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1.  Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients 
Lung adenocarcinoma is the most common type of primary lung cancer. The purpose of this study was to delineate gene expression patterns for survival prediction in lung adenocarcinoma. Gene expression profiles of 82 (discovery set) and 442 (validation set 1) lung adenocarcinoma tumor tissues were analyzed using a systems biology-based network approach. We also examined the expression profiles of 78 adjacent normal lung tissues from 82 patients. We found a significant correlation of an expression module with overall survival (adjusted hazard ratio or HR=1.71; 95% CI=1.06-2.74 in discovery set; adjusted HR=1.26; 95% CI=1.08-1.49 in validation set 1). This expression module contained genes enriched in the biological process of the cell cycle. Interestingly, the cell cycle gene module and overall survival association were also significant in normal lung tissues (adjusted HR=1.91; 95% CI, 1.32-2.75). From these survival-related modules, we further defined three hub genes (UBE2C, TPX2 and MELK) whose expression-based risk indices were more strongly associated with poor 5-year survival (HR=3.85, 95% CI=1.34-11.05 in discovery set; HR=1.72, 95% CI=1.21-2.46 in validation set 1; and HR=3.35, 95% CI=1.08-10.04 in normal lung set). The 3-gene prognostic result was further validated using 92 adenocarcinoma tumor samples (validation set 2); patients with a high-risk gene signature have a 1.52 fold increased risk (95% CI, 1.02–2.24) of death than patients with a low-risk gene signature. These results suggest that network-based approach may facilitate discovery of key genes that are closely linked to survival in patients with lung adenocarcinoma.
PMCID: PMC3595338  PMID: 23357462
Lung cancer; survival; gene expression profiling; cell cycle; systems biology
2.  Farletuzumab in Lung Cancer 
Folate is essential for proliferating cells and folate transport pathways and folate-dependent metabolic processes show promise as targets for anti-neoplastic therapy. Folate receptor α (FOLR1), a folate transporter, is an attractive target for anti-neoplastic therapy due to its high affinity for folate, restricted range of expression in normal tissue and differential over-expression in malignant tissue. FOLR1 is expressed in non-small cell lung cancer, with a higher expression in adenocarcinoma compared with squamous cell carcinoma. Farletuzumab is a monoclonal antibody targeting FOLR1 which in pre-clinical studies led to cytotoxicity of FOLR1-expressing cells, inhibited tumor growth in animal models and showed limited reactivity with normal tissue. In phase I/II trials, farletuzumab was well tolerated as a single-agent and in combination, without additive toxicity with chemotherapy. An ongoing phase II, double blind, placebo-controlled study is evaluating farletuzumab in patients with FOLR1 expressing metastatic adenocarcinoma of lung.
PMCID: PMC3595339  PMID: 23357463
adenocarcinoma; farletuzumab; folate receptor α; monoclonal antibody; non-small cell lung cancer; immunohistochemistry
3.  Family history of lung cancer in never smokers with non-small-cell lung cancer and its association with tumors harboring EGFR mutations 
Inherited susceptibility to lung cancer is understudied. Never smokers are an important subgroup of patients enriched for tumors harboring oncogene aberrations in the EGFR and ALK genes. We aimed to better characterize the incidence of family history of lung cancer among never smokers with NSCLC.
Clinicopathologic data, tumor genotype, family history of cancer, and specifically family history of lung cancer from 230 consecutive never smokers was retrospectively compiled and analyzed.
In our cohort, the median age was 56 years, 67% were women, 75% were white, 59% had advanced NSCLC and 87% had adenocarcinoma histology. In these tumors, 98/230 (42%) had an EGFR mutation, 17/155 (11%) had KRAS mutations and 27/127 (21%) had an ALK translocation. Family history of any cancer was common (57%) and specific family history of lung cancer was present in 42/230 cases (18%). The percentage of cases with family history of lung cancer was higher in the EGFR mutated versus EGFR wild-type NSCLCs. Out of the cases with a family history of any cancer, 22/53 (41.5%) EGFR mutated, 1/5 (20%) KRAS mutated and 3/19 (15.5%) ALK translocated cohorts had a family history of lung cancer. The ratio of family history of lung cancer to family history of cancer was significantly higher in the EGFR mutated cohort when compared to the ALK translocated plus KRAS mutated cohorts (p=0.039).
Family history of lung cancer is common in never smokers with NSCLC, and there seems to be a particular link in families in which the proband has an EGFR mutated tumor when compared to ALK translocated or KRAS mutated tumors. Further study of families with EGFR-mutated NSCLC may yield insights into the pathogenesis of this tumor type.
PMCID: PMC3566317  PMID: 23273562
lung cancer; non-small-cell lung cancer; family history; never smokers; epidermal growth factor receptor; EGFR; anaplastic lymphoma kinase; ALK; KRAS
4.  Gene silencing of SLC5A8 identified by genome-wide methylation profiling in lung cancer 
Aberrant DNA hypermethylation has been implicated as a component of an epigenetic mechanism that silences genes in cancers.
We performed a genome-wide search to identify differentially methylated loci between 26 tumor and adjacent non-tumor paired tissues from same lung cancer patients using restriction landmark genomic scanning (RLGS) analysis. Among 229 loci which were hypermethylated in lung tumors as compared to adjacent non-tumor tissues, solute carrier family 5, member 8 (SLC5A8) was one of the hypermethylated genes, and known as a tumor suppressor gene which is silenced by epigenetic changes in various tumors. We investigated the significance of DNA methylation in SLC5A8 expression in lung cancer cell lines, and 23 paired tumor and adjacent non-tumor lung tissues by reverse transcription-PCR (RT-PCR), quantitative methylation specific PCR (QMSP) and bisulfite modified DNA sequencing analyses.
Reduced or lost expression of SLC5A8 was observed in 39.1% (9/23) of the tumor tissues as compared with paired adjacent non-tumor tissues. Bisulfite sequencing results of lung cancer cell lines and tissues which did not express SLC5A8 showed a densely methylated promoter region of SLC5A8. SLC5A8 was reactivated by treatment with DNA methyltransferase inhibitor, 5-Aza and/or HDAC inhibitor, trichostatin A (TSA) in lung cancer cell lines, which did not express SLC5A8. Hypermethylation was detected at the promoter region of SLC5A8 in primary lung tumor tissues as compared with adjacent non-tumor tissues (14/23, 60.9%).
These results suggest that DNA methylation in the SLC5A8 promoter region may suppress the expression of SLC5A8 in lung tumor.
PMCID: PMC3566332  PMID: 23273563
Lung cancer; Gene silencing; SLC5A8; Tumor suppressor gene; DNA methylation; Restriction landmark genomic scanning
5.  Randomized Phase II Trial of Sulindac for Lung Cancer Chemoprevention 
Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN).
At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index.
Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92).
Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.
PMCID: PMC3566344  PMID: 23261228
lung cancer; chemoprevention; phase II clinical trial; sulindac; NSAIDs
6.  Reproducibility of the WHO classification of thymomas: practical implications 
The WHO-classification was shown to be an independent prognostic marker in some but not all retrospective studies possibly due to lack of reproducibility. We investigated the reproducibility of the WHO-classification and its prognostic implication using a large series of resected thymomas.
Four independent pathologists histologically classified a surgical series of 129 thymic tumors in a blinded fashion. Fleiss’ kappa-coefficient was used to assess the pathologists’ overall agreement, and Cohen-Kappa to assess the agreement between two observers. Disease-related-survival (DRS) and progression-free-survival (PFS) curves were generated by Kaplan-Meier method and compared by log-rank test.
In 63/129 (48.8%) cases there was a complete agreement; in 43/129 (33.3%) cases 3/4 pathological diagnoses were identical; in 15/129 (11.6%) cases the diagnoses were identical by pair; in 8/129 (6.2%) cases three different pathological diagnoses were on record. The Kappa-correlation coefficient was only moderate (0.53). A following web review carried out on the 23 cases with at least two different diagnoses reached a complete consensus. The histotype showed a statistically significant impact on PFS and DRS in the classification provided by only two pathologists.
In this study, the agreement on WHO classification of thymomas was only moderate and this impacted on patients management. Web consensus conference on the diagnosis, more stringent diagnostic criteria or the adoption of referral diagnostic centres may substantially reduce discrepancies.
PMCID: PMC3575111  PMID: 23279873
Thymomas; WHO classification; reproducibility; practical implications
7.  Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors☆ 
Advanced NSCLC harboring epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) typically progresses after initial response due to acquired resistance. TKIs are often continued beyond progressive disease by RECIST. We investigated the practice of continuing EGFR-TKIs after RECIST-PD via CT findings.
Among 101 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line EGFR-TKIs, 70 patients had baseline and at least one follow-up CT for retrospective radiographic assessments using RECIST1.1; 56 patients had experienced PD by the data closure date of June 2011.
Among 56 patients experiencing PD, 82% were female, median age was 63 years, 50% were never-smokers, 57% had distant metastasis, 57% had exon 19 deletion, and 89% were treated with erlotinib. 49 patients (88%) continued TKI therapy beyond retrospectively assessed PD. 31/32 (97%) patients who progressed by an increase in their target lesions continued TKI. 13/16 (81%) patients who progressed by appearance of a new lesion remained on TKI. 5/6 (83%) patients with both increase of target lesions and new lesion at PD continued TKI. Two patients with PD in non-target lesions discontinued therapy at PD. In 49 continuing patients, the median time from retrospectively assessed RECIST-PD to termination of TKI was 10.1 months.
88% of EFGR-mutant NSCLC patients who progressed on first-line TKI continued therapy beyond RECIST-PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC patients. Additional radiographically defined progression criteria are needed for this population.
PMCID: PMC3580850  PMID: 23254265
Lung cancer; Computed tomography; Drug resistance; Epidermal growth factor receptor mutations; EGFR tyrosine kinase inhibitors; RECIST
8.  Natural growth and disease progression of non-small cell lung cancer evaluated with 18F-fluorodeoxyglucose PET/CT✩ 
The aims of this study were to: (1) estimate the volumetric and metabolic growth rate of non-small cell lung cancer (NSCLC), (2) evaluate disease progression prior to treatment, and (3) explore the effects of tumor growth rate and time to treatment (TTT) on survival outcome.
Patients with inoperable stages I–III NSCLC with serial pre-treatment PET/CT scans were eligible for this study. PET-derived metabolic tumor volumes (PET-MTV) and CT-derived gross tumor volumes (CT-GTV) were contoured using PET/CT information. Normalized standardized uptake values (NSUV) in tumors including the NSUVmean and NSUVmax were measured. Tumor growth rates expressed as doubling time (DT) were estimated using an exponential model. Pre-treatment disease progression defined as the development of any new site of disease on PET/CT and change in TNM stage (AJCC 7th ed.) were recorded. Growth rate and tumor progression were analyzed with respect to overall (OS) and progression free survival (PFS).
Thirty-four patients with a median inter-scan interval (ISI) of 43 days and TTT of 48 days were analyzed. Tumor volumes showed remarkable inter-scan growth while NSUV did not increase significantly. The DT for PET-MTV, CT-GTV, NSUVmean and NSUVmax were 124, 139, 597, and 333 days, respectively. Pre-treatment disease progression occurred in 20.6% patients with longer ISI being a significant risk factor (OR = 1.027, p = 0.02). The optimal threshold ISI to predict progression was 58 days (4.8% vs. 46.2%, p = 0.007). Neither tumor growth rates nor TTT were significantly correlated to OS or PFS.
NSCLC displays rapid tumor volume growth whereas NSUVmean and NSUVmax are relatively stable over the same time period. Longer delays before initiation of treatment are associated with higher risk of pre-treatment disease progression.
PMCID: PMC3933267  PMID: 22841591
Positron emission tomography/computed; tomography; Non-small cell lung cancer; Doubling time; Disease progression; Waiting time
9.  Physical activity level and quality of life in long term lung cancer survivors 
Lung cancer (Amsterdam, Netherlands)  2012;77(3):10.1016/j.lungcan.2012.05.096.
Lung cancer is associated with a multitude of challenges, and lung cancer survivors report significantly lower quality of life (QOL) than other cancer survivors.
This study aimed to examine the relationship between physical activity level and QOL in a large sample of long term lung cancer survivors (N = 1937). Average age at diagnosis was 65 years, 92% were Caucasian, and 51% male. Surveys were completed at lung cancer diagnosis and then average 4.2 years post-diagnosis.
Most survivors reported having a sedentary lifestyle at both timepoints. However, 256 survivors reported a change in physical activity level from diagnosis to follow-up. Decreased physical activity (n = 140) was associated with decreased overall, mental, physical, emotional, social, and spiritual QOL (all ps < .001) and decreased symptom control as seen in reported pain, dry coughing, coughing with phlegm, shortness of breath, and level of fatigue (all ps < .05). In contrast, increased physical activity (n = 116) was associated with improved QOL (all ps < .05), and improved symptom control as seen in frequency and severity of pain (p < .01). For all participants, those engaging in regular physical activity (30 min or more per day, at least five days per week) reported significantly higher QOL scores (all ps < .001), and better symptom control than more sedentary survivors.
Results indicate a significant association between change in physical activity and QOL and symptom control for long term lung cancer survivors, and research exploring interventions designed to improve activity level for lung cancer survivors is further warranted.
PMCID: PMC3882512  PMID: 22681871
Long term lung cancer survivors; Physical activity; Exercise; Quality of life; Symptom control
10.  A Phase II Study of Modulated-Capecitabine and Docetaxel in Chemonaive Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) 
This phase II single-arm trial of docetaxel and capecitabine in previously untreated non-small cell lung cancer (NSCLC) patients was designed to evaluate response rate of this regimen based on promising efficacy data from phase II testing in pre-treated NSCLC patients. The trial also evaluated the correlation between peripheral blood dihydropyrimidine dehydrogenase (DPD) expression and efficacy/toxicity.
Patients with advanced NSCLC (metastatic, including malignant pleural effusion) without prior chemotherapy were enrolled. Baseline DPD screening was performed; patients with baseline DPD level < 0.07 nmol/min/mg protein were considered ineligible for the study. Treatment included a 28-day cycle of docetaxel 36 mg/m2 days 1, 8, 15 and capecitabine 1250 mg/m2/day in divided doses on days 5–18. Overall response rate (RR) was the primary endpoint with a target RR of 50%. Correlative studies included evaluation of DPD activity levels in peripheral blood and correlation with clinical responses.
Twenty-eight patients received 86 cycles of treatment (median 3 cycles) and were evaluable for response. The RR was 18% (5 patients); RR did not meet the pre-specified efficacy endpoint and the trial was stopped. 14 patients had stable disease (SD - 50%) and 4 pts had SD > 12 weeks. Median time to progression was 3.3 months (95% CI 1.5 – 4.6 months). Median overall survival was 10.5 months (95% CI: 3.2 – 15 months). Main toxicities included fatigue, stomatitis and leukopenia. DPD levels ranged from 0.06 to 0.26 nmol/min/mg. The majority of responders (4/5) had DPD levels ≤ 0.1 nmol/min/mg. Most of the responders (4/5) experienced grade 3 toxicities including leukopenia, dehydration, fatigue, and diarrhea. None of the patients (0/4) with higher DPD levels (>0.2 nmol/min/mg) had a response.
The response rate for the regimen did not demonstrate sufficient activity and further study of this regimen in this setting is not indicated. Interestingly, the results suggest that low DPD expression may be associated with response to capecitabine but also with increased toxicity.
PMCID: PMC3549571  PMID: 23079156
non-small cell lung cancer; dihydropyrimidine deficiency; capecitabine
11.  Patterns and Predictors of First-line Chemotherapy Use among Adults with Advanced Non-small Cell Lung Cancer in the Cancer Research Network 
Relatively low rates of chemotherapy receipt have been observed in older patients diagnosed with advanced non-small cell lung cancer (NSCLC) in SEER-Medicare-based studies. However, little is known about variation in first-line NSCLC chemotherapy use in younger patients, health maintenance organization (HMO)-based settings, and for high-cost, novel agents, such as bevacizumab and erlotinib.
A cohort of 6,614 stage IIIB/IV NSCLC patients aged >21 years diagnosed between 2000 and 2007 was identified at four HMOs that participate in the Cancer Research Network (CRN). Demographic, comorbidity, tumor characteristics, and chemotherapy treatment data were included in logistic regression models to identify factors associated with chemotherapy receipt and tests of association examined secular and age-specific variation in first-line chemotherapy regimens.
Within 120 days of diagnosis, 3,612 (55%) patients received chemotherapy; increasing from 52% of patients diagnosed in 2000 to 59% in 2007 (p<0.001). Receipt was significantly higher for patients aged <65 years (64% versus 46% in ≥65) and was inversely related to stage and comorbidites (all p<0.001). Carboplatin and paclitaxel were received most frequently. Erlotinib and bevacizumab use in the later years of the study was associated with a significant change in distributions of first-line chemotherapies (p<0.001).
For patients alive 30 days post diagnosis, chemotherapy use was higher in the aged population (>65 years) than previously published estimates, and higher still in among younger patients. Chemotherapy use increased over the observation period, and the mix of first-line therapies used changed substantially over time. Of note, novel, high cost treatments were used in first-line therapy prior to FDA approval, increasing significantly throughout the study period.
These findings demonstrate the utility of HMO CRN data to augment SEER-Medicare to conduct comparative effectiveness research related to chemotherapy use and the use of specific agents, especially among younger patients.
PMCID: PMC3490021  PMID: 23022316
HMO; chemotherapy; Non-small cell lung cancer; advanced stage; Erlotinib; bevacizumab
12.  Dithiolethione modified valproate and diclofenac increase E-cadherin expression and decrease proliferation of non-small cell lung cancer cells 
Lung cancer (Amsterdam, Netherlands)  2009;68(2):10.1016/j.lungcan.2009.06.012.
The effects of dithiolethione-modified valproate, diclofenac and sulindac on non-small cell lung cancer (NSCLC) cells were investigated. Sulfur(S)-valproate and S-diclofenac at 1 μg/ml concentrations significantly reduced prostaglandin (PG)E2 levels in NSCLC cell lines A549 and NCI-H1299 as did the COX-2 inhibitor DuP-697. In vitro, S-valproate, S-diclofenac and S-sulindac half-maximally inhibited the clonal growth of NCI-H1299 cells at 6, 6 and 15 μg/ml, respectively. Using the MTT assay, 10 μg/ml S-valproate, NO-aspirin and Cay10404, a selective COX-2 inhibitor, but not SC-560, a selective COX-1 inhibitor, inhibited the growth of A549 cells. In vivo, 18 mg/kg i.p. of S-valproate and S-diclofenac, but not S-sulindac, significantly inhibited A549 or NCI-H1299 xenograft proliferation in nude mice, but had no effect on the nude mouse body weight. The mechanism by which S-valproate and S-diclofenac inhibited the growth of NSCLC cells was investigated. Nitric oxide-aspirin but not S-valproate caused apoptosis of NSCLC cells. By Western blot, S-valproate and S-diclofenac increased E-cadherin but reduced vimentin and ZEB1 (a transcriptional suppressor of E-cadherin) protein expression in NSCLC cells. Because S-valproate and S-diclofenac inhibit the growth of NSCLC cells and reduce PGE2 levels, they may prove beneficial in the chemoprevention and/or therapy of NSCLC,
PMCID: PMC3835159  PMID: 19628293
S-valproate; S-diclofenac; lung cancer; PGE2; E-cadherin
13.  Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells 
EZH2 (enhancer of zeste homolog 2) is the catalytic subunit of PRC2 (polycomb repressive complex 2), which mediates histone methyltransferase activity and functions as transcriptional repressor involved in gene silencing. EZH2 is involved in malignant transformation and biological aggressiveness of several human malignancies. We previously demonstrated that non-small cell lung cancers (NSCLCs) also overexpress EZH2 and that high expression of EZH2 correlates with poor prognosis. Growing evidence indicates that EZH2 may be an appropriate therapeutic target in malignancies, including NSCLCs. Recently, an S-adenosyl-L homocysteine hydrolase inhibitor, 3-Deazaneplanocin A (DZNep), has been shown to deplete and inhibit EZH2. The aim of this study was to determine the effect of DZNep in NSCLC cells. Knockdown of EZH2 by small-interfering RNA (siRNA) resulted in decreased growth of four NSCLC cell lines. MTT assays demonstrated that DZNep treatment resulted in dose-dependent inhibition of proliferation in the NSCLC cell lines with a half maximal inhibitory concentration (IC50) ranging from 0.08 to 0.24 μM. Immortalized but non-cancerous bronchial epithelial and fibroblast cell lines were less sensitive to DZNep than the NSCLC cell lines. Soft agarose assays demonstrated that anchorage-independent growth was also reduced in all three NSCLC cell lines that were evaluated using this assay. Flow cytometry analysis demonstrated that DZNep induced apoptosis and G1 cell cycle arrest in NSCLC cells, which was partially associated with cyclin A decrease and p27Kip1 accumulation. DZNep depleted cellular levels of EZH2 and inhibited the associated histone H3 lysine 27 trimethylation. These results indicated that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treatment of NSCLCs.
PMCID: PMC3472089  PMID: 22925699
3-deazaneplanocin A (DZNep); polycomb-group protein; EZH2; non-small cell lung cancer; epigenetics; proliferation; apoptosis
14.  Unsuspected pulmonary embolism in lung cancer patients: Comparison of clinical characteristics and outcome with suspected pulmonary embolism ☆ 
Compare the clinical characteristics, rate of recurrent venous thromboembolism (VTE) and outcome of suspected and unsuspected pulmonary embolism (PE) detected on computed tomography in patients with lung cancer.
In this IRB-approved retrospective study, 77 patients [38 men, 39 women; mean age 64 (range, 35-90)] with lung cancer who developed PE between January 2004 and December 2009 were identified using research patient data registry and medical records. Patients with suspected (45/77,58%) and unsuspected (32/77,42%) PE were compared for the characteristics, treatment of PE, and rate of recurrent VTE using Fisher's exact test. The survival was compared using log-rank test, and Cox proportional hazards regression models were applied for univariate and multivariable analyses.
Most cases of PE were found in patients undergoing chemotherapy (79%) and with metastatic disease (70%). Suspected PE more commonly involved main/lobar pulmonary arteries (33/45,73% vs. 9/32, 28%), while unsuspected PE more frequently involved of segmental/subsegmental arteries (p = 0.0001). All 11 cases of squamous cell carcinoma had suspected PE. Suspected and unsuspected PE did not differ in terms of age, gender, presence of metastatic disease at the time of PE or treatment for PE. 44/45 (98%) patients with suspected PE and 30/32 (94%) patients with unsuspected PE were treated for PE, mostly with anticoagulation (68/74,92%). Recurrent VTE was seen in 20% (9/45) of suspected PE and 19% (6/32) of unsuspected PE (p = 1.00). Median survival after PE was 5.6 months in suspected group and 6.2 month in unsuspected group, without significant difference by univariate or multivariate analyses.
Although unsuspected PE more frequently involved peripheral pulmonary arteries, the treatments of PE, bleeding complications, rates of recurrent VTE, and survival after PE were similar for clinically suspected and unsuspected PE.
PMCID: PMC3605722  PMID: 22959241
Lung cancer; Pulmonary embolism; Venous thromboembolism
15.  Smoking cessation is challenging even for patients recovering from lung cancer surgery with curative intent 
Although it is recommended that smokers undergoing surgery for lung cancer quit smoking to reduce post-operative complications, few studies have examined patterns of smoking in the peri-operative period. The goals of this study were to determine: 1) patterns of smoking during post-operative recovery, 2) types of cessation strategies used to quit smoking, and 3) factors related to smoking after lung cancer surgery.
Data were collected from 94 patients through chart review, tobacco, health-status, and symptom questionnaires at 1, 2, and 4-months after surgery. Smoking status was assessed through self-report and urinary cotinine measurement.
Eighty-four patients (89%) were ever-smokers and 35 (37%) reported smoking at diagnosis. Thirty-nine (46%) ever-smokers remained abstinent, 13 (16%) continued smoking at all time-points, and 32 (38%) relapsed. Ten (46%) of those who relapsed were former-smokers and had not smoked for at least 1-year. Sixteen (46%) of those who were smoking at diagnosis received cessation assistance with pharmacotherapy being the most common strategy. Factors associated with smoking during recovery were younger age and quitting smoking ≤ six-months before the diagnosis of lung cancer. Factors that were marginally significant were lower educational level, male gender, lower number of comorbidities, and the presence of pain
Only half of those who were smoking received assistance to quit prior to surgery. Some patients were unable to quit and relapse rates post-surgery were high even among those who quit more than 1-year prior. Innovative programs incorporating symptom management and relapse prevention may enhance smoking abstinence during post-operative care.
PMCID: PMC3805262  PMID: 19321223
lung cancer; thoracic surgery; smoking cessation; symptom management
16.  Survival among Non-Small Cell Lung Cancer Patients with Poor Performance Status after First Line Chemotherapy 
Performance status (PS) is a commonly used factor in determining the appropriateness for chemotherapy of patients with non-small cell lung cancer (NSCLC). The prevalence of poor PS and impact of chemotherapy on survival among NSCLC patients has not been studied in community populations.
Patients and Methods
Insured patients, aged 50+ years, diagnosed with advanced stage NSCLC between 2000 and 2007 were identified via tumor registry (n=292) and linked to electronic medical records, automated medical claims, and Census tract information. A multivariate Cox proportional hazards model was used to determine the factors associated with survival.
Of 292 stage IIIB-IV patients, 82 (28%) had PS 3 or 4, and 39% of PS 3–4 patients received first line chemotherapy. Those who received chemotherapy lived 4.8 months compared to 2.4 months for those who did not. Factors associated with a reduced likelihood of death included receipt of chemotherapy (hazard ratio [HR], 0.64), and female gender (HR, 0.71).
Modern chemotherapy may be associated with positive effects on survival for poor PS patients, as for good PS patients. Further trials, especially randomized trials, in this neglected subgroup are indicated.
PMCID: PMC3423534  PMID: 22633939
chemotherapy; non-small cell lung cancer; performance status; survival; advanced stage; guidelines
17.  Issues Surrounding Clinical Trial Endpoints in Solid Malignancies With a Focus on Metastatic Non-Small Cell Lung Cancer 
Relative to best supportive care alone, cytotoxic chemotherapy has an established role in prolonging overall survival (OS) in patients with or without previous treatment for metastatic non-small cell lung cancer (NSCLC). OS has been the principal endpoint influencing regulatory decisions regarding targeted therapies for metastatic NSCLC, including the vascular endothelial growth factor monoclonal antibody bevacizumab in the frontline setting and the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib in patients after prior treatment. Progression-free survival (PFS), another common endpoint in oncology clinical trials, has been discussed as a potential surrogate for OS in metastatic NSCLC. A number of phase III clinical trials of investigational targeted agents for treatment of metastatic NSCLC are ongoing, with OS designated as the primary endpoint in some cases and PFS in others. Both endpoints have been developed largely to evaluate outcomes in unselected populations in which a fraction of patients are anticipated to derive significant benefit. New approaches are being considered for the evaluation of targeted agents. Recent high profile trials have been designed to assess PFS using a randomized discontinuation design and disease control rate after 8 weeks of treatment. With a series of recent advances towards increasingly personalized biomarker-directed anticancer therapies, the appropriateness of the traditional regulatory approach has been questioned.
PMCID: PMC3737740  PMID: 22795702
lung cancer; progression-free survival; overall survival; surrogate endpoint; disease control rate; clinical research
18.  Single agent maintenance therapy for advanced stage non-small cell lung cancer: A meta-analysis 
Maintenance therapy is a new treatment paradigm for advanced non-small cell lung cancer (NSCLC). We conducted a meta-analysis of randomized studies with single agent maintenance therapy.
An electronic literature search of public databases (MEDLINE, EMBASE, Cochrane library) and manual search of relevant conference proceedings was performed. A formal meta-analysis was conducted using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as hazard ratio (HR). The primary outcome of interest was overall survival (OS) and secondary outcome was progression free survival (PFS).
Twelve studies were included (5 meeting abstracts, 7 full manuscripts) with a total of 4286 patients (maintenance arm/control arm- 2449/1837, median age 61 years, males -69 %). The OS (HR 0.86, 95% confidence intervals [CI] 0.80-0.92; P=0.0003) and PFS (HR 0.80, 95% CI 0.77-0.84; P<0.0001) were superior with maintenance therapy. ‘Switch’ maintenance was associated with significant OS and PFS improvement (OS HR 0.84, 95% CI 0.77-0.91; P=0.00026; PFS HR 0.62, 95% CI 0.57-0.67; P<0.0001). Despite a modest improvement in PFS (HR 0.90, 95%CI 0.85-0.95; P=0.007), “continuation” maintenance was not associated with survival benefit (HR 0.927, 95%CI 0.78-1.09; P=0.33). Improvements in OS and PFS were observed with both EGFR-targeted agents (HR 0.83, 95% CI 0.74-0.92; P=0.004; HR 0.64, 95% CI 0.58-0.71 P<0.0001) and cytotoxic agents (HR 0.89, 95% CI 0.80-0.98; P=0.018; HR 0.85, 95% CI 0.80-0.89; P < 0.0001).
Single agent maintenance therapy improves overall survival, though statistical significance was only noted with ‘switch’ maintenance.
PMCID: PMC3396772  PMID: 22546678
Maintenance therapy; non-small cell lung cancer; NSCLC; EGFR; pemetrexed; erlotinib; gefitinib
19.  Characterization of vitamin D receptor (VDR) in lung adenocarcinoma 
The anti-proliferative effects of 1α,25-dihydroxyvitamin D3 (1,25-D3, calcitriol, the active form of vitamin D) are mediated by the nuclear vitamin D receptor (VDR). In the present study, we characterized VDR expression in lung adenocarcinoma (AC).
Experimental Design
We examined VDR mRNA expression using a quantitative real-time PCR (qRT-PCR) in 100 patients who underwent surgery for lung AC. In a subset of these patients (n = 89), we examined VDR protein expression using immunohistochemistry. We also examined the association of VDR protein expression with circulating serum levels of 25-hydroxyvitamin D3 (25-D3) and 1,25-D3. The antiproliferative effects and cell cycle arrest of 1,25-D3 were examined using lung cancer cell lines with high (SKLU-1) as well as low (A549) expression of VDR mRNA.
Higher VDR expression correlates with longer survival after adjusting for age, sex, disease stage and tumor grade (HR 0.73, 95% CI 0.58–0.91). In addition, there was a positive correlation (r = 0.38) between serum 1,25-D3 and tumor VDR protein expression. A greater anti-proliferative effect of 1,25-D3 was observed in high compared to low VDR-expressing cell lines; these effects corresponded to G1 cell cycle arrest; this was associated with a decline in cyclin D1, S-phase kinase protein 2 (Skp2), retinoblastoma (Rb) and minichromosome maintenance 2 (MCM2) proteins involved in S-phase entry.
Increased VDR expression in lung AC is associated with improved survival. This may relate to a lower proliferative status and G1 arrest in high VDR-expressing tumors.
PMCID: PMC3396768  PMID: 22564539
VDR; Vitamin D; 1,25-D3; Lung Adenocarcinoma; Survival
20.  Non-steroidal anti-inflammatory drugs and small cell lung cancer risk in the VITAL study 
Few studies have examined the association between non-steroidal anti-inflammatory drug (NSAID) use and risk of small cell lung cancer (SCLC); among them, findings are mixed. Recently, we found that use of NSAIDs was differentially associated with lung cancer risk by histology. Here, we examine, more comprehensively, the association between individual NSAIDs and SCLC risk. 75,546 residents of western Washington State, ages 50–76, completed a baseline questionnaire in 2000–2002 and reported on their use of individual NSAIDs over the past 10 years. NSAID use was categorized as non-users, low (<4 days/week or <4 years), and high (≥4 days/week and ≥4 years). 111 SCLC were identified through linkage to a population-based cancer registry. Multivariable-adjusted Cox proportional hazards models including strong adjustment for smoking were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Compared to non-use, high use of regular-strength aspirin was associated with an elevated risk of SCLC (HR 1.78, 95% CI: 1.05–3.02; P-trend = 0.03). Findings for low-dose aspirin were elevated but did not reach statistical significance. Use of non-aspirin NSAIDs was not associated with SCLC risk. Our findings provide further indication of heterogeneity in the association between aspirin and lung cancer morphologies. Large, prospective studies with comprehensive assessments of NSAID use and smoking history and data on both men and women, are needed in order to better understand the association between use of aspirin and SCLC.
PMCID: PMC3552491  PMID: 22608142
Aspirin; Ibuprofen; NSAID; Small cell lung cancer
21.  Dietary chemoprevention strategies for induction of phase II xenobiotic-metabolizing enzymes in lung carcinogenesis: A review 
Lung cancer is the leading cause of cancer mortality for men and women in the United States and is a growing worldwide problem. Protection against lung cancer is associated with higher dietary intake of fruits and vegetables, according to recent large epidemiologic studies. One strategy for lung cancer chemoprevention focuses on the use of agents to modulate the metabolism and disposition of tobacco, environmental and endogenous carcinogens through upregulation of detoxifying phase II enzymes. We summarize the substantial evidence that suggests that induction of phase II enzymes, particularly the glutathione S-transferases, plays a direct role in chemoprotection against lung carcinogenesis. The engagement of the Keap1–Nrf2 complex regulating the antioxidant response element (ARE) signaling pathway has been identified as a key molecular target of chemopreventive phase II inducers in several systems. Monitoring of phase II enzyme induction has led to identification of novel chemopreventive agents such as the isothiocyanate sulforaphane, and the 1,2-dithiole-3-thiones. However, no agents have yet demonstrated clear benefit in human cell systems, or in clinical trials. Alternative strategies include: (a) using intermediate cancer biomarkers for the endpoint in human trials; (b) high-throughput small molecule discovery approaches for induced expression of human phase II genes; and (c) integrative approaches that consider pharmacogenetics, along with pharmacokinetics and pharmacodynamics in target lung tissue. These approaches may lead to a more effective strategy of tailored chemoprevention efforts using compounds with proven human activity.
PMCID: PMC3730487  PMID: 19185948
Lung cancer; Phase II enzymes; Chemoprevention; Induction; Phytochemicals
22.  A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer 
We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy.
This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14 mg/m2 on days 1 and 3 with IV topotecan at 1.25 mg/m2 on days 1–5 of an every 3-week cycle. The primary end-point of this study was overall response rate.
Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%).
Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.
PMCID: PMC3715068  PMID: 21620511
Obatoclax mesylate; Topotecan; Small cell lung cancer (SCLC); Apoptosis
23.  A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma 
Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody–drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Ley) antigen, conjugated to doxorubicin. Ley is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Ley-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients.
Experimental design
Sixty-two patients with recurrent or metastatic NSCLC expressing Ley, one or two prior chemotherapy regimens, and PS ≤ 2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life.
Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A.
SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.
PMCID: PMC3715069  PMID: 16934909
Immunoconjugate; Targeted therapy; NSCLC; Lewis Y; SGN-15; Monoclonal antibody
24.  Polymorphisms in the promoter region of neutrophil elastase gene and lung cancer risk 
The neutrophil elastase (NE) gene encodes a powerful serine protease that is involved in the process of normal tissue turnover, natural host defense or tissue damage in acute and chronic inflammatory disorders. Furthermore, NE was suggested as one of the determinant factors of individual susceptibility to lung cancer resulting from imbalance between α1-antitrypsin (AT) and NE. To determine whether NE plays a role in risk for lung cancer, we screened polymorphisms in the promoter region of the NE gene and assessed the role of the NE polymorphisms in the risk for lung cancer. We confirmed three previously identified polymorphisms which are located at −903, −741, and extra 52 bp STS relative to the transcription initiation site. In addition, two new polymorphisms at −832 (G/T) and −789 (C/T) were identified. Their rare allelic frequencies of new polymorphism are 0.02 and 0.01, respectively, among Caucasians. The prevalence of the NE −903 (T/T) and (T/G) genotypes were 0.88 and 0.12 in controls as compared to 0.96 and 0.04 in lung cancer patients using genomic DNA isolated from 113 Caucasian lung cancer cases and 131 controls. A significant increase in lung cancer risk was observed for expected high NE activity genotypes (OR = 3.2, 95% CI = 1.02–10.3) as compared to low NE activity genotypes. These results were consistent with previous in vitro functional analysis, which reported an approximately two-fold increase enzyme expression with the −903T/−741G allele as compared to the −903G/−741A variant. These results confirm that the NE promoter region polymorphisms may influence in risk for lung cancer.
PMCID: PMC3698610  PMID: 15892999
Neutrophil elastase; Lung cancer; Genetic polymorphism; Cancer susceptibility
Disagreements between cancer patients and their caregivers about treatment and care can affect the patient’s physical and mental well-being. Therefore it is important to understand if oncologists can accurately identify the presence of patient-caregiver decisional conflict. This study examined assessments made by lung cancer patients, their caregivers, and their oncologists regarding patient-caregiver disagreements concerning treatment and care decisions.
Participants and methods
We assessed the extent to which the patient, caregiver, and oncologist reported disagreement between the patient and the family member regarding treatment decisions in 134 patient-caregiver-oncologist triads. Descriptive statistics were used to explore rates of concordance amongst all possible combinations of raters. Loglinear models were tested for 3-way agreement.
Most patient-caregiver pairs, 82.1% (n=110), reported agreement concerning presence or absence of decisional conflict. Oncologists were more successful in detecting absence of conflict than the presence of conflict. When the caregiver and the oncologist agreed, it was regarding the absence of conflict (64.9%), rather than the presence of conflict. In 10.6 % (n = 15) of cases, oncologists reported that conflictual relationships negatively impacted their ability to provide patient care.
Recent models of cancer patient care promote including the caregiver fully in the process while respecting the primacy of the patient’s perspective. However, these models assume that the oncologist will recognize when disagreements exist and be able to assist in conflict resolution. The degree to which the oncologist identified that conflict exists and implications for their ability to provide patient care when familial disagreements existed are discussed.
PMCID: PMC3368070  PMID: 22405569
lung cancer; family caregivers; treatment; decision making; conflict; patient care

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