Publications by authors named "Edward Gabrielson"

124 Publications

Proteomic signatures of 16 major types of human cancer reveal universal and cancer-type-specific proteins for the identification of potential therapeutic targets.

J Hematol Oncol 2020 12 7;13(1):170. Epub 2020 Dec 7.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, 21231, USA.

Background: Proteomic characterization of cancers is essential for a comprehensive understanding of key molecular aberrations. However, proteomic profiling of a large cohort of cancer tissues is often limited by the conventional approaches.

Methods: We present a proteomic landscape of 16 major types of human cancer, based on the analysis of 126 treatment-naïve primary tumor tissues, 94 tumor-matched normal adjacent tissues, and 12 normal tissues, using mass spectrometry-based data-independent acquisition approach.

Results: In our study, a total of 8527 proteins were mapped to brain, head and neck, breast, lung (both small cell and non-small cell lung cancers), esophagus, stomach, pancreas, liver, colon, kidney, bladder, prostate, uterus and ovary cancers, including 2458 tissue-enriched proteins. Our DIA-based proteomic approach has characterized major human cancers and identified universally expressed proteins as well as tissue-type-specific and cancer-type-specific proteins. In addition, 1139 therapeutic targetable proteins and 21 cancer/testis (CT) antigens were observed.

Conclusions: Our discoveries not only advance our understanding of human cancers, but also have implications for the design of future large-scale cancer proteomic studies to assist the development of diagnostic and/or therapeutic targets in multiple cancers.
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http://dx.doi.org/10.1186/s13045-020-01013-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720039PMC
December 2020

NRF2 Activation Promotes Aggressive Lung Cancer and Associates with Poor Clinical Outcomes.

Clin Cancer Res 2021 Feb 19;27(3):877-888. Epub 2020 Oct 19.

Translational Oncology, Genentech Inc., South San Francisco, California.

Purpose: Stabilization of the transcription factor NRF2 through genomic alterations in and occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, loss often co-occurs with loss and -activating alterations. Despite its prevalence, the impact of NRF2 activation on tumor progression and patient outcomes is not fully defined.

Experimental Design: We model NRF2 activation, loss, and activation using novel genetically engineered mouse models. Furthermore, we derive a NRF2 activation signature from human non-small cell lung tumors that we use to dissect how these genomic events impact outcomes and immune contexture of participants in the OAK and IMpower131 immunotherapy trials.

Results: Our data reveal roles for NRF2 activation in (i) promoting rapid-onset, multifocal intrabronchiolar carcinomas, leading to lethal pulmonary dysfunction, and (ii) decreasing elevated redox stress in -mutant, -null tumors. In patients with nonsquamous tumors, the NRF2 signature is negatively prognostic independently of loss. Patients with lung squamous cell carcinoma with low NRF2 signature survive longer when receiving anti-PD-L1 treatment.

Conclusions: Our modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with loss and activation to promote aggressive lung adenocarcinoma. In patients, oncogenic events alter the tumor immune contexture, possibly having an impact on treatment responses. Importantly, patients with NRF2-activated nonsquamous or squamous tumors have poor prognosis and show limited response to anti-PD-L1 treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1985DOI Listing
February 2021

Multimodal genomic features predict outcome of immune checkpoint blockade in non-small-cell lung cancer.

Nat Cancer 2020 Jan 13;1(1):99-111. Epub 2020 Jan 13.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Despite progress in immunotherapy, identifying patients that respond has remained a challenge. Through analysis of whole-exome and targeted sequence data from 5,449 tumors, we found a significant correlation between tumor mutation burden (TMB) and tumor purity, suggesting that low tumor purity tumors are likely to have inaccurate TMB estimates. We developed a new method to estimate a corrected TMB (cTMB) that was adjusted for tumor purity and more accurately predicted outcome to immune checkpoint blockade (ICB). To identify improved predictive markers together with cTMB, we performed whole-exome sequencing for 104 lung tumors treated with ICB. Through comprehensive analyses of sequence and structural alterations, we discovered a significant enrichment in activating mutations in receptor tyrosine kinase (RTK) genes in nonresponding tumors in three immunotherapy treated cohorts. An integrated multivariable model incorporating cTMB, RTK mutations, smoking-related mutational signature and human leukocyte antigen status provided an improved predictor of response to immunotherapy that was independently validated.
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http://dx.doi.org/10.1038/s43018-019-0008-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514475PMC
January 2020

Induction of STK11-dependent cytoprotective autophagy in breast cancer cells upon honokiol treatment.

Cell Death Discov 2020 6;6:81. Epub 2020 Sep 6.

Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231 USA.

Cancer cells hijack autophagy pathway to evade anti-cancer therapeutics. Many molecular signaling pathways associated with drug-resistance converge on autophagy induction. Honokiol (HNK), a natural phenolic compound purified from , has recently been shown to impede breast tumorigenesis and, in the present study, we investigated whether breast cancer cells evoke autophagy to modulate therapeutic efficacy and functional networks of HNK. Indeed, breast cancer cells exhibit increased autophagosomes-accumulation, MAP1LC3B-II/LC3B-II-conversion, expression of ATG proteins as well as elevated fusion of autophagosomes and lysosomes upon HNK treatment. Breast cancer cells treated with HNK demonstrate significant growth inhibition and apoptotic induction, and these biological processes are blunted by macroautophagy/autophagy. Consequently, inhibiting autophagosome formation, abrogating autophagosome-lysosome fusion or genetic-knockout of and effectively increase HNK-mediated apoptotic induction and growth inhibition. Next, we explored the functional impact of tumor suppressor STK11 in autophagy induction in HNK-treated cells. STK11-silencing abrogates LC3B-II-conversion, and blocks autophagosome/lysosome fusion and lysosomal activity as illustrated by LC3B-Rab7 co-staining and DQ-BSA assay. Our results exemplify the cytoprotective nature of autophagy invoked in HNK-treated breast cancer cells and put forth the notion that a combined strategy of autophagy inhibition with HNK would be more effective. Indeed, HNK and chloroquine (CQ) show synergistic inhibition of breast cancer cells and HNK-CQ combination treatment effectively inhibits breast tumorigenesis and metastatic progression. Tumor-dissociated cells from HNK-CQ treated tumors exhibit abrogated invasion and migration potential. Together, these results implicate that breast cancer cells undergo cytoprotective autophagy to circumvent HNK and a combined treatment with HNK and CQ can be a promising therapeutic strategy for breast cancer.
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http://dx.doi.org/10.1038/s41420-020-00315-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475061PMC
September 2020

Concurrent Targeting of Potential Cancer Stem Cells Regulating Pathways Sensitizes Lung Adenocarcinoma to Standard Chemotherapy.

Mol Cancer Ther 2020 10 26;19(10):2175-2185. Epub 2020 Aug 26.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined with chemotherapy in lung adenocarcinoma. Here, we showed that YAP1 contributes to CSC regulation and enhances tumor formation while suppressing apoptosis. Mechanistically, YAP1 promotes phosphorylation of STAT3 by upregulating IL6. In lung adenocarcinoma clinical specimens, expression correlated with that of ( < 0.01). More importantly, YAP1 and phosphorylated STAT3 (pSTAT3) protein expressions were significantly correlated ( < 0.0001) in primary lung adenocarcinoma as determined by IHC. Immunoblotting of 13 lung adenocarcinoma patient-derived xenografts (PDX) showed that all YAP1-expressing PDXs also exhibited pSTAT3. Additional investigations revealed that chemotherapy resistance and malignant stemness were influenced by upregulating NANOG, OCT4, and SOX2, and the expression of these targets significantly attenuated by genetically and pharmacologically hindering the activities of YAP1 and STAT3 and Therapeutically, the dual inhibition of YAP1 and STAT3 elicits a long-lasting therapeutic response by limiting CSC expansion following chemotherapy in cell line xenograft and PDX models of lung adenocarcinoma. Collectively, these findings provide a conceptual framework to target the YAP1 and STAT3 pathways concurrently with systemic chemotherapy to improve the clinical management of lung adenocarcinoma, based on evidence that these two pathways expand CSC populations that mediate resistance to chemotherapy.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541748PMC
October 2020

Proteomic Analysis of the Air-Way Fluid in Lung Cancer. Detection of Periostin in Bronchoalveolar Lavage (BAL).

Front Oncol 2020 3;10:1072. Epub 2020 Jul 3.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.

Bronchoalveolar lavage (BAL) is a specific type of air-way fluid. It is a commonly used clinical specimen for the diagnosis of benign diseases and cancers of the lung. Although previous studies have identified several disease-associated proteins in the BAL, the potential utility of BAL in lung cancer is still not well-studied. Based upon the fact that the majority of secreted proteins are glycoproteins, we have profiled -glycoproteins in BAL collected from lung cancers, and investigated the expression of glycoproteins such as the matrix glycoprotein, periostin, in lung cancers. BAL specimens ( = 16) were collected from lung cancer patients, and analyzed using mass spectrometry-based quantitative -glycoproteomic technique. Additional BAL specimens ( = 39) were independently collected to further evaluate the expression of periostin by using an enzyme-linked immunosorbent assay (ELISA). A total of 462 glycoproteins were identified in BAL samples using -glycoproteomic technique, including 290 in lung adenocarcinoma (ADC, = 5), 376 in squamous cell carcinoma (SQCC, = 4), 309 in small cell lung carcinoma (SCLC, = 4), and 316 in benign lung disease ( = 3). The expressions of several glycoproteins were elevated, including 8 in ADC, 12 in SQCC, and 17 in SCLC, compared to benign BALs. The expression of periostin was detected in all subtypes of lung cancers. To further investigate the expression of periostin, an ELISA assay was performed using additional independently collected BALs ( = 39) The normalized levels of periostin in benign disease, ADC, SQCC, and SCLC were 255 ± 104 (mean ± SE) and 4,002 ± 2,181, 3,496 ± 1,765, and 1,772 ± 1,119 ng/mg of total BAL proteins. Our findings demonstrate that proteomic analysis of BAL can be used for the study of cancer-associated extracellular proteins in air-way fluid from lung cancer patients.
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http://dx.doi.org/10.3389/fonc.2020.01072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350406PMC
July 2020

DNA methylation markers predict recurrence-free interval in triple-negative breast cancer.

NPJ Breast Cancer 2020 31;6. Epub 2020 Jan 31.

1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.

We lack tools to risk-stratify triple-negative breast cancer (TNBC). Our goal was to develop molecular tools to predict disease recurrence. Methylation array analysis was performed on 110 samples treated by locoregional therapy obtained from institutional cohorts. Discovered marker sets were then tested by Kaplan-Meier analyses in a prospectively collected TNBC cohort of 49 samples from the no-chemotherapy arms of IBCSG trials VIII and IX, and by logistic regression in a chemotherapy-treated cohort of 121 TNBCs from combined IBCSG trials and institutional repositories. High methylation was associated with shorter recurrence-free interval in the no-chemotherapy arm of the IBCSG studies, as well as in the chemotherapy-treated patients within the combined institutional and IBCSG chemotherapy cohorts (100 marker panel,  = 0.002; 30 marker panel,  = 0.05). Chromosome 19 sites were enriched among these loci. In conclusion, our hypermethylation signatures identify increased recurrence risk independent of whether patients receive chemotherapy.
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http://dx.doi.org/10.1038/s41523-020-0145-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994477PMC
January 2020

Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 03 21;26(6):1327-1337. Epub 2019 Nov 21.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.

Purpose: Neoadjuvant PD-1 blockade is a promising treatment for resectable non-small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade.

Experimental Design: T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as a molecular barcode.

Results: Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patients with MPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti-PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor.

Conclusions: Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073288PMC
March 2020

DNA Methylation Markers for Breast Cancer Detection in the Developing World.

Clin Cancer Res 2019 11 12;25(21):6357-6367. Epub 2019 Jul 12.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: An unmet need in low-resource countries is an automated breast cancer detection assay to prioritize women who should undergo core breast biopsy and pathologic review. Therefore, we sought to identify and validate a panel of methylated DNA markers to discriminate between cancer and benign breast lesions using cells obtained by fine-needle aspiration (FNA). Two case-control studies were conducted comparing cancer and benign breast tissue identified from clinical repositories in the United States, China, and South Africa for marker selection/training ( = 226) and testing ( = 246). Twenty-five methylated markers were assayed by Quantitative Multiplex-Methylation-Specific PCR (QM-MSP) to select and test a cancer-specific panel. Next, a pilot study was conducted on archival FNAs (49 benign, 24 invasive) from women with mammographically suspicious lesions using a newly developed, 5-hour, quantitative, automated cartridge system. We calculated sensitivity, specificity, and area under the receiver-operating characteristic curve (AUC) compared with histopathology for the marker panel.

Results: In the discovery cohort, 10 of 25 markers were selected that were highly methylated in breast cancer compared with benign tissues by QM-MSP. In the independent test cohort, this panel yielded an AUC of 0.937 (95% CI = 0.900-0.970). In the FNA pilot, we achieved an AUC of 0.960 (95% CI = 0.883-1.0) using the automated cartridge system.

Conclusions: We developed and piloted a fast and accurate methylation marker-based automated cartridge system to detect breast cancer in FNA samples. This quick ancillary test has the potential to prioritize cancer over benign tissues for expedited pathologic evaluation in poorly resourced countries.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825533PMC
November 2019

A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer.

AAPS J 2019 06 24;21(5):79. Epub 2019 Jun 24.

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Immunotherapy and immune checkpoint blocking antibodies such as anti-PD-1 are approved and significantly improve the survival of advanced non-small cell lung cancer (NSCLC) patients, but there has been little success in identifying biomarkers capable of separating the responders from non-responders before the onset of the therapy. In this study, we developed a quantitative system pharmacology (QSP) model to represent the anti-tumor immune response in human NSCLC that integrated our knowledge of tumor growth, antigen processing and presentation, T cell activation and distribution, antibody pharmacokinetics, and immune checkpoint dynamics. The model was calibrated with the available data and was used to identify potential biomarkers as well as patient-specific response based on the patient parameters. The model predicted that in addition to tumor mutational burden (TMB), a known biomarker for anti-PD-1 therapy in NSCLC, the number of effector T cells and regulatory T cells in the tumor and blood is a predictor of the responders. Furthermore, the model simulated a set of 12 patients with known TMB and MHC/antigen-binding affinity from a recent clinical trial ( ClinicalTrials.gov number, NCT02259621) on neoadjuvant nivolumab therapy in resectable lung cancer and predicted an augmented durable response in patients with adjuvant nivolumab treatment in addition to the clinical trial protocol of neoadjuvant nivolumab treatment followed by resection. Overall, the model provides a valuable framework to model tumor immunity and response to immune checkpoint blockers to enhance biomarker discovery and performing virtual clinical trials to aid in design and interpretation of the current trials with fewer patients.
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http://dx.doi.org/10.1208/s12248-019-0350-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591205PMC
June 2019

Expression of p16 and p53 in non-small-cell lung cancer: clinicopathological correlation and potential prognostic impact.

Biomark Med 2019 06 3;13(9):761-771. Epub 2019 Jun 3.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA.

p16 and p53 are frequently altered intracellular pathways in cancers. We investigated the aberrant expression of p16 and its relationship with p53 and HPV status in primary non-small-cell lung carcinoma. Lung tumor tissue microarray (n = 163), immunohistochemical study of p16 and p53, and HPV hybridization were analyzed. p16 and p53 were detected in 50.7 and 57.3% of adenocarcinoma (ADCs; n = 75), and 35.2 and 63.6% of squamous cell carcinoma (n = 88). HPV was detected in 16 and 10.2% of ADC and squamous cell carcinoma. In ADCs, p16 positive tumors demonstrated a favorable median overall survival time of 60.9 months, compared with p16 negative tumors of 46.9 months (p < 0.05). Furthermore, we did not find significant relationships between p16 expression and HPV status, nor with p53 expression. p16 play an unique role in lung cancer survival. The mechanism of p16 needs to be further studied.
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http://dx.doi.org/10.2217/bmm-2018-0441DOI Listing
June 2019

Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer.

Cell Rep 2019 04;27(2):491-501.e6

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.
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http://dx.doi.org/10.1016/j.celrep.2019.03.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472703PMC
April 2019

Prognostic Impact of Phosphorylated Discoidin Domain Receptor-1 in Esophageal Cancer.

J Surg Res 2019 03 26;235:479-486. Epub 2018 Nov 26.

Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Background: Esophageal squamous cell carcinoma (ESCC) is common in East Asia and also is often deadly. We sought to determine whether measuring the discoidin domain receptor-1 (DDR1)-both total and phosphorylated proteins-could improve our ability to predict recurrence in ESCC.

Materials And Methods: Total DDR1 and phosphorylated DDR1 (pDDR1) were measured using semiquantitative immunohistochemistry in a cohort of 60 patients with ESCC. Association between these immunohistochemical measurements and standard clinical-pathological variables such as patient recurrence-free survival was examined using univariate and multivariate analyses.

Results: Six patients (10.0%) had regional recurrence and eight patients (13.3%) had distant recurrence. In univariate analysis, early disease recurrence correlated with intense staining of total DDR1 (P = 0.03) as well as intense staining of pDDR1 (P < 0.001). On multivariate analysis, only regional lymph node metastasis (P = 0.04, HR = 4.20) and intensity of pDDR1 immunohistochemistry (P = 0.03, HR = 4.27) emerged as significant independent prognostic factors for recurrence.

Conclusions: This study suggests that immunohistochemical measurements of both the DDR1 protein and pDDR1 can provide prognostic value in ESCC, even when other clinical and pathological factors are also being considered.
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http://dx.doi.org/10.1016/j.jss.2018.10.032DOI Listing
March 2019

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Cancer Res 2019 03 12;79(6):1214-1225. Epub 2018 Dec 12.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients ( = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; = 0.007 and HR 6.91; 95% CI, 1.37-34.97; = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer ( = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies. Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432636PMC
March 2019

Peptide-based PET quantifies target engagement of PD-L1 therapeutics.

J Clin Invest 2019 02 7;129(2):616-630. Epub 2019 Jan 7.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Immune checkpoint therapies have shown tremendous promise in cancer therapy. However, tools to assess their target engagement, and hence the ability to predict their efficacy, have been lacking. Here, we show that target engagement and tumor-residence kinetics of antibody therapeutics targeting programmed death ligand-1 (PD-L1) can be quantified noninvasively. In computational docking studies, we observed that PD-L1-targeted monoclonal antibodies (atezolizumab, avelumab, and durvalumab) and a high-affinity PD-L1-binding peptide, WL12, have common interaction sites on PD-L1. Using the peptide radiotracer [64Cu]WL12 in vivo, we employed positron emission tomography (PET) imaging and biodistribution studies in multiple xenograft models and demonstrated that variable PD-L1 expression and its saturation by atezolizumab, avelumab, and durvalumab can be quantified independently of biophysical properties and pharmacokinetics of antibodies. Next, we used [64Cu]WL12 to evaluate the impact of time and dose on the unoccupied fraction of tumor PD-L1 during treatment. These quantitative measures enabled, by mathematical modeling, prediction of antibody doses needed to achieve therapeutically effective occupancy (defined as >90%). Thus, we show that peptide-based PET is a promising tool for optimizing dose and therapeutic regimens employing PD-L1 checkpoint antibodies, and can be used for improving therapeutic efficacy.
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http://dx.doi.org/10.1172/JCI122216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355241PMC
February 2019

Detection of RAS and RAS-associated alterations in primary lung adenocarcinomas. A correlation between molecular findings and tumor characteristics.

Hum Pathol 2019 02 25;84:18-25. Epub 2018 Sep 25.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA; Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA. Electronic address:

Rat sarcoma (RAS) and RAS-associated pathways play important roles in the pathogenesis of lung cancers and in the development of targeted therapies. However, the clinical significance of RAS pathways is still not fully understood. We investigated the RAS-associated molecular aberrations in primary lung adenocarcinomas and correlated molecular findings with clinicopathological characteristics of tumors. A total of 220 surgically resected tumors were identified for which a lung cancer molecular panel (testing 7 genes by next-generation sequencing and 3 genes for rearrangement by fluorescence in situ hybridization) had been performed. The overall molecular alterations were detected in 143 cases (65.00%), including 58 cases (26.36%) of KRAS, 40 cases (18.18%) of EGFR, 24 cases (10.91%) of BRAF, 8 cases (3.64%) of PIK3CA, 7 cases (3.18%) of NRAS, 6 cases (2.73%) of ALK alterations. KRAS, BRAF, NRAS, and PIK3CA mutations were more commonly seen in smokers and occurred with much higher rates than previously published data. BRAF mutations were commonly seen in female smokers, whereas, BRAF mutations were seen in both male and female smokers with moderately to poorly differentiated tumors. PIK3CA mutations were predominantly occurred in p.E545K and p.E542K on exon 9 in moderately to poorly differentiated tumors.
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http://dx.doi.org/10.1016/j.humpath.2018.09.004DOI Listing
February 2019

C3a is required for ILC2 function in allergic airway inflammation.

Mucosal Immunol 2018 11 13;11(6):1653-1662. Epub 2018 Aug 13.

Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Aberrant type 2 responses underlie the pathologies in allergic diseases like asthma, yet, our understanding of the mechanisms that drive them remains limited. Recent evidence suggests that dysregulated innate immune factors can perpetuate asthma pathogenesis. In susceptible individuals, allergen exposure triggers the activation of complement, a major arm of innate immunity, leading to the aberrant generation of the C3a anaphylatoxin. C3 and C3a have been shown to be important for the development of Th2 responses, yet remarkably, the mechanisms by which C3a regulates type 2 immunity are relatively unknown. We demonstrate a central role for C3a in driving type 2 innate lymphoid cells (ILC2)-mediated inflammation in response to allergen and IL-33. Our data suggests that ILC2 recruitment is C3a-dependent. Further, we show that ILC2s directly respond to C3a, promoting type 2 responses by specifically: (1) inducing IL-13 and granulocyte-macrophage colony-stimulating factor, whereas inhibiting IL-10 production from ILC2; and (2) enhancing their antigen-presenting capability during ILC-T-cell cross-talk. In summary, we identify a novel mechanism by which C3a can mediate aberrant type 2 responses to aeroallergen exposure, which involves a yet unrecognized cross-talk between two major innate immune components-complement and group 2 innate lymphoid cells.
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http://dx.doi.org/10.1038/s41385-018-0064-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279480PMC
November 2018

Quantitative phosphoproteomic analysis reveals reciprocal activation of receptor tyrosine kinases between cancer epithelial cells and stromal fibroblasts.

Clin Proteomics 2018 15;15:21. Epub 2018 Jun 15.

1Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD USA.

Background: Cancer-associated fibroblasts (CAFs) are one of the most important components of tumor stroma and play a key role in modulating tumor growth. However, a mechanistic understanding of how CAFs communicate with tumor cells to promote their proliferation and invasion is far from complete. A major reason for this is that most current techniques and model systems do not capture the complexity of signal transduction that occurs between CAFs and tumor cells.

Methods: In this study, we employed a stable isotope labeling with amino acids in cell culture (SILAC) strategy to label invasive breast cancer cells, MDA-MB-231, and breast cancer patient-derived CAF this has already been defined above cells. We used an antibody-based phosphotyrosine peptide enrichment method coupled to LC-MS/MS to catalog and quantify tyrosine phosphorylation-mediated signal transduction events induced by the bidirectional communication between patient-derived CAFs and tumor cells.

Results: We discovered that distinct signaling events were activated in CAFs and in tumor epithelial cells during the crosstalk between these two cell types. We identified reciprocal activation of a number of receptor tyrosine kinases including EGFR, FGFR1 and EPHA2 induced by this bidirectional communication.

Conclusions: Our study not only provides insights into the mechanisms of the interaction between CAFs and tumor cells, but the model system described here could be used as a prototype for analysis of intercellular communication in many different tumor microenvironments.
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http://dx.doi.org/10.1186/s12014-018-9197-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003199PMC
June 2018

De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.

FASEB J 2018 Jun 15:fj201800204. Epub 2018 Jun 15.

Department of Pathology, Stony Brook School of Medicine, Stony Brook, New York, USA.

Oncogenic Kras mutations are one of the most common alterations in non-small cell lung cancer and are associated with poor response to treatment and reduced survival. Driver oncogenes, such as Kras are now appreciated for their ability to promote tumor growth via up-regulation of anabolic pathways. Therefore, we wanted to identify metabolic vulnerabilities in Kras-mutant lung cancer. Using the Kras lung cancer model, we show that mutant Kras drives a lipogenic gene-expression program. Stable-isotope analysis reveals that mutant Kras promotes de novo fatty acid synthesis in vitro and in vivo. The importance of fatty acid synthesis in Kras-induced tumorigenesis was evident by decreased tumor formation in Kras mice after treatment with a fatty acid synthesis inhibitor. Importantly, with gain and loss of function models of mutant Kras, we demonstrate that mutant Kras potentiates the growth inhibitory effects of several fatty acid synthesis inhibitors. These studies highlight the potential to target mutant Kras tumors by taking advantage of the lipogenic phenotype induced by mutant Kras.-Singh, A., Ruiz, C., Bhalla, K., Haley, J. A., Li, Q. K., Acquaah-Mensah, G., Montal, E., Sudini, K. R., Skoulidis, F., Wistuba, I. I., Papadimitrakopoulou, V., Heymach, J. V., Boros, L. G., Gabrielson, E., Carretero, J., Wong, K.-k., Haley, J. D., Biswal, S., Girnun, G. D. De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.
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http://dx.doi.org/10.1096/fj.201800204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219836PMC
June 2018

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.

N Engl J Med 2018 May 16;378(21):1976-1986. Epub 2018 Apr 16.

From the Bloomberg-Kimmel Institute for Cancer Immunotherapy and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore (P.M.F., K.N.S., V.A., T.R.C., M.Z., S.C.Y., S.B., R.J.B., J.N., K.A.M., F.V., H.G., J.Z., J.X.C., H.Y.C., J.-W.S., R.B.S., J.W., E.G., H.W., G.L.R., J.M.T., V.E.V., S.L.T., J.R.B., D.M.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (J.E.C., M.D.H., D.R.J., M.J.V., N.R., Z.O., V.R., J.D.W., T.M.) and the Ludwig Collaborative (J.D.W., T.M.) - all in New York; the Parker Institute for Cancer Immunotherapy, San Francisco (J.D.W., T.M.); and Swim Across America Laboratory, Charlotte, NC (J.D.W., T.M.).

Background: Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade.

Methods: In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses.

Results: Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab.

Conclusions: Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .).
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http://dx.doi.org/10.1056/NEJMoa1716078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223617PMC
May 2018

Nrf2 signaling and autophagy are complementary in protecting breast cancer cells during glucose deprivation.

Free Radic Biol Med 2018 05 9;120:407-413. Epub 2018 Apr 9.

Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, 1550 East Orleans Street, Baltimore, MD 21231, United States. Electronic address:

Autophagy can serve as a mechanism for survival of cells during nutrient deprivation by recycling cellular macromolecules and organelles transiently to provide essential metabolic substrates. However, autophagy itself causes metabolic stress to cells, and other cellular protective mechanisms likely cooperate with autophagy to promote cell survival during nutrient deprivation. In this study, we explored protective mechanisms in breast cancer cells in the setting of glucose deprivation. While breast cancer cells (MCF7 and T47D) survive in glucose-free medium for three days or more, autophagy is induced in this setting. Blocking autophagy pharmacologically with chloroquine or by knock-out of an essential autophagy gene, such as Beclin 1 or ATG7, markedly reduces the ability of cells to survive during glucose deprivation. Autophagy previously was shown to degrade p62, a protein that sequesters KEAP1, and KEAP1 in turn sequesters Nrf2, a master regulator of the antioxidant response. Hence, we investigated how the Nrf2 signaling pathway might be affected by glucose deprivation and autophagy. We found that while glucose deprivation does cause decreased cellular levels of p62, Nrf2 protein levels and activity unexpectedly increase in this setting. Moreover, this increase in Nrf2 activity provides important protection to breast cancer cells during glucose deprivation, since siRNA knockdown of Nrf2 markedly impairs survival during glucose deprivation. Antioxidants, N-acetyl cysteine and glutathione also protect these cells during glucose deprivation, leading us to conclude that Nrf2 signaling via its antioxidant activity has a critical and previously undescribed role of protecting cells during glucose deprivation-induced autophagy.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186426PMC
May 2018

A Randomized Phase II Study of Metformin plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy-Naïve Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer.

Oncologist 2018 07 27;23(7):859-865. Epub 2018 Feb 27.

Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland

Background: In the absence of a targeted oncogenic driver mutation or high programmed death-ligand 1 expression, systemic therapy with platinum-based doublet chemotherapy with or without bevacizumab has been the standard treatment in advanced or metastatic non-small cell lung cancer (NSCLC). Metformin has been shown to have antitumor effects via a variety of insulin-dependent and insulin-independent mechanisms and to be potentially synergistic with chemotherapy.

Materials And Methods: This open-label single-center phase II study (NCT01578551) enrolled patients with chemotherapy-naïve advanced or metastatic nonsquamous NSCLC and randomized them (3:1) to receive carboplatin, paclitaxel, and bevacizumab with (Arm A) or without (Arm B) concurrent metformin for four to six cycles followed by maintenance therapy with bevacizumab ± metformin continued until disease progression, intolerable toxicity, or study withdrawal. The primary outcome was 1-year progression free survival (PFS). Secondary outcomes included overall survival, response to therapy, and toxicity.

Results: A total of 25 patients were enrolled from August 2012 to April 2015, of whom 24 received at least one cycle of therapy administration. The study was stopped early due to slow accrual and changes in standard first-line therapy of advanced NSCLC. The 1-year PFS on Arm A ( = 18) was 47% (95% confidence interval [CI]: 25%-88%), which exceeded the historical control 1-year PFS of 15%. Median overall survival of patients treated on Arm A was 15.9 months (95% CI: 8.4-not available [NA]) and 13.9 months (95% CI: 12.7-NA) on Arm B. There were no significant differences in toxicity between the study arms.

Conclusion: To the authors' knowledge, this is the first study to show a significant benefit in PFS with the use of metformin in this patient population and is a signal of efficacy for metformin in advanced NSCLC.

Implications For Practice: The anticancer effects of metformin continue to be elucidated. To the authors' knowledge, this is the first trial in nondiabetic advanced non-small cell lung cancer patients to show a significant change in outcome with the addition of metformin to standard first-line chemotherapy. Well tolerated and widely available, metformin is a drug that should be considered for further study in the lung cancer treatment landscape.
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http://dx.doi.org/10.1634/theoncologist.2017-0465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058336PMC
July 2018

Chemotherapy induces enrichment of CD47/CD73/PDL1 immune evasive triple-negative breast cancer cells.

Proc Natl Acad Sci U S A 2018 02 24;115(6):E1239-E1248. Epub 2018 Jan 24.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

Triple-negative breast cancer (TNBC) is treated with cytotoxic chemotherapy and is often characterized by early relapse and metastasis. To form a secondary (recurrent and/or metastatic) tumor, a breast cancer cell must evade the innate and adaptive immune systems. CD47 enables cancer cells to evade killing by macrophages, whereas CD73 and PDL1 mediate independent mechanisms of evasion of cytotoxic T lymphocytes. Here, we report that treatment of human or murine TNBC cells with carboplatin, doxorubicin, gemcitabine, or paclitaxel induces the coordinate transcriptional induction of CD47, CD73, and PDL1 mRNA and protein expression, leading to a marked increase in the percentage of CD47CD73PDL1 breast cancer cells. Genetic or pharmacological inhibition of hypoxia-inducible factors (HIFs) blocked chemotherapy-induced enrichment of CD47CD73PDL1 TNBC cells, which were also enriched in the absence of chemotherapy by incubation under hypoxic conditions, leading to T cell anergy or death. Treatment of mice with cytotoxic chemotherapy markedly increased the intratumoral ratio of regulatory/effector T cells, an effect that was abrogated by HIF inhibition. Our results delineate an HIF-dependent transcriptional mechanism contributing to TNBC progression and suggest that combining chemotherapy with an HIF inhibitor may prevent countertherapeutic induction of proteins that mediate evasion of innate and adaptive antitumor immunity.
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http://dx.doi.org/10.1073/pnas.1718197115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819443PMC
February 2018

Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy.

Semin Cancer Biol 2018 10 26;52(Pt 1):103-109. Epub 2017 Nov 26.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21224, United States. Electronic address:

Recent large scale genomic studies from the Clinical Lung Cancer Genome Project have identified different driver gene mutations in the subtypes of non-small cell lung carcinoma (NSCLC). These findings not only lead to remarkable progress in targeted therapies for lung cancer patients, but also provide fundamental knowledge for the subclassification of NSCLC. More recently, the advancement and clinical application of immunotherapy have reinforced the need for the accurate subclassification of NSCLC. In 2015, the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) updated their guidelines for the subclassification of lung cancers. These guidelines emphasize: (1) the subclassification of NSCLC, (2) the critical role of molecular characterization of tumors for targeted therapy, (3) the unique terminology for subclassifying NSCLC using small biopsy specimens, and (4) the utility of IHC biomarkers in the accurate diagnosis and subclassification of lung cancer. The guidelines have significant prognostic impact on oncologic practice and patient care. In this review, we summarize the current WHO guidelines for the classification of lung cancer, discuss advancements of targeted therapy and immunotherapy, and address the utility and limitation of immunomarkers in the subclassification of NSCLC, as well as the prospective future of the field.
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http://dx.doi.org/10.1016/j.semcancer.2017.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970946PMC
October 2018

Unique pulmonary immunotoxicological effects of urban PM are not recapitulated solely by carbon black, diesel exhaust or coal fly ash.

Environ Res 2018 02 24;161:304-313. Epub 2017 Nov 24.

Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States. Electronic address:

Background: Exposure to particulate matter (PM) is increasing worldwide as a result of increased human activity, the rapid industrialization of developing countries, and effects of climate change. Adverse effects of PM on human health are well documented, and because PM exposure occurs mostly through the airways, PM has especially deleterious impact on the lungs.

Objective: We investigated whether surrogate PM particles like carbon black (CB), diesel exhaust particle (DEP), coal fly ash (CFA) can recapitulate the allergic airway inflammatory response induced by urban particulate matter.

Methods: We compared the pro-inflammatory potential of urban PM collected from New York (NYC) and Baltimore (Balt) with CB, DEP and CFA surrogate PM particles. Eight to ten weeks old BALB/cJ mice were exposed through the airways to particulate material, and markers of airway inflammation were determined. Specifically, we assessed cellular influx, mucus production, lung function, cytokine levels as well as immune cell profiling of the lungs.

Results: Herein, we demonstrate that exposure to equivalent mass of stand-alone surrogate PM particles like CB, DEP and CFA, fails to induce significant airway inflammatory response seen after similar exposure to urban PMs. Specifically, we observe that PM collected from New York (NYC) and Baltimore city (Balt) triggers a mixed Th2/Th17 response accompanied by eosinophilic and neutrophilic influx, mucus production and airway hyperresponsiveness (AHR). Although the immune profile of NYC and Baltimore PMs are similar, they demonstrate considerable differences in their potency. Baltimore PM induced more robust airway inflammation, AHR, and Th2 cytokine production, possibly due to the greater metal content in Baltimore PM.

Conclusions: Urban particulate matter with its unique physiochemical properties and heterogeneous composition elicits a mixed Th2/Th17 allergic airway response that is not seen after similar exposures to surrogate PM particles.
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http://dx.doi.org/10.1016/j.envres.2017.10.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747992PMC
February 2018

Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008.

Breast Cancer Res Treat 2018 01 16;167(1):107-116. Epub 2017 Sep 16.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans St., Baltimore, MD, 21287, USA.

Background: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy.

Methods: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses.

Results: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37-0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients.

Conclusion: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).
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http://dx.doi.org/10.1007/s10549-017-4503-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793219PMC
January 2018

Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations.

Cancer Cell 2017 09;32(3):360-376.e6

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.
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http://dx.doi.org/10.1016/j.ccell.2017.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596892PMC
September 2017

Added Value of Computer-aided CT Image Features for Early Lung Cancer Diagnosis with Small Pulmonary Nodules: A Matched Case-Control Study.

Radiology 2018 01 5;286(1):286-295. Epub 2017 Sep 5.

From the Departments of Oncology (P. Huang, D.S.E.), Radiology (E.K.F., L.C.C., C.T.L., A.H.), Radiation Oncology and Molecular Radiation Sciences (S.P., J.L., R.H.), Surgery (M.B.), Pathology (E.G.), and Biostatistics (J.S.), Johns Hopkins University School of Medicine, 550 N Broadway, Suite 1103, Baltimore, MD 21205; Department of Medicine, the University of British Columbia, Vancouver, BC, Canada (S.L.); Information Management Services, Rockville, Md (J.R., B.T.); Biometry Research Group, National Cancer Institute, Bethesda, Md (P. Hu); Department of Radiology, Nongken General Hospital of Hainan Medical University, Haikou, Hainan, China (R.Y.); and Department of Thoracic Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China (C.C.).

Purpose To test whether computer-aided diagnosis (CAD) approaches can increase the positive predictive value (PPV) and reduce the false-positive rate in lung cancer screening for small nodules compared with human reading by thoracic radiologists. Materials and Methods A matched case-control sample of low-dose computed tomography (CT) studies in 186 participants with 4-20-mm noncalcified lung nodules who underwent biopsy in the National Lung Screening Trial (NLST) was selected. Variables used for matching were age, sex, smoking status, chronic obstructive pulmonary disease status, body mass index, study year of the positive screening test, and screening results. Studies before lung biopsy were randomly split into a training set (70 cancers plus 70 benign controls) and a validation set (20 cancers plus 26 benign controls). Image features from within and outside dominant nodules were extracted. A CAD algorithm developed from the training set and a random forest classifier were applied to the validation set to predict biopsy outcomes. Receiver operating characteristic analysis was used to compare the prediction accuracy of CAD with the NLST investigator's diagnosis and readings from three experienced and board-certified thoracic radiologists who used contemporary clinical practice guidelines. Results In the validation cohort, the area under the receiver operating characteristic curve for CAD was 0.9154. By default, the sensitivity, specificity, and PPV of the NLST investigators were 1.00, 0.00, and 0.43, respectively. The sensitivity, specificity, PPV, and negative predictive value of CAD and the three radiologists' combined reading were 0.95, 0.88, 0.86, and 0.96 and 0.70, 0.69, 0.64, and 0.75, respectively. Conclusion CAD could increase PPV and reduce the false-positive rate in the early diagnosis of lung cancer. RSNA, 2017 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2017162725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779085PMC
January 2018

The critical role of EBUS-TBNA cytology in the staging of mediastinal lymph nodes in lung cancer patients: A correlation study with positron emission tomography findings.

Cancer Cytopathol 2017 Sep 13;125(9):717-725. Epub 2017 Jun 13.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.

Background: The sensitivity and specificity of positron emission tomography (PET) have been significantly improved for the identification of malignancies in recent years; however, it is still necessary to confirm PET findings in a lymph node (LN) by direct tissue sampling. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the most commonly used approach for diagnosing and staging mediastinal LNs, particularly in lung cancer patients with locally advanced disease. Despite this fact, evidence-based studies of EBUS-TBNA cytology and PET findings are still suboptimal.

Methods: The electronic database at the Johns Hopkins Medical Institutions and the pathology archives were searched to identify patients with mediastinal lymphadenopathy who had both EBUS-TBNA mediastinal LN sampling and a PET scan over a 14-month period. Patients suspected of having lung cancer and patients with a history of lung cancer were included in this study. Cytological diagnoses and follow-up surgical LN diagnoses were reviewed and correlated with PET scan findings.

Results: A total of 140 LNs from 79 patients, including 86 PET-positive LNs and 54 PET-negative LNs, were included. The most frequently sampled LNs were 4R and 7. The average size of PET-positive and PET-negative LNs was 1.2 and 1.6 cm, respectively. Among PET-positive LNs, 41.9% were malignant, 41.9% showed reactive changes or granulomatous inflammation, and 9.3% were nondiagnostic by EBUS-TBNA. However, among PET-negative LNs, 74.1% showed reactive changes or granulomatous inflammation, 7.4% were malignant, and 18.5% were nondiagnostic by EBUS-TBNA.

Conclusions: The data demonstrate that EBUS-TBNA cytology improves the diagnostic accuracy of mediastinal LNs and clinical staging. Furthermore, EBUS-TBNA may identify additional malignant LNs (7.4%), and this highlights the risk for false-negative findings with PET scanning in isolation. Cancer Cytopathol 2017;125:717-25. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncy.21886DOI Listing
September 2017