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1.  Systemic Therapy, Clinical Outcomes, and Overall Survival in Locally Advanced or Metastatic Pulmonary Carcinoid 
Background
Data to guide the management of advanced pulmonary carcinoid (APC) come from retrospective reports and subgroup analyses of trials that included mainly extrapulmonary carcinoid tumors. We report the largest series to date of 49 patients with locally advanced or metastatic pulmonary carcinoid.
Methods
The Johns Hopkins Pathology Database was reviewed for APC patients treated between January 1992 and December 2012. Data on time to recurrence, progression-free survival, and overall survival were estimated by using the Kaplan–Meier method.
Results
Forty-nine patients were treated for APC in the specified time period. Median time to recurrence after surgical resection was 2.5 years (atypical carcinoid [AC] versus typical carcinoid [TC], 2.5 versus 6.3 years; p = 0.063). Median survival with advanced disease was 7.1 years and significantly longer for TC compared with AC (10.2 versus 4 years; p = 0.009). Among the diverse systemic therapies used, responses occurred in four of 17 patients (23.5%) who received platinum/ etoposide with a median progression-free survival of 7 months.
Conclusion
Although systemic chemotherapy has moderate activity for APC, novel approaches are required. TC and AC, although both classified as pulmonary carcinoid, are clearly different clinical and molecular entities and require separate treatment paradigms in the advanced/metastatic setting.
doi:10.1097/JTO.0000000000000065
PMCID: PMC4322909  PMID: 24518093
Pulmonary carcinoid; Metastatic carcinoid; Chemotherapy pulmonary carcinoid; Chemotherapy bronchial carcinoid; Therapy carcinoid; Atypical carcinoid; Typical carcinoid
2.  Role of CYB5A in Pancreatic Cancer Prognosis and Autophagy Modulation 
Background
Loss of 18q22.3 is a prognostic marker in pancreatic ductal adenocarcinoma (PDAC). This study investigated genes encoded by this cytoband.
Methods
We studied mRNA/protein expression in radically resected (n = 130) and metastatic patients (n = 50). The role of CYB5A was tested in 11 PDAC cell lines and five primary cultures through retrovirus-mediated upregulation and small interfering RNA using wound-healing, invasion, annexin-V, electron microscopy, and autophagic assays, as well as autophagy genes and kinases arrays. CYB5A+ orthotopic models (n = 6 mice/group) were monitored by Firefly and Gaussia-luciferase bioluminescence, magnetic resonance imaging, and high-frequency ultrasound. Data were analyzed by t test, Fisher exact-test, log-rank test and Cox proportional hazards models. All statistical tests were two-sided.
Results
Both resected and metastatic patients with low mRNA or protein expression of CYB5A had statistically significantly shorter survival (eg, median = 16.7 months, 95% confidence interval [CI] = 13.5 to 19.9; vs median = 24.8 months, 95% CI = 12.8 to 36.9; P = .02, two-sided log-rank test; n = 82 radically resected PDACs), and multivariable analyses confirmed prognostic relevance. Moreover, we characterized a novel function to CYB5A, autophagy induction, concomitant with reduced proliferation and migration/invasion of PDAC cells. Network analysis of proautophagic pathways suggested CYB5A interaction with TRAF6, which was confirmed by TRAF6 downregulation after CYB5A reconstitution (−69% in SU.86.86-CYB5A+; P = .005, two-sided t test). CYB5A silencing had opposite effects, restoring TRAF6 expression and wound healing. In vivo studies showed that CYB5A induced autophagy while inhibiting tumor growth/metastasis and increasing survival (median = 57 days, 95% CI = 52 to 61; vs median = 44 days, 95% CI = 21 to 57; P = .03, two-sided log-rank test).
Conclusions
These results define CYB5A as a novel prognostic factor for PDAC that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation.
doi:10.1093/jnci/djt346
PMCID: PMC3906994  PMID: 24301457
3.  The janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo 
Purpose
The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of janus kinases (JAKs) inhibitor AZD1480 for treatment of SCLC in vitro and in vivo.
Experimental Design
JAK1 or JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell cycle distribution and apoptosis induction were studied. Antitumor effects of AZD1480 in tumor xenografts were assessed.
Results
AZD1480 significantly inhibited growth of 6 out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μM. Knocking-down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in increase of 4N DNA content and Histone 3 serine 10 phosphorylation, indicative of G2/M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved-Caspase 3, cleaved PARP and increase of annexin-V positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31 positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment.
Conclusions
Janus kinases inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation.
doi:10.1158/1078-0432.CCR-13-1110
PMCID: PMC3872034  PMID: 24158701
Small cell lung carcinoma; Janus kinases; Therapy
4.  Mutations of epigenetic regulatory genes are common in thymic carcinomas 
Scientific Reports  2014;4:7336.
Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78 TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy.
doi:10.1038/srep07336
PMCID: PMC4258655  PMID: 25482724
5.  Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs 
IMPORTANCE
Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
OBJECTIVES
To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival.
DESIGN, SETTING, AND PARTICIPANTS
From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival.
INTERVENTIONS
Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies.
MAIN OUTCOMES AND MEASURES
Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival.
RESULTS
From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score–adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006).
CONCLUSIONS AND RELEVANCE
Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.
doi:10.1001/jama.2014.3741
PMCID: PMC4163053  PMID: 24846037
6.  Capillary isoelectric-focusing immunoassays to study dynamic oncoprotein phosphorylation and drug response to targeted therapies in non-small cell lung cancer 
Molecular cancer therapeutics  2013;12(11):10.1158/1535-7163.MCT-13-0074.
Developing proteomic biomarkers is valuable for evaluating therapeutic effects of drugs and generating better treatment strategies. However, conventional protein analysis is often challenging due to inadequate sample size of clinical specimens, lack of assay reproducibility, accuracy and sensitivity. A novel capillary isoelectricfocusing (IEF) immunoassay system (NanoPro) was used to study the dynamic phosphorylation status of signaling molecules in non-small cell lung cancer (NSCLC) cells treated with EGFR tyrosine kinase and MEK inhibitors. NanoPro showed the same dynamic ERK phosphorylation as western blotting with good assay reproducibility using 1,000 times less protein. The IEF separation in NanoPro system enables multiple protein phosphorylation isoforms to be resolved and detected simultaneously. With NanoPro, we identified a specific on-target MEK response pattern to MEK inhibitor PD325901, which was not detectable by western blotting. We also revealed a MEK2 signal that may be associated with NSCLC cell sensitivity to EGFR inhibitor erlotinib, and distinguish erlotinib-sensitive from -intrinsic as well as -acquired resistant cells. Moreover, NanoPro could differentiate human ERK1 isoforms from the mouse isoforms based on their pI differences and demonstrated that erlotinib effectively inhibited ERK phosphorylation in targeted human xenograft cancer cells but not in surrounding mouse stromal cells. With 8 ug of tumor aspirates, we precisely quantified the response of 18 signaling molecules to erlotinib and MEK1 inhibitor treatments in a NSCLC patient.
NanoPro’s higher sensitivity, better resolution of protein phosphorylation status and reduced tissue requirement warrant NanoPro’s investigation for future drug development and evaluation of drug effects of targeted therapies.
doi:10.1158/1535-7163.MCT-13-0074
PMCID: PMC3823739  PMID: 23979919
Lung cancer; Methodology for proteomics; Novel assay technology; Xenograft models; Cellular responses to anticancer drugs
8.  Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors 
Objective
To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed.
Participants
Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies.
Evidence
Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation.
Consensus Process
Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4).
Conclusions
The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
doi:10.5858/arpa.2012-0720-OA
PMCID: PMC4162344  PMID: 23551194
9.  Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors 
Objective
To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed.
Participants
Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies.
Evidence
Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation.
Consensus Process
Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4).
Conclusions
The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
doi:10.1097/JTO.0b013e318290868f
PMCID: PMC4159960  PMID: 23552377
10.  Effect of Talactoferrin Alfa on the Immune System in Adults With Non-Small Cell Lung Cancer 
The Oncologist  2013;18(7):821-822.
Background.
Talactoferrin alfa (talactoferrin), an agent with immune-stimulating properties, has demonstrated safety and preliminary efficacy in clinical trials.
Methods.
Ten patients (five males and five females) with stage IV non-small cell lung cancer (NSCLC) in a single-arm pilot study received orally administered talactoferrin (1.5 g, b.i.d.) for up to 24 weeks. Radiographic and immunologic studies were performed at baseline and at weeks 6 and 12. Circulating immune cells (natural killer cells [NKCs], CD4+, CD8+, and regulatory T cells) and systemic cytokine levels were measured to assess immune response.
Results.
Patients enrolled in the study had received a median of four prior chemotherapy regimens, and all patients were symptomatic. Talactoferrin was well tolerated, with no grade 3 or 4 toxicities. Median time to progression (TTP) and overall survival were 6 weeks and 14.5 weeks, respectively. The four patients with ≥9 weeks TTP had evidence of immunologic activity (three with increased NKC activity).
Conclusions.
The median of four previous chemotherapy regimens, with elevated levels of interleukin (IL) 6 and tumor necrosis factor-alfa in most patients, suggests these patients were poor candidates for immunotherapy.
doi:10.1634/theoncologist.2013-0199
PMCID: PMC3720636  PMID: 23847257
11.  CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance 
The Journal of Clinical Investigation  2014;124(7):3003-3015.
The majority of non–small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI–sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC.
doi:10.1172/JCI73048
PMCID: PMC4071378  PMID: 24911146
12.  Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors 
Purposes
To determine if the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors.
Experimental Design
Using array comparative genomic hybridization, we evaluated the copy number aberrations of genes regulating thymus development. The expression of genes most commonly involved in copy number aberrations was evaluated by immunohistochemistry and correlated with patients' outcome. Correlation between FOXC1 copy number loss and gene expression was determined in a confirmation cohort. Cell lines were used to test the role of FOXC1 in tumors.
Results
Among 31 thymus development-related genes, PBX1 copy number gain and FOXC1 copy number loss were presented in 43.0% and 39.5% of the tumors respectively. Immunohistochemistry on a series of 132 thymic epithelial tumors including those evaluated by comparative genomic hybridization, revealed a correlation between protein expression and copy number status only for FOXC1 but not for PBX1. Patients with FOXC1–negative tumors had a shorter time to progression and a trend for a shorter disease related survival. The correlation between FOXC1 copy number loss and mRNA expression was confirmed in a separate cohort of 27 thymic epithelial tumors. Ectopic FOXC1 expression attenuated anchorage-independent cell growth and cell migration in vitro.
Conclusion
Our data support a tumor suppressor role of FOXC1 in thymic epithelial tumors.
doi:10.1158/1078-0432.CCR-12-3260
PMCID: PMC3630263  PMID: 23444221
thymic epithelial tumors; thymoma; thymic carcinoma; FOXC1; PBX1; thymus development
14.  18F-Fluorodeoxyglucose positron emission tomography in the management of patients with thymic epithelial tumors 
Purpose
There is limited data regarding the role of 18F-Fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) imaging in management of patients with thymic epithelial tumors (TET). The primary objective of this study was to assess the usefulness of early [18F]-FDG PET to monitor treatment efficacy and its correlation with Response Evaluation Criteria in Solid Tumors (RECIST) in patients with TETs.
Experimental Design
[18F]-FDG PET/CT scans were performed at baseline and after six weeks of treatment in patients enrolled in two phase II and one phase I/II clinical trials. Based on data from other solid tumors, metabolic response was defined as a reduction of [18F]-FDG uptake by more than 30% as assessed by average standardized uptake values (SUV) of up to five most metabolically active lesions.
Results
Fifty six patients with unresectable Masaoka stage III or IV TETs were included. There was a close correlation between early metabolic response and subsequent best response using RECIST (P <0.0001 to 0.0003): sensitivity and specificity for prediction of best response were 95% and 100% respectively. Metabolic responders had significantly longer progression-free survival (median 11.5 vs. 4.6 months, P = 0.044) and a trend towards longer overall survival (median 31.8 vs. 18.4 months, P = 0.14) than non-responders. [18F]-FDG uptake was significantly higher in thymic carcinoma compared with thymoma (P= 0.0004 to 0.0010).
Conclusion
In patients with advanced TETs, early metabolic response closely correlates with outcome of therapy. [18F]-FDG PET may be used to monitor treatment efficacy and assess histological differences in patients with advanced TETs.
doi:10.1158/1078-0432.CCR-12-2929
PMCID: PMC3602145  PMID: 23382114
thymoma; thymic carcinoma; 18F-Fluorodeoxyglucose positron emission tomography; Response Evaluation Criteria in Solid Tumors; Metabolic response
15.  Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells 
European journal of pharmacology  2010;637(0):38-45.
Neuromedin B (NMB), a member of the bombesin family of peptides, is an autocrine growth factor for many lung cancer cells. The present study investigated the ability of NMB to cause transactivation of the epidermal growth factor (EGF) receptor in lung cancer cells. By Western blot, addition of NMB or related peptides to NCI-H1299 human non-small cell lung cancer (NSCLC) cells, caused phosphorylation of Tyr1068 of the EGF receptor. The signal was amplified using NCI-H1299 cells stably transected with NMB receptors. The transactivation of the EGF receptor or the tyrosine phosphorylation of ERK caused by NMB-like peptides was inhibited by AG1478 or gefitinib (tyrosine kinase inhibitors) and NMB receptor antagonist PD168368 but not the GRP receptor antagonist, BW2258U89. The transactivation of the EGF receptor caused by NMB-like peptides was inhibited by GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), or transforming growth factor (TGF)α antibody. The transactivation of the EGF receptor and the increase in reactive oxygen species caused by NMB-like peptides was inhibited by N-acetylcysteine (NAC) or Tiron. Gefitinib inhibited the proliferation of NCI-H1299 cells and its sensitivity was increased by the addition of PD168368. The results indicate that the NMB receptor regulates EGF receptor transactivation by a mechanism dependent on Src as well as metalloprotease activation and generation of reactive oxygen species.
doi:10.1016/j.ejphar.2010.03.057
PMCID: PMC3921891  PMID: 20388507
lung cancer; neuromedin B; epidermal growth factor receptor; transactivation; reactive oxygen species
16.  BRIEF REPORT: CHARACTERIZATION AND MANAGEMENT OF CARDIAC INVOLVEMENT OF THYMIC EPITHELIAL TUMORS 
Introduction
Although thymic epithelial tumors (TET) commonly infiltrate mediastinal structures, cardiac involvement is uncommon and has not been systematically studied. The purpose of this study was to describe our single-institution experience of the clinical presentation, treatment and follow up of cardiac involvement in patients with TETs.
Methods
A single institution retrospective review of cardiac involvement among patients with TETs from 2008 to 2012.
Results
The frequency of cardiac involvement was 4%. All five patients with confirmed cardiac disease had left heart involvement. Only one patient was symptomatic. Myocardial invasion was the most common mode of involvement followed by trans-venous spread. Surgical resection of the involved area was attempted in three patients: in one, surgery was aborted due to extensive myocardial involvement; in the other two patients, resection was incomplete. Surgery averted a potentially catastrophic hemodynamic complication in one patient. However, cardiac tumor recurred in both patients who underwent incomplete resection. One patient underwent radiation therapy resulting in complete regression of an aortic root mass.
Conclusions
This study represents the most comprehensive review of cardiac involvement in patients with TETs. In contrast to previous single-case reports, we found a preponderance of asymptomatic presentation, left heart involvement and myocardial invasion. Dynamic cardiovascular magnetic resonance imaging should be considered in cases when cardiac involvement is suspected. While immediate surgical resection is indicated for impending hemodynamic compromise, long-term palliation with surgery for myocardial involvement appears poor, especially when complete resection cannot be performed. Radiation therapy should be considered in selected patients.
doi:10.1097/JTO.0b013e31827bd931
PMCID: PMC3552332  PMID: 23328550
thymic epithelial tumors; cardiac tumors; cardiovascular magnetic resonance imaging
17.  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,
doi:10.1016/j.lungcan.2009.06.012
PMCID: PMC3835159  PMID: 19628293
S-valproate; S-diclofenac; lung cancer; PGE2; E-cadherin
19.  Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer 
Purpose
Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-xL. The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy.
Experimental Design
Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates.
Results
The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III–IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro–gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit.
Conclusion
Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.
doi:10.1158/1078-0432.CCR-11-3090
PMCID: PMC3715059  PMID: 22496272
20.  Tyrosine Kinase Inhibitors in Lung Cancer 
SYNOPSIS
‘Driver mutations’ are essential for carcinogenesis as well as tumor progression as they confer a selective growth advantage to cancer cells. Identification of driver mutations in growth related protein kinases, especially tyrosine kinases have led to clinical development of an array of tyrosine kinase inhibitors in various malignancies, including lung cancer. Inhibition of epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinases have proven to be of meaningful clinical benefit, while inhibition of several other tyrosine kinases have been of limited clinical benefit, thus far. An improved understanding of tyrosine kinase biology has also led to faster drug development, identification of resistance mechanisms and ways to overcome resistance. In this review, we discuss the clinical data supporting the use and practical aspects of management of patients on epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors.
doi:10.1016/j.hoc.2012.02.001
PMCID: PMC3334853  PMID: 22520981
Non-small cell lung cancer; tyrosine kinase inhibitor; epidermal growth factor receptor; ALK-translocation; Vascular endothelial growth factor
21.  Whole Genome and Transcriptome Sequencing of a B3 Thymoma 
PLoS ONE  2013;8(4):e60572.
Molecular pathology of thymomas is poorly understood. Genomic aberrations are frequently identified in tumors but no extensive sequencing has been reported in thymomas. Here we present the first comprehensive view of a B3 thymoma at whole genome and transcriptome levels. A 55-year-old Caucasian female underwent complete resection of a stage IVA B3 thymoma. RNA and DNA were extracted from a snap frozen tumor sample with a fraction of cancer cells over 80%. We performed array comparative genomic hybridization using Agilent platform, transcriptome sequencing using HiSeq 2000 (Illumina) and whole genome sequencing using Complete Genomics Inc platform. Whole genome sequencing determined, in tumor and normal, the sequence of both alleles in more than 95% of the reference genome (NCBI Build 37). Copy number (CN) aberrations were comparable with those previously described for B3 thymomas, with CN gain of chromosome 1q, 5, 7 and X and CN loss of 3p, 6, 11q42.2-qter and q13. One translocation t(11;X) was identified by whole genome sequencing and confirmed by PCR and Sanger sequencing. Ten single nucleotide variations (SNVs) and 2 insertion/deletions (INDELs) were identified; these mutations resulted in non-synonymous amino acid changes or affected splicing sites. The lack of common cancer-associated mutations in this patient suggests that thymomas may evolve through mechanisms distinctive from other tumor types, and supports the rationale for additional high-throughput sequencing screens to better understand the somatic genetic architecture of thymoma.
doi:10.1371/journal.pone.0060572
PMCID: PMC3618227  PMID: 23577124
22.  NUT Rearrangement is Uncommon in Human Thymic Epithelial Tumors 
Journal of Thoracic Oncology  2012;7(4):744-750.
INTRODUCTION
Thymic carcinomas represent the most aggressive histotype of thymic epithelial tumors (TETs). The 2004 World Health Organization (WHO) classification has assigned a subgroup of thymic carcinomas as t(15:19) carcinomas based on the presence of t(15;19), a translocation found in poorly differentiated and highly aggressive NUT midline carcinomas (NMC). These tumors are characterized by rearrangement of the NUT (nuclear protein in testis) gene on chromosome 15q14, which in most cases fuses to the bromomdomain containing 4 (BRD4) gene on chromosome 19p13.1 through reciprocal t(15;19) translocation, resulting in constitutive BRD4-NUT fusion protein expression. To our knowledge, NUT translocation has been reported only in four thymic carcinomas. Due to the rarity of TETs, the prevalence of NUT rearrangement in TETs has however never been systematically explored.
METHODS
Formalin-fixed paraffin-embedded samples of histologically-confirmed TETs were evaluated for NUT expression and rearrangement by immunohistochemistry and fluorescence in-situ hybridization respectively.
RESULTS
A series of 148 TETs (37 carcinomas and 111 thymomas) were examined for NUT expression and rearrangement. Only one thymic carcinoma (2.7% of thymic carcinomas or 0.68% of TETs) was found positive for NUT expression and rearrangement.
CONCLUSIONS
Rearrangement of NUT is infrequent in TETs. We propose that caution should be taken to distinguish t(15;19) thymic carcinoma from other mediastinal carcinomas, as NMCs are often associated with dreadful prognosis or overt lethality.
doi:10.1097/JTO.0b013e3182460f8f
PMCID: PMC3308127  PMID: 22425924
t(15;19) translocation; BRD4-NUT; thymoma; thymic carcinoma
23.  Treatment of Non Small Cell Lung Cancer: Overcoming the resistance to EGFR inhibitors 
Current Opinion in Oncology  2012;24(2):123-129.
PURPOSE OF REVIEW
Testing for epidermal growth factor receptor (EGFR) mutations has become standard practice in treating patients with advanced nonsmall cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are being offered as first line therapy in patients with EGFR activating mutations. These drugs offer an increased progression free survival and response rate compared to standard chemotherapy in this setting, however resistance invariably occurs. This review discusses the development of resistance to EGFR TKIs and the progress that is being made to better understand how to overcome this resistance.
RECENT FINDINGS
Results from recently published papers dealing with resistance to EGFR TKIs are allowing for a better understanding of this mechanism. No one treatment allows for overcoming this resistance. Understanding this resistance will likely become an individualized patient/tumor approach. Selecting which drug or drugs that may be suitable can only be determined based on the molecular mechanism of resistance.
SUMMARY
Progress is being made in our understanding of the multiple pathways of resistance. Using a tumors molecular signature at the time of progression can determine the best treatment option.
doi:10.1097/CCO.0b013e32834ec6a7
PMCID: PMC3277209  PMID: 22314615
Epidermal Growth Factor Receptor; Tyrosine Kinase Inhibitors; Resistance; Lung Cancer
24.  Loss of 18q22.3 involving the carboxypeptidase of glutamate-like gene is associated with poor prognosis in resected pancreatic cancer 
Clinical Cancer Research  2011;18(2):524-533.
Purposes
Pancreatic cancer is the 4th-leading cause of cancer-related death, and studies on the clinical relevance of its genomic imbalances are warranted.
Experimental Design
Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens. Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent validation cohort of 61 resected pancreatic cancers. The functions of gene identified were evaluated by proliferation, cell cycle and migration assays in pancreatic cancer cells.
Results
We demonstrated recurrent copy number gains and losses in the first cohort. Loss of 18q22.3 was significantly associated with short-term overall survival in the first cohort (p=0.019). This cytoband includes the Carboxypeptidase of glutamate-like (CPGL) gene. CPGL gene deletion was associated with shorter overall survival in the validation cohort (p=0.003). CPGL deletion and mutations of TP53 or Kras appear to be independent events. A Cox model analysis of the two cohorts combined showed that loss of 18q22.3/deletion of the CPGL gene was an independent poor prognostic factor for overall survival (hazard ratio=2.72, p=0.0007). Reconstitution of CPGL or its splicing-variant CPGL-B into CPGL-negative pancreatic cancer cells attenuated cell growth, migration, and induced G1-accumulation.
Conclusion
Loss of 18q22.3/deletion of the CPGL gene is a poor prognostic marker in resected pancreatic cancer, and functional studies suggest the CPGL gene as growth suppressor gene in pancreatic cancer.
doi:10.1158/1078-0432.CCR-11-1903
PMCID: PMC3261299  PMID: 22128300
Pancreatic cancer; Comparative genomics; CPGL protein; human; Prognosis; Growth suppressor
25.  Targeting the Epigenome in Lung Cancer: Expanding Approaches to Epigenetic Therapy 
Frontiers in Oncology  2013;3:261.
Epigenetic aberrations offer dynamic and reversible targets for cancer therapy; increasingly, alteration via overexpression, mutation, or rearrangement is found in genes that control the epigenome. Such alterations suggest a fundamental role in carcinogenesis. Here, we consider three epigenetic mechanisms: DNA methylation, histone tail modification and non-coding, microRNA regulation. Evidence for each of these in lung cancer origin or progression has been gathered, along with evidence that epigenetic alterations might be useful in early detection. DNA hypermethylation of tumor suppressor promoters has been observed, along with global hypomethylation and hypoacetylation, suggesting an important role for tumor suppressor gene silencing. These features have been linked as prognostic markers with poor outcome in lung cancer. Several lines of evidence have also suggested a role for miRNA in carcinogenesis and in outcome. Cigarette smoke downregulates miR-487b, which targets both RAS and MYC; RAS is also a target of miR-let-7, again downregulated in lung cancer. Together the evidence implicates epigenetic aberration in lung cancer and suggests that targeting these aberrations should be carefully explored. To date, DNA methyltransferase and histone deacetylase inhibitors have had minimal clinical activity. Explanations include the possibility that the agents are not sufficiently potent to invoke epigenetic reversion to a more normal state; that insufficient time elapses in most clinical trials to observe true epigenetic reversion; and that doses often used may provoke off-target effects such as DNA damage that prevent epigenetic reversion. Combinations of epigenetic therapies may address those problems. When epigenetic agents are used in combination with chemotherapy or targeted therapy it is hoped that downstream biological effects will provoke synergistic cytotoxicity. This review evaluates the challenges of exploiting the epigenome in the treatment of lung cancer.
doi:10.3389/fonc.2013.00261
PMCID: PMC3793201  PMID: 24130964
epigenetics; non-small cell lung cancer; small-cell lung cancer; DNA methylation; histone modification; microRNA

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