects with a serum trough concentration of AMA above a median of 38.2 µg /mL had a median OS of 583 days while those with a median serum concentration of AMA below 38.2 µg /mL had a median OS of 375 days, p=0.0202. The most commonly reported adverse event was that of hypersensitivity to the chimeric antibody at first dose second cycle.

Conclusion
The safety profile of AMA in combination with P/C was consistent with that seen previously for the PC regimen. Although PFS is not significantly different from historical results of P/C alone, the median OS was 14.8 months (as compared to 13.3 months for P/C[1]). PK/PD analysis demonstrated that AMA trough concentrations were a significant predictor of both PFS and OS where higher concentrations were associated with longer OS and PFS. [1]Reference: Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma. J Clin Oncol, 2003; 21:2636-2644.

Background
The role of maximal cyto-reductive surgery in malignant pleural mesothelioma (MPM) remains controversial. Although selected patients achieve long-term disease control following extended pleurectomy and decortication (PD), not all patients benefit. In addition surgical complications and side effects may adversely affect quality of life (QoL). We previously observed significant improvement in the quality of life following PD in patients who were symptomatic at baseline (Mollberg et al, Ann Thorac Surg 2012). In this study, we further examined the effects of PD on pulmonary function and correlated changes in pulmonary function with QOL.

Methods
Consecutive patients with MPM undergoing PD were prospectively enrolled at a single center. The primary endpoint was to determine the effects of PD on QoL. Health related QoL was assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 (EORTC QLQ-C30) before operation and at one,4-5, 7-8 , 10-11 and 12-13monthsmonths postoperatively. Pulmonary function testing was performed (PFTs) were measured immediately before the operation and at 6-7 months postoperatively. Patients were grouped according to the World Health Organization baseline performance status (PS) and compared.

Results
Twenty-seven patients with a median age of 71 years old (range 59 to 91 years), 19 males and 8 females, were enrolled in the study from March 2010 to October 2012. At the time of the operation, 17 patients were WHO PS 0, 10 were PS 1. At baseline, the PS 1 patients had a significantly worse global QoL (p<.0001), functional (p<0.0001) and symptoms scores (p<0.0001). PS 0 patients had not significant change in global QoL or functional) and symptoms scores (except for emotional function and insomnia p<0.01) following the operation. In addition they demonstrated a significant decrease in FVC (p<0.003), FEV1 (p<0.005), TLC (<0.001) and DLCO (<0.009) following PD. PS 1 patients showed significant improvements in Global Health (p=0.05) functional measures (p< 0.01) and symptoms scores (p <0.03) at 4-5 months and this was maintained at 6-7 months following PD. Improvement also was noted in the FVC (p=0.09), FEV1(p=0.04) and DLCO (p=0.09) in these patients.

Conclusion
At intermediate follow-up, extended PD for MPM had a negative impact on pulmonary function in minimally symptomatic patients without any significant improvement in QoL. In contrast, patients who were symptomatic at baseline significantly improved in QoL and showed a modest improvement in pulmonary function after PD. The change in pulmonary function may be partially responsible for the observed QoL in symptomatic patients undergoing PD.

Background
Medical management of malignant pleural mesothelioma (MPM) has obtained a moderate survival improvement over the years, while surgery with pleurectomy / decortication (P/D) or extrapleural pneumonectomy (EPP) can be an option for selected patients with resectable disease. The aim of this study was to investigate the impact of surgical treatment on the outcome of patients with MPM.

Methods
We retrospectively reviewed data from 1365 consecutive patients with histologically proven MPM, treated from 1982 to 2012 in six Institutions.Patients received either chemotherapy alone (n=172) or best supportive care (n=690) or surgical treatment (n=503), by either P/D (n=202) or EPP (n=301) with or without chemotherapy. All patients were followed up until death or for a minimum period of one year. The cox proportional hazards regression model was used to estimate relative improvements and to test the statistical hypothesis; a p-value less than 0.05 was considerd statistical significant.

Results
Figure 1 Figure1. Kaplan-Meier survival curves according to the treatment (non surgical treatment vs EPP vs P/D) considering only patients with independent good prognostic factors After a median follow-up of 6.7 years (range 1.1-14.8), 230 (16.8%) patients were alive; median survival for patients who received palliative treatment or chemotherapy alone, P/D and EPP groups were 11.7 (95%CI: 10.5-12.5) months, 20.5 (95%CI: 18.2-23.1) months, and 18.8 (95%CI: 17.2-20.9) months, respectively. Testing the hypothesis of equal survival distributions the statistical significance was reached for the P/D and EPP groups versus non surgical treatment group (p <0.001) but not for the EPP versus P/D groups (p=0.885). The 30 day mortality was 2.6% after P/D and 4.1% after EPP (p=0.401). According to multivariate analysis (n=1227) age < 70, epithelial histology and chemotherapy were independent favourable prognostic factors. In the subset of 312 (25.4%) patients with all favourable prognostic factors median survival was 15.5 months after medical therapy alone, 19.4 months after P/D, and 18.7 months after EPP (Figure 1). A risk reduction of 31% (95%CI: 14-45%) for the P/D group and of 23% (95%CI: 7-36%) for the EPP group was observed compared to the medical treatment group.

Conclusion
Our data suggest that patients with good prognostic factors had a similar survival whether they received medical therapy only, P/D or EPP. The modest benefit observed after surgery over medical treatment requires further investigation, and a large multicenter randomized trial, testing P/D after induction chemotherapy versus chemotherapy alone in MPM patients with good prognostic factors, is needed.

Abstract not provided