Objective(s): Unmet needs of relatives of patients with advanced cancer not only reduce their own health-related quality of life, but may also negatively affect patients' health outcomes. The aim of this study was to assess changes in relatives' unmet needs of patients with advanced cancer in the last year of life and to identify differences in unmet needs by gender and type of relationship. Methods: Relatives of patients with advanced cancer in the Netherlands were included in a prospective, longitudinal, observational study. Relatives' unmet needs were measured every 3 months with an adapted version of the Problems and Needs in Palliative Care (PNPC) questionnaire Caregiver form (44 items, 12 domains). Questionnaires completed in the patients' last year of life were analyzed. Change of unmet needs in the last year, and differences in unmet needs by gender and type of relationship were analyzed. Results: A total of 409 relatives were included with a median of 4 unmet needs in the patient's last year. Unmet needs were most prevalent at all time points during the last year in the domains "caring for the patient" (highest need = 35%) and "psychological issues" (highest need = 40%). The number of unmet needs of relatives did not change significantly during the last year of life (P=.807). There were no significant differences in the number of unmet needs between male and female partners and between partners and other relatives. Conclusion: The most unmet needs for relatives were in the domains "caring for the patient" and "psychological issues." Professional support should focus on these items. Within these domains, it seems especially important that relatives get more knowledge and support about what scenarios to expect and how to deal with them.

Objective To assess the degree of openness of communication about illness and death between patients with advanced cancer and their relatives during the last three months of the patient’s life, and its association with relatives’ characteristics and bereavement distress. Methods We used data from bereaved relatives of patients with advanced cancer from the prospective, longitudinal, multicenter, observational eQuipe study. Univariate and multivariable linear regression analyses were used to assess the association between the degree of openness of communication (measured using the validated Caregivers’ Communication with patients about Illness and Death scale), the a priori defined characteristics of the relatives, and the degree of bereavement distress (measured using the Impact of Event Scale). Results A total of 160 bereaved relatives were included in the analysis. The average degree of open communication about illness and death between patients with advanced cancer and their relatives was 3.86 on a scale of 1 to 5 ( SE = 0.08), A higher degree of open communication was associated with a lower degree of bereavement distress ( p = 0.003). No associations were found between the degree of open communication and the relatives’ age ( p = 0.745), gender ( p = 0.196), level of education ( p > 0.773), (religious) worldview ( p = 0.435), type of relationship with the patient ( p > 0.548), or level of emotional functioning before the patient’s death ( p = 0.075). Conclusions Open communication about illness and death between patients and relatives seems to be important, as it is associated with a lower degree of bereavement distress. Healthcare professionals can play an important role in encouraging the dialogue. However, it is important to keep in mind that some people not feel comfortable talking about illness and death.

Background In the Netherlands, the clinical benefit of systemic anti-cancer treatments (SACTs) is assessed by the Committee for the Evaluation of Oncological Agents (cieBOM). For non-curative SACTs, the assessment is based on the hazard ratio (HR) for progression-free survival and/or overall survival (OS), and the difference in median survival. We evaluated the impact of different thresholds for effectiveness by reassessing the clinical benefit of SACTs. Methods We reassessed SACTs that were initially assessed by cieBOM between 2015 and 2017. Four scenarios were formulated: replacing an “OR” approach (initial assessment) by an “AND” approach (used in all scenarios), changing the HR threshold from <0.70 (initial assessment) to <0.60, changing the threshold for the difference in median survival from >12 weeks (initial assessment) to >16 weeks, and including thresholds for OS rates. The outcomes of these scenarios were compared to the outcomes of the initial assessment. Results Reassessments were conducted for 41 treatments. Replacing the “OR” approach by an “AND” approach substantially decreased the number of positive assessments (from 33 to 22), predominantly affecting immunotherapies. This number further decreased (to 21 and 19, respectively) in case more restrictive thresholds for the HR and difference in median survival were used. Including thresholds for OS rates slightly mitigated the impact of applying an “AND” approach. Conclusions The scenario-specific thresholds had a substantial impact; the number of negative assessments more than doubled. Since this was not limited to treatments with marginal survival benefits, understanding the potential challenges that may arise from applying more restrictive thresholds is essential.

Background: The Dutch Committee for the Evaluation of Oncological Agents (cieBOM) assesses the clinical benefit of systemic anti-cancer treatments (SACTs). For SACTs tested in non-randomized trials (NRTs), cieBOM primarily utilizes response-related thresholds as assessment criteria. As sufficiency of NRT-based evidence for benefit assessments is questionable, this study investigated whether and how NRTs can be used to assess the clinical benefit of new SACTs initially appraised by cieBOM based on randomized controlled trials (RCTs). Methods: Using the RCTs underpinning cieBOM recommendations issued between 2015 and 2017, we searched for matching NRTs and applied the NRT-related assessment criteria by cieBOM to them. We then compared the assessment outcomes to the respective RCT-based cieBOM recommendations. Further, we investigated how the assessments would change when applying different response-related thresholds and adding a progression-free survival (PFS) threshold. Results: For 13 of the 37 eligible recommendations, a matching NRT was found. Two treatments were assessed positively and six negatively; five treatments were non-assessable. Two positive recommendations matched a positive NRT-based assessment; one matching negative assessment was found, and one treatment could not be assessed based on either trial results. Adding a > 6 months PFS threshold decreased the number of non-assessable NRTs (five to two). Conclusions: Limited publications and inconsistent data reporting hampered the viability of NRTs for clinical benefit assessments of SACTs beyond the scope of rare indications. Further, response-related assessment criteria alone might not fully grasp the clinical benefit of novel SACTs. NRT-based assessments should be considered with caution due to uncertainty of the trial results.

IntroductionPatients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks.Methods and analysisThe L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients.Ethics and disseminationThe protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences.Trial registration numberNCT06087952.

OBJECTIVE:Advanced cancer has a major impact on both patients and their relatives. To allow for personalized support, it is important to recognize which relatives will experience a decline in emotional functioning during the patient's last year of life, when this decline will occur, and what factors are associated with it. This study aimed to examine the trajectory of emotional functioning of relatives during that time and the characteristics associated with changes in this trajectory. METHODS:A prospective, longitudinal, multicenter, observational study in patients with advanced cancer and their relatives was conducted (eQuiPe). We analyzed relatives' changes in emotional functioning in the patient's last year using the EORTC QLQ-C30 and assessed associations with sociodemographic and care characteristics using multivariable mixed-effects analysis. RESULTS:409 relatives completed ≥1 questionnaires during the patient's last year of life. Mean age was 64 years, 61% were female and 75% were the patient's partner. During this year, mean emotional functioning declined significantly over time from 73.9 to 64.6 (p = 0.023, effect size = 0.43). The type of relationship between relatives and patients (p = 0.002), patient' sleep problems (p = 0.033), and continuity of care (p = 0.002) were significantly associated with changes in emotional functioning. CONCLUSIONS:Relatives' emotional functioning declined during the patient's last year of life. Support for them, especially partners and relatives of patients with sleep problems, is important. Relatives who experienced more continuity of care had a less steep decline in emotional functioning.

BACKGROUND:Support for health-related quality of life (HRQOL) is an essential part of cancer care in the final stages of life, yet empirical guidance regarding HRQOL and symptom trajectories is lacking. AIM:To assess the change in HRQOL and symptom burden in the last year of life in patients with advanced cancer and its association with health care-related factors, cancer-specific treatment, and comorbidity. METHODS:A prospective, multicenter, observational study in patients with advanced cancer (eQuiPe). Three monthly questionnaires included European Organization for Research and Treatment of Cancer Quality of Life-C30 and reported continuity of care. Multivariable mixed-effects analysis was used to assess the association between HRQOL and health care-related factors. RESULTS:A total of 762 deceased patients were included with a mean age of 66 (SD, 10) years and 52% were male. The most common primary tumors were lung (29%), colorectal (20%), and breast cancer (13%). Mean overall HRQOL decreased in the last 9 months of life, with the greatest decrease in the last 3 months (β -16.2). Fatigue, pain, appetite loss, dyspnea, constipation, and nausea worsened significantly in the last year of life. Multimorbidity (β -7.5) and a better reported continuity of care (β 0.7) were both significantly associated with the trajectory of HRQOL. CONCLUSION:Mean overall HRQOL begins to decline 9 months before death, highlighting the need for early identification and (re)assessment of different symptoms as aspects of HRQOL follow different trajectories. Multimorbidity and reported continuity of care may be associated with the trajectory of HRQOL.

Purpose Advance Care Planning (ACP) is positively associated with the quality of care, but its impact on emotional functioning is ambiguous. This study investigated the association between perceptions of ACP involvement and emotional functioning in patients with advanced cancer. Methods This study analyzed baseline data of 1,001 patients of the eQuiPe study, a prospective, longitudinal, multicenter, observational study on quality of care and quality of life in patients with advanced cancer in the Netherlands. Patients with metastatic solid cancer were asked to participate between November 2017 and January 2020. Patients’ perceptions of ACP involvement were measured by three self-administered statements. Emotional functioning was measured by the EORTC-QLQ-C30. A linear multivariable regression analysis was performed while taking gender, age, migrant background, education, marital status, and symptom burden into account. Results The majority of patients (87%) reported that they were as much involved as they wanted to be in decisions about their future medical treatment and care. Most patients felt that their relatives (81%) and physicians (75%) were familiar with their preferences for future medical treatment and care. A positive association was found between patients’ perceptions of ACP involvement and their emotional functioning (b=0.162, p<0.001 , 95%CI[0.095;0.229]) while controlling for relevant confounders. Conclusions Perceptions of involvement in ACP are positively associated with emotional functioning in patients with advanced cancer. Future studies are needed to further investigate the effect of ACP on emotional functioning. Trial registration number NTR6584 Date of registration: 30 June 2017 Implications for Cancer Survivors Patients’ emotional functioning might improve from routine discussions regarding goals of future care. Therefore, integration of ACP into palliative might be promising.

F-18-fluoro-2-deoxy-D-glucose positron emission tomography (PET) complements conventional imaging for diagnosing and staging lung cancer. Two literature-based meta-analyses suggest that maximum standardised uptake value (SUVmax) on PET has univariate prognostic value in nonsmall cell lung cancer (NSCLC). We analysed individual data pooled from 12 studies to assess the independent prognostic value of binary SUVmax for overall survival.After searching the published literature and identifying unpublished data, study coordinators were contacted and requested to provide data on individual patients. Cox regression models stratified for study were used.Data were collected for 1526 patients (median age 64 years, 60% male, 34% squamous cell carcinoma, 47% adenocarcinoma, 58% stage I-II). The combined univariate hazard ratio for SUVmax was 1.43 (95% CI 1.22-1.66) and nearly identical if the SUV threshold was calculated stratifying for histology. Multivariate analysis of patients with stage I-III disease identified age, stage, tumour size and receipt of surgery as independent prognostic factors; adding SUV (HR 1.58, 95% CI 1.27-1.96) improved the model significantly. The only detected interaction was between SUV and stage IV disease.SUV seems to have independent prognostic value in stage I-III NSCLC, for squamous cell carcinoma and for adenocarcinoma.

Overlapping immunoglobulin G4-related disease and Rosai-Dorfman disease mimicking lung cancerTo the Editors:We report the case of an elderly male referred with pulmonary opacities and extensive mediastinal lymphadenopathy suspicious for lung cancer.He was found to have Rosai-Dorfman disease in a lymph node and concomitant immunoglobulin (Ig)G4-related disease in the lung and kidney.An 83-yr-old male was referred with a pulmonary consolidation in the left lung with extensive lymphadenopathy without a pathological diagnosis.His past medical record showed gout for which he used colchicine only occasionally.Initially, he was referred to an internist with complaints of loss of appetite, weight loss and fatigue.His sense of taste was diminished and he had a dry mouth.No dyspnoea was present.He had a longstanding, non-productive cough.Until recently, he was remarkably fit for his age.He had quit smoking 45 yrs earlier after 30 pack-yrs.

printing supported by . Visit Chiesi at Stand D.30 MONDAY, SEPTEMBER 26TH 2011 P2750 Late-breaking abstract: Is primary tumour standardized uptake value (SUV) an independent prognostic factor for non small cell lung cancer (NSCLC)? A meta-analysis based on individual data Marianne Paesmans1, Ching-Yee Oliver Wong2, Edward F. Patz3, Ritsuko Komaki4, Susanne Eschmann5, Ramaswamy Govindan6, Johan Vansteenkiste7, Anne-Pascale Meert14, Wouter de Jong8, Kotaro Higashi9, Gerben Borst10, Angela Van Baardwijk11, Lieveke Ameye1, Jean-Jacques Lafitte12, Thierry Berghmans14, Camilo Garcia15, Patrick Flamen15, Ramon Rami Porta13, Jean-Paul Sculier1. 1Data Centre, Institut Jules Bordet, Brussels, Belgium; 2Nuclear Medicine, William Beaumont School of Medicine, Royal Oak, United States; 3Radiology, Duke University Medical Center, Durham, United States; 4Medicine, MD Anderson Cancer Center, Houston, United States; 5Nuclear Medicine, University of Tubingen, Tubingen, Germany; 6Medical Oncology, University School of Medicine, St-Louis, United States; 7Pulmonology, University Hospital Gasthuisberg, Leuven, Belgium; 8Pulmonology, University Medical Center Groningen, Groningen, Netherlands; 9Radiology, Kanazawa Medical University, Ishikawa, Japan; 10Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands; 11Radiation Oncology, University Hospital Maastricht, Maastricht, Netherlands; 12Pulmonology, CHRU de Lille, Lille, France; 13Thoracic Surgery, Hospital Universitari Mutua Terrassa, Barcelona, Spain; 14Medicine and Intensive Care, Institut Jules Bordet, Brussels, Belgium; 15Nuclear Medicine, Institut Jules Bordet, Brussels, Belgium Background: 18F-fluoro-2-deoxy-D-glucose positron emission tomography has an important role in staging lung cancer. In addition, its prognostic value has been studied in numerous studies as well as in two literature based meta-analyses. To assess further its independent value, we carried out a meta-analysis based on individual data. Methods: Following literature search, we contacted the authors of identified studies and tried to identify some unpublished data with a written protocol for the meta-analysis. Primary outcome was overall survival (OS) and data analysis used Cox regression models stratified for study. SUV was used as a binary covariate (cut-off: median value for each study). Results: Data were collected for 1462 patients (out of 2596 identified patients) from 10 publications and 1 unpublished series (median age: 64 years, gender: 61% male, 35% squamous cell, 45% adenocarcinoma, stage I: 49%, II: 8%, III: 32%, IV: 12%). Lower SUV was significantly associated with female gender, smaller tumour size, earlier stage and adenocarcinoma. Analyzing OS, univariate hazard ratio for SUV was 1.44 (95% CI: 1.23-1.68) without important heterogeneity in subgroups except for stage IV. When adjusted for stage, histology, age, tumour size and gender, HR estimate for SUV effect was 1.62, statistically significant (95% CI: 1.28-2.04, p<0.001). Conclusions: This meta-analysis based on individual patients data shows that SUV is an independent prognostic factor for OS, at least in non metastatic stage. Selection bias and methodological differences are however present and further prospective studies are needed. P2751 Is our preoperative TNM staging reliable? Marta Inchausti1, Larraitz Garcia1, Maria Alfonso1, Ruth Diez1, Amaia Urrutia1, Amaia Sagarna1, Estibaliz Perez1, Unai Jimenez2, Pedro Ansola1. 1Pneumology, Cruces Hospital, Barakaldo, Bizkaia, Spain; 2Thoracic Surgery, Cruces Hospital, Barakaldo, Bizkaia, Spain Introduction: Agreement between preoperative and surgical TNM staging is usually <50%. Aim: To compare our preoperative staging (cTNM) with surgical-pathological staging (pTNM). Methods: Cross-sectional study of patients with lung cancer surgically treated from 1-1-08 to 31-12-09, excluding relapses or neoadjuvant therapies. Preoperative staging based on: CT scan, positron emission tomography (PET-CT), endobronchial ultrasonography (EBUS), endoscopic ultrasonography (EUS), mediastinoscopy. Agreement between cTNM and pTNM (according to 1997 TNM classification) was analyzed. Results: 166 cases (characteristics in table 1). In table 2, concordance between cTNM and pTNM. cTNM and pTNM matched in 80 cases (48,2%), understaging occurred in 5 cases (3%) and overstaging in 81 (48,8%). But in most cases, this lack of agreement would not suppose changes in the therapeutic decision, just in 21 cases (12,5%) the cTNM carried out a wrong therapeutic procedure (18 N2 found in thoracotomy and 3 T4 unresectables). TC and PET-TC used in all cases, EBUS in 35, EUS in 2 and mediastinoscopy in 3. In N staging, PET-CT was cN0 in 133 cases (where 7 were pN2, 5,2%) and cN1 21 (8 pN2, 25,8%). We performed 35 EBUS (33 cN0, 2 cN1) and final pN was N2 in 3 cases (FN rate 8,5%). Conclusions: 1. Low agreement between cTNM and pTNM (48,2%), but only in 12,5% of cases would suppose a change in the treatment. 2. 25% of pN2 when cN1 by PET-CT (EBUS should be done). 3. When EBUS negative for N2, only 8,5% pN2. P2752 Prevalence of silent brain metastasis (BM) in the initial staging of non-small cell lung carcinoma (NSCLC) L. Marizell PariEspinoza, Daniel Huertas Almela, Susana Padrones Sanchez, Samantha Aso González, Antoni Rosell Gratacós, J. Ignacio Martínez Ballarín, Jordi Dorca Sargatal, Nuria González Calzada. Respiratory Diseases, Hospital Universitari de Bellvitge, Barcelona, Spain Introduction: Positron emission tomography (PET) can detect up to 15% of distant metastases in lung cancer, but it has a low sensibility in detecting BM.Guidelines recommend performing MRI only if there are neurological symptoms (NS). Our aim was to assess the role of MRI in detecting silent BM in the initial staging of NSCLC. Material and methods: Retrospective analysis of new cases of NSCLC without distant metastasis by PET.MRI was performed in all of NSCLC patients as initial work up,except those in stage IV. Results: MRI was made in 95 patients with NSCLC.39%,40% and 21% had squamous cell carcinoma, adenocarcinoma and other histology respectively. 20%, 21% and 59% were stage I, II and III respectively.BM were diagnosed by MRI in 11,6% (11/95) of the patients,and six of them (6/95, 6.35%), did not present NS.A stratified binary logistic regression analysis showed that there were not any clinical variable associated with the presence of silent BM in the asymptomatic subgroup, whereas central tumours (p=0,005) and ADK (p=0,01) were associated to BM in patients with NS. In both subgroups; staging, SUVm, tumour size and lymph nodes were not statistically indicative of BM. Conclusions: Prevalence of silent BM at initial staging was 6.35%. Neither clinical nor radiological variables could predict silent BM. We concluded MRI is justified as a routine procedure in NSCLC patients without BM in the PET. Partially funded by SOCAP. 508s Thematic Poster Session Hall 2-38 12:50-14:40 Abstract printing supported by . Visit Chiesi at Stand D.30printing supported by . Visit Chiesi at Stand D.30 MONDAY, SEPTEMBER 26TH 2011 P2753 Assessment of physical functioning in surgical candidates with non-small cell lung cancer: Preliminary comparison of performance status to symptom-limited cardiopulmonary exercise testing Michael A. Roman1, Neil D. Eves2, Lee W. Jones3. 1Department of Medicine, Rockyview Hospital, University of Calgary, Calgary, AB, Canada; 2Human Kinetics, University of Bristish Columbia, Kelowna, BC, Canada; 3Department of Radiation Oncology, Duke University Medical Center, Durham, NC, United States Background: Performance status (PS) scoring systems are used routinely by clinicians to guide management of patients with non-small cell lung cancer (NSCLC). However, PS scoring systems are subjective with poor inter-rater reliability and do not provide an objective measure of functional status. The aim of this study was to compare the variability in an objective measure of cardiorespiratory fitness (VO2peak), among surgical candidates with histologically confirmed NSCLC across different PS categories as assessed by the Eastern Cooperative Oncology Group (ECOG) score. Methods: Using a cross-sectional design, 389 subjects underwent an incremental cardiopulmonary exercise test with expired gas analysis to determine VO2peak prior to surgical resection. Results: Mean VO2peak significantly declined across increasing ECOG categories (Table 1). There was a wide range in VO2peak in each ECOG category with similar ranges in VO2peak within groups, in particular in subjects classified as ECOG 1 and 2. Table 1. Comparison of VO2peak to ECOG PS in NSCLC Variable (n=187) (n=174) (n=28) ECOG 0 1 2 Mean VO2peak (ml kg–1 min–1) 17.2±4.5 15.0±3.7 13.5±3.1 VO2peak Range (ml kg–1 min–1) 5.0–31.5 4.3–24.8 8.9–21.9 Conclusions: VO2peak may provide a more sensitive evaluation of physical functioning than ECOG. Accurate assessment of functional status may have important implications for mortality risk and therapeutic management in the oncology setting. P2754 Comparison of predictive respiratory function parameters of lung cancer patients having COPD diagnosis with postoperative values and relation with mortality and morbidity Selma Altun1, Mustafa Kahraman2, Dilek Kanmaz2, Esin Yentürk2, Firdevs Atabey2, Celalettin Kocatürk2, Esin Tuncay2, Mehmet Ali Bedirhan2, Yasemin Toraman2. 1Ahievren Chest Hospital, Pulmonary Medicine, Trabzon, Turkey; 2Yedikule Chest Diseases and Surgery Hospital, Pulmonary Medicine,

Background: 18 F-fluoro-2-deoxy-D-glucose positron emission tomography has an important role in staging lung cancer. In addition, its prognostic value has been studied in numerous studies as well as in two literature based meta-analyses. To assess further its independent value, we carried out a meta-analysis based on individual data. Methods: Following literature search, we contacted the authors of identified studies and tried to identify some unpublished data with a written protocol for the meta-analysis. Primary outcome was overall survival (OS) and data analysis used Cox regression models stratified for study. SUV was used as a binary covariate (cut-off: median value for each study). Results: Data were collected for 1462 patients (out of 2596 identified patients) from 10 publications and 1 unpublished series (median age: 64 years, gender: 61% male, 35% squamous cell, 45% adenocarcinoma, stage I: 49%, II: 8%, III: 32%, IV: 12%). Lower SUV was significantly associated with female gender, smaller tumour size, earlier stage and adenocarcinoma. Analyzing OS, univariate hazard ratio for SUV was 1.44 (95% CI: 1.23-1.68) without important heterogeneity in subgroups except for stage IV. When adjusted for stage, histology, age, tumour size and gender, HR estimate for SUV effect was 1.62, statistically significant (95% CI: 1.28-2.04, p Conclusions: This meta-analysis based on individual patients data shows that SUV is an independent prognostic factor for OS, at least in non metastatic stage. Selection bias and methodological differences are however present and further prospective studies are needed.

Cigarette smoking is the main risk factor for the development of squamous cell lung carcinoma (SCC). However, the smoking‐related molecular changes in SCC have not been studied. Gene expression studies in both histologically normal bronchial epithelium and SCC epithelial samples identified genes differentially expressed between current and ex‐smokers. Subsequently, expression levels of the smoking‐related genes in normal bronchial epithelium were compared with those in SCC cells, since we hypothesized that the smoking‐induced changes would be also deregulated in SCC. Gene expression profiles were generated using Agilent whole human genome microarrays on laser‐microdissected normal bronchial epithelium and SCC samples. Expression levels of 246 genes, mainly related to oxidative stress response, were significantly different between normal bronchial epithelium of current and ex‐smokers. Such a differential gene expression profile did not exist in SCC cells of smokers and ex‐smokers. Interestingly, when comparing SCC and normal bronchial epithelium from ex‐smokers, the vast majority of these 246 genes were also deregulated in SCC. When comparing SCC with normal epithelium from smokers, 22% of the up‐regulated genes showed a similar high expression in SCC whereas 79% of the down‐regulated genes were even further reduced in SCC as compared to current smokers. The down‐regulated genes included several tumour suppressor genes, such as C9orf9, INHBB, LRIG1, SCGB3A1, SERPINI2, STEAP3 and ZMYND10 . Thus, our study shows that the majority of genes up‐regulated in normal bronchial epithelium of current smokers show similar high expression levels in SCC, while down‐regulated genes are even further repressed in SCC. Our data indicate that smoking‐related changes in normal bronchial epithelial cells persist in malignant transformed squamous cells. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND:The distribution of promoter methylation throughout the lungs of patients with non-small cell lung cancer (NSCLC) is unknown. In this explorative study, we assessed the methylation status of the promoter region of 11 genes in brush samples of 3 well-defined endobronchial locations in patients with NSCLC and in brushes of former and current smokers without NSCLC.MATERIALS AND METHODS:The methylation status of RASSF1A, GATA4, GATA5, SFRP1, RARbeta2, DAPK, MGMT, p16, p14, CHFR and APC2 was determined in all samples using real-time methylation-specific PCR.RESULTS:Ten patients with NSCLC and 18 non-NSCLC controls were included. Eight patients had one or more methylated genes in their tumor brush. Promoter methylation of genes in proximal or contralateral locations was much less frequent than in tumor brushes, and almost exclusively occurred in normal tissue if the same gene was also methylated in the tumor brush.CONCLUSION:Promoter methylation almost exclusively occurred in tumor cells of patients with NSCLC.

BACKGROUND:Recent temporal trends in histology and stage of pulmonary tumours in the Netherlands were studied. The incidence of rare pulmonary tumours was determined.METHODS:All tumours originating from the trachea, bronchus and lung recorded in the Netherlands Cancer Registry were included. Based on ICD-O morphology codes, five major subgroups were constructed: squamous carcinoma (SC), adenocarcinoma (AC), large cell (undifferentiated) carcinoma (LC), small cell lung cancer (SCLC) and other (including uncommon tumours).RESULTS:Between 1989 and 2003, 134,894 tumours were diagnosed. In men the age-adjusted incidence of SC and SCLC decreased, AC remained stable and LC increased. In women the incidence of all subgroups increased. Since 1996, a stage shift was observed with fewer patients in stage I and more patients in stage IV at diagnosis. This stage shift occurred equally in SC, AC and LC. In SC, fewer patients presented with stage IV disease than in AC and LC (25% vs 44% and 49% in 2003, respectively). The incidence of adenosquamous carcinoma decreased from 0.6 to 0.29/100 000 (p<0.001). The incidence of carcinoid tumours, sarcomatoid carcinomas and primary pulmonary sarcomas remained stable (0.44, 0.17 and 0.08/100 000, respectively).CONCLUSION:The incidence of smoking-related tumours decreased in men (especially SC and SCLC) and increased in women (all subgroups). More patients presented with stage IV disease. The incidence of non-smoking-related uncommon tumours remained constant.

The population-based incidence, diagnostic procedures, therapy and survival of thymic epithelial tumours were determined using the Netherlands National Pathological Archives and the Netherlands Cancer Registry. Excess mortality compared to the Netherlands standard population was estimated by relative survival analysis.Between 1994 and 2003, 537 thymic epithelial tumours were diagnosed. The incidence of all thymic epithelial tumours was 3.2/1,000,000. Diagnosis was obtained by primary resection in 56% of cases. Survival data were available for 232 cases. Not only thymic carcinomas (type C) but also thymomas (types B1-B3) were associated with excess mortality. Cases that underwent resection (78%) had a better survival than non-operated cases (median survival >10 years versus 1.1 years, p < 0.001). Amongst the surgically treated cases (n = 180), the completeness of resection did not predict survival (p = 0.53).Thymic epithelial tumours are rare. Excess mortality was observed in the majority of tumours. Surgery offers the best perspectives, even if the resection is incomplete. (c) 2007 Elsevier Ltd. All rights reserved.

1730 Rationale: Cigarette smoking is the main risk factor for both development of squamous cell lung carcinoma (SCC) and chronic obstructive pulmonary disease (COPD). Additionally, COPD itself is an independent risk factor for SCC. This suggests a common genetic background of COPD and SCC. Objectives: To analyze smoke-induced and COPD-related gene expression changes in histologically normal bronchial epithelium and compare the expression levels of the differentially expressed genes to the levels in SCC. Methods: Gene expression profiles were generated using Agilent whole human genome microarray for 28 laser microdissected bronchus epithelial samples of current and ex-smokers from patients with and without COPD, and 35 laser microdissected SCC samples. Results: Gene expression analysis revealed 246 genes that were significantly different between current and ex-smokers, independent of smoking history. Despite the important role of epithelium in pathogenesis of COPD we found no significant differences in gene expression levels between individuals with and without COPD. To assess whether an association exists between the 246 smoking related differentially expressed genes and SCC, we compared these expression levels with those in the SCC samples. Genes that were upregulated in current smokers, mainly related to oxidative stress response, showed similar expression levels in SCC. Interestingly, the downregulated genes in current smokers including several tumor suppressor genes showed a further reduction in expression levels in SCC. Conclusions: This is the first study that demonstrated persistence or even enhancement of smoke-induced genetic changes in SCC, indicating a role in early genetic changes in SCC oncogenesis.