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1.  Pretreatment Dysphagia in Esophageal Cancer Patients May Eliminate the Need for Staging by Endoscopic Ultrasonography 
The Annals of thoracic surgery  2015;101(1):226-230.
Neoadjuvant therapy is typically given to patients with localized disease who have T3-4 esophageal disease by endoscopic ultrasound (EUS). Previously, we noted that patients who present with dysphagia have a higher EUS T stage. We hypothesized that the presence of dysphagia is predictive of EUS T3-4 disease and that staging EUS could be eliminated for esophageal cancer patients with dysphagia.
We performed a prospective, intent-to-treat, single-cohort study in which patients with potentially resectable esophageal cancer completed a standardized 4-tier dysphagia score survey. EUS was performed as part of our standard evaluation. To determine whether presence of dysphagia predicted EUS T3-4 disease, the dysphagia score was compared with EUS T stage.
A total of 114 consecutive patients were enrolled between August 2012 and February 2014: 77% (88/114) received neoadjuvant therapy, 18% (20/114) did not, and 5% (6/114) pursued treatment elsewhere. In total, 70% (80/114) underwent esophagectomy. Fifty-four percent (61/114) had dysphagia; 46% (53/114) did not. Dysphagia scores were as follows: 66% (40/61) grade 1, 25% (15/61) grade 2, and 10% (6/61) grade 3-4. Among patients with dysphagia, 89% (54/61) had T3-4 disease by EUS; among those without dysphagia, only 53% (28/53) had T3-4 disease by EUS (p<0.001).
The presence of dysphagia in patients with esophageal cancer was highly predictive of T3-4 disease by EUS. On the basis of this finding, approximately 50% of patients currently undergoing staging EUS could potentially forgo EUS before neoadjuvant therapy. In contrast, patients without dysphagia should still undergo EUS.
PMCID: PMC4765728  PMID: 26603024
Endoscopic ultrasound; esophageal cancer
2.  International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification predicts occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma 
We investigated the role of the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification in predicting occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma.
We reviewed lung adenocarcinoma patients who had clinically N2-negative status, were evaluated by preoperative positron emission tomography combined with computed tomography (PET/CT) and had undergone lobectomy or pneumonectomy at Memorial Sloan Kettering Cancer Center (n = 297). Tumours were classified according to the 2011 IASLC/ATS/ERS classification. The associations between occult lymph node metastasis and clinicopathological variables were analysed using Fisher's exact test and logistic regression analysis.
Thirty-two (11%) cN0-1 patients had occult mediastinal lymph node metastasis (pN2) whereas 25% of cN1 patients had pN2 disease. Increased micropapillary pattern was associated with increased risk of pN2 disease (P = 0.001). On univariate analysis, high maximum standard uptake value of the primary tumour on PET/CT (P = 0.019) and the presence of micropapillary (P = 0.014) and solid pattern (P = 0.014) were associated with occult pN2 disease. On multivariable analysis, micropapillary pattern was positively associated with risk of pN2 disease (odds ratio = 3.41; 95% confidence intervals = 1.42–8.19; P = 0.006).
The presence of micropapillary pattern is an independent predictor of occult mediastinal lymph node metastasis. Our observations have potential therapeutic implications for management of early-stage lung adenocarcinoma.
PMCID: PMC4678972  PMID: 26377636
Metastasis; Micropapillary; Lung cancer; Early stage; Non-small cell lung cancer
3.  Genomic Classification and Prognosis in Acute Myeloid Leukemia 
The New England journal of medicine  2016;374(23):2209-2221.
Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice.
We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes.
We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2R172 mutations (in 1%). Patients with chromatin–spliceosome and TP53–aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene–gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials.
The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; number, NCT00146120.)
PMCID: PMC4979995  PMID: 27276561
4.  Solid Predominant Histologic Subtype in Resected Stage I Lung Adenocarcinoma Is an Independent Predictor of Early, Extrathoracic, Multisite Recurrence and of Poor Postrecurrence Survival 
Journal of Clinical Oncology  2015;33(26):2877-2884.
To examine the significance of the proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) histologic subtypes of lung adenocarcinoma for patterns of recurrence and, among patients who recur following resection of stage I lung adenocarcinoma, for postrecurrence survival (PRS).
Patients and Methods
We reviewed patients with stage I lung adenocarcinoma who had undergone complete surgical resection from 1999 to 2009 (N = 1,120). Tumors were subtyped by using the IASLC/ATS/ERS classification. The effects of the dominant subtype on recurrence and, among patients who recurred, on PRS were investigated.
Of 1,120 patients identified, 188 had recurrent disease, 103 of whom died as a result of lung cancer. Among patients who recurred, 2-year PRS was 45%, and median PRS was 26.1 months. Compared with patients with nonsolid tumors, patients with solid predominant tumors had earlier (P = .007), more extrathoracic (P < .001), and more multisite (P = .011) recurrences. Multivariable analysis of primary tumor factors revealed that, among patients who recurred, solid predominant histologic pattern in the primary tumor (hazard ratio [HR], 1.76; P = .016), age older than 65 years (HR, 1.63; P = .01), and sublobar resection (HR, 1.6; P = .01) were significantly associated with worse PRS. Presence of extrathoracic metastasis (HR, 1.76; P = .013) and age older than 65 years at the time of recurrence (HR, 1.7; P = .014) were also significantly associated with worse PRS.
In patients with stage I primary lung adenocarcinoma, solid predominant subtype is an independent predictor of early recurrence and, among those patients who recur, of worse PRS. Our findings provide a rationale for investigating adjuvant therapy and identify novel therapeutic targets for patients with solid predominant lung adenocarcinoma.
PMCID: PMC4554749  PMID: 26261257
5.  Landscape of somatic mutations in 560 breast cancer whole genome sequences 
Nik-Zainal, Serena | Davies, Helen | Staaf, Johan | Ramakrishna, Manasa | Glodzik, Dominik | Zou, Xueqing | Martincorena, Inigo | Alexandrov, Ludmil B. | Martin, Sancha | Wedge, David C. | Van Loo, Peter | Ju, Young Seok | Smid, Marcel | Brinkman, Arie B | Morganella, Sandro | Aure, Miriam R. | Lingjærde, Ole Christian | Langerød, Anita | Ringnér, Markus | Ahn, Sung-Min | Boyault, Sandrine | Brock, Jane E. | Broeks, Annegien | Butler, Adam | Desmedt, Christine | Dirix, Luc | Dronov, Serge | Fatima, Aquila | Foekens, John A. | Gerstung, Moritz | Hooijer, Gerrit KJ | Jang, Se Jin | Jones, David R. | Kim, Hyung-Yong | King, Tari A. | Krishnamurthy, Savitri | Lee, Hee Jin | Lee, Jeong-Yeon | Li, Yilong | McLaren, Stuart | Menzies, Andrew | Mustonen, Ville | O’Meara, Sarah | Pauporté, Iris | Pivot, Xavier | Purdie, Colin A. | Raine, Keiran | Ramakrishnan, Kamna | Rodríguez-González, F. Germán | Romieu, Gilles | Sieuwerts, Anieta M. | Simpson, Peter T | Shepherd, Rebecca | Stebbings, Lucy | Stefansson, Olafur A | Teague, Jon | Tommasi, Stefania | Treilleux, Isabelle | Van den Eynden, Gert G. | Vermeulen, Peter | Vincent-Salomon, Anne | Yates, Lucy | Caldas, Carlos | van’t Veer, Laura | Tutt, Andrew | Knappskog, Stian | Tan, Benita Kiat Tee | Jonkers, Jos | Borg, Åke | Ueno, Naoto T | Sotiriou, Christos | Viari, Alain | Futreal, P. Andrew | Campbell, Peter J | Span, Paul N. | Van Laere, Steven | Lakhani, Sunil R | Eyfjord, Jorunn E. | Thompson, Alastair M. | Birney, Ewan | Stunnenberg, Hendrik G | van de Vijver, Marc J | Martens, John W.M. | Børresen-Dale, Anne-Lise | Richardson, Andrea L. | Kong, Gu | Thomas, Gilles | Stratton, Michael R.
Nature  2016;534(7605):47-54.
We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
PMCID: PMC4910866  PMID: 27135926
6.  Tumoral CD10 Expression Correlates with Aggressive Histology and Prognosis in Patients with Malignant Pleural Mesothelioma 
Annals of surgical oncology  2015;22(9):3136-3143.
Currently, tumor-node-metastasis stage and histologic type are the established prognostic factors for malignant pleural mesothelioma, whereas no prognostic markers have been established for clinical practice. We investigated the prognostic value of CD10, a metalloproteinase that can promote cancer aggressiveness through enzymatic degradation and intracellular signaling crosstalk, in malignant pleural mesothelioma.
CD10 immunostaining was performed for 176 cases of malignant pleural mesothelioma (epithelioid, 148; biphasic, 14; sarcomatoid, 14), and its expression was dichotomized as negative (no staining) or positive (any staining). Epithelioid tumors were classified as pleomorphic subtype when cytologic pleomorphism was ≥10 % of the tumor. Overall survival (OS) was analyzed by log-rank tests and Cox proportional hazard models.
Tumoral CD10 expression was identified in 42 % of epithelioid non-pleomorphic tumors, 57 % of epithelioid pleomorphic tumors, 79 % of biphasic tumors, and 93 % of sarcomatoid tumors (p < 0.001). Positive CD10 expression was correlated with higher mitotic count (p = 0.002). Overall survival for patients with positive CD10 expression was significantly shorter than that for patients with negative CD10 expression in all patients (p = 0.001) and in patients with epithelioid tumor (p = 0.04). On multivariate analysis, CD10 expression was an independent prognostic factor for all patients (hazard ratio 1.48; p = 0.019).
Tumoral CD10 expression correlated with aggressive histologic types and higher mitotic activity and is an independent prognostic factor for patients with malignant pleural mesothelioma.
PMCID: PMC4511716  PMID: 25608772
7.  In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles 
A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles.
Three hundred and fifty-five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen: N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively.
Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014).
The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.
PMCID: PMC4631184  PMID: 25907378
activity score; CYP2D6; endoxifen; N-desmethyl-tamoxifen; pharmacogenetic; tamoxifen
9.  Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition 
The Journal of Clinical Investigation  null;126(8):3130-3144.
Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1–mediated (PD-1–mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB–based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.
PMCID: PMC4966328  PMID: 27454297
10.  Randomized Trial of Mediastinal Lymph Node Sampling Versus Complete Lymphadenectomy During Pulmonary Resection in the Patient with N0 or N1 (Less Than Hilar) Non-Small Cell Carcinoma: Results of the ACOSOG Z0030 Trial 
To determine if mediastinal lymph node dissection (MLND) improves survival compared to mediastinal lymph node sampling (MLNS) in patients undergoing resection for N0 or non-hilar N1, T1 or T2 non-small cell lung cancer (NSCLC).
Patients with NSCLC underwent sampling of 2R, 4R, 7 and 10R for right sided tumors, and 5, 6, 7 and 10L for left sided tumors. If all were negative for malignancy, patients were randomized to no further lymph node sampling (MLNS) or complete MLND.
Of 1,111 patients randomized, 1,023 (498 MLNS, 525 MLND) were eligible/evaluable. There were no significant differences between the two groups in terms of demographics, ECOG status, histology, location of the cancer, type or extent of resection, or pathological stage. Occult N2 disease was found in 21 patients in the MLND group. At median follow-up of 6.5 years, 435 (43%) patients have died; (MLNS: 217 (44%);MLND:218 (42%)). The median survival for MLNS is8.1 years, and 8.5 years for MLND (p=0.25). The 5-year disease free survival rate was 69% (95% CI: 64%-74%) in the MLNS group versus 68%(95% CI: 64%-73%) years in the MLND group (p=0.92). There was no difference for local (p=0.52), regional (p=0.10), or distant (p=0.76) recurrence between the two groups.
If systematic, thorough presection sampling of the mediastinal and hilar lymph nodes is negative, MLND does not improve survival in patients with early stage NSCLC but these results are not generalizable to patients staged radiographically or those with higher stage tumors.
PMCID: PMC5082844  PMID: 21335122
Lung Cancer; lymph nodes; mediastinum; staging; randomized controlled trial
11.  Tissue Transglutaminase Activates Cancer-Associated Fibroblasts and Contributes to Gemcitabine Resistance in Pancreatic Cancer123 
Neoplasia (New York, N.Y.)  2016;18(11):689-698.
Resistance to chemotherapy is a hallmark of pancreatic ductal adenocarcinoma (PDA) and has been partly attributed to the dense desmoplastic stroma, which forms a protective niche for cancer cells. Tissue transglutaminase (TG2), a Ca2+-dependent enzyme, is secreted by PDA cells and cross-links proteins in the tumor microenvironment (TME) through acyl-transfer between glutamine and lysine residues, promoting PDA growth. The objective of the current study was to determine whether secreted TG2 by PDA cells alters the response of pancreatic tumors to gemcitabine. Orthotopic pancreatic xenografts and co-culture of PDA and stromal cells were employed to determine the mechanisms by which TG2 alters tumor-stroma interactions and response to gemcitabine. Analysis of the pancreatic The Cancer Genome Atlas (TCGA) database demonstrated that increased TG2 expression levels correlate with worse overall survival (hazard ratio = 1.37). Stable TG2 knockdown in PDA cells led to decreased size of pancreatic xenografts and increased sensitivity to gemcitabine in vivo. However, TG2 downregulation did not increase cytotoxicity of gemcitabine in vitro. Additionally, multivessel density and gemcitabine uptake in pancreatic tumor tissue, as measured by mass spectrometry (MS-HPLC), were not significantly different in tumors expressing TG2 versus tumors in which TG2 was knocked down. Fibroblasts, stimulated by TG2 secreted by PDA cells, secrete laminin A1, which protects cancer cells from gemcitabine-induced cytotoxicity. In all, our results demonstrate that TG2 secreted in the pancreatic TME orchestrates the cross talk between cancer cells and stroma, impacting tumor growth and response to chemotherapy. Our study supports TG2 inhibition to increase the antitumor effects of gemcitabine in PDA.
PMCID: PMC5094382  PMID: 27792935
12.  Chest Wall Reconstruction Using a Methyl Methacrylate Neo-rib and Mesh 
The Annals of thoracic surgery  2015;100(2):744-747.
Prosthetic reconstruction of the chest wall after oncologic resection is performed by means of various techniques using different materials. We describe a new technique of chest wall reconstruction that includes the use of Marlex mesh and the creation of a neo-rib from a Steinmann pin and methyl methacrylate.
PMCID: PMC4978354  PMID: 26234861
Chest wall; Surgery/incision/exposure/techniques
13.  Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of neurofibromatosis type 1 
Pediatric blood & cancer  2015;62(10):1709-1716.
Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes affected individuals to formation of benign neurofibromas, peripheral nerve tumors that can be associated with significant morbidity. Loss of the NF1 Ras-GAP protein causes increased Ras-GTP, and we previously found that inhibiting MEK signaling downstream of Ras can shrink established neurofibromas in a genetically engineered murine model.
We studied effects of MEK inhibition using 1.5 mg/kg/day PD-0325901 prior to neurofibroma onset in the Nf1 flox/flox;Dhh-Cre mouse model. We also treated mice with established tumors at 0.5 and 1.5 mg/kg/day dosees of PD-0325901. We monitored tumor volumes using MRI and volumetric measurements, and measured pharmacokinetic and pharmacodynamic endpoints.
Early administration significantly delayed neurofibroma development as compared to vehicle controls. When treatment was discontinued neurofibromas grew, but no rebound effect was observed and neurofibromas remained significantly smaller than controls. Low dose treatment of mice with PD-0325901 resulted in neurofibroma shrinkage equivalent to that observed at higher doses. Tumor cell proliferation decreased, although less than at higher doses with drug. Tumor blood vessels per area correlated with tumor shrinkage.
Neurofibroma development was not prevented by MEK inhibition, beginning at 1 month of age, but tumor size was controlled by early treatment. Moreover, treatment with PD-0325901 at very low doses may shrink neurofibromas while minimizing toxicity. These studies highlight how genetically engineered mouse models can guide clinical trial design.
PMCID: PMC4546559  PMID: 25907661
NF1; neurofibroma; nerve; MEK; therapy
14.  Resection of Primary and Secondary Tumors of the Sternum: An Analysis of Prognostic Variables 
The Annals of thoracic surgery  2015;100(1):215-222.
We sought to determine the prognostic variables associated with overall survival (OS) and recurrence-free probability (RFP) in patients with primary and secondary sternal tumors treated with surgical resection.
A retrospective analysis of patients who underwent resection of primary or secondary sternal tumors at two cancer institutes between 1995 and 2013 was performed. OS and RFP were estimated using the Kaplan-Meier method, and predictors of OS and RFP were analyzed using the Cox proportional hazards model.
Seventy-eight patients underwent sternal resection with curative (n=67; 86%) or palliative (n=6; 8%) intent. Seventy-three patients (94%) had malignant tumors, of which 28 (36%) were primary and 45 (57%) were secondary malignant. Thirteen patients (17%) underwent complete and 65 (83%) underwent partial sternal resection. There were no perioperative deaths, and grade III/IV complications were noted in 17 patients (22%). The 5-year OS was 80% for patients with primary malignant tumors, 73% for patients with non-breast secondary malignant tumors, and 58% for patients with breast tumors (p=0.85). In the overall cohort, R0 resection was associated with prolonged 5-year OS (84% vs 20%) on both univariate (p=0.004) and multivariate (adjusted HR, 3.37; p=0.029) analysis. On subgroup analysis, R0 resection was associated with improved OS and RFP only for patients with primary malignant tumors.
Sternal resection can achieve favorable OS for patients with primary and secondary sternal tumors. R0 resection is associated with improved 5-year OS and RFP in patients with primary malignant tumors. We did not detect a similar effect in patients with breast or non-breast secondary tumors.
PMCID: PMC4634707  PMID: 26002443
sternum; cancer; outcomes
15.  Tumoral CD10 Expression Correlates with High-Grade Histology and Increases Risk of Recurrence in Patients with Stage I Lung Adenocarcinoma 
CD10 (neutral endopeptidase) is expressed in various normal and tumor cells, and its biological function can be controlled through enzymatic activity and signaling pathways. We investigated whether CD10 expression predicted disease recurrence and whether it correlated with histologic subtypes of stage I lung adenocarcinoma.
Material and Methods
We reviewed tumor slides of resected pathologic stage I lung adenocarcinomas (1995–2009). Tumors were classified according to the IASLC/ATS/ERS classification. CD10 immunohistochemistry was performed using tissue microarrays (n = 915). We combined the intensity (0–3) and distribution scores (0–2) for CD10 to create a total score (0–5). Risk of recurrence was estimated using competing risks methods.
In the training cohort (n = 313), risk of recurrence of patients with high tumoral CD10 (score > 1, n = 57) was significantly higher (5-year cumulative incidence of recurrence [CIR], 37%) than in those with low CD10 (score ≤ 1; n = 256; 5-year CIR, 16%; P < 0.001); this finding was confirmed in the validation cohort (n = 602, P = 0.036). High tumoral CD10 was associated with higher risk of recurrence in acinar (P = 0.007) and papillary predominant tumors (P = 0.022). High tumoral CD10 was most frequently identified in micropapillary predominant (41%) and solid predominant tumors (34%). On multivariate analysis of intermediate-grade tumors, high tumoral CD10 remained a significant independent risk factor of recurrence (hazard ratio, 1.88; P = 0.025).
In stage I lung adenocarcinoma, tumoral CD10 correlated with high-grade histology and was an independent predictor of recurrence in intermediate-grade tumors.
PMCID: PMC4532592  PMID: 26141216
adenocarcinoma; lung; CD10; histology; recurrence
16.  Prognostic Impact of Immune Microenvironment in Lung Squamous Cell Carcinoma: Tumor-Infiltrating CD10+ Neutrophil/CD20+ Lymphocyte Ratio as an Independent Prognostic Factor 
We previously reported the prognostic significance of the lung adenocarcinoma immune microenvironment. In this study, we preformed comprehensive analysis of immune markers and their associations with prognosis in patients with lung squamous cell carcinoma.
We reviewed surgically resected, solitary lung squamous cell carcinoma patients (n = 485; 1999 to 2009) that were randomly split into a training cohort (n = 331) and validation cohort (n = 154). We constructed tissue microarrays and performed immunostaining for CD3, CD45RO, CD8, CD4, FoxP3, CD20, CD68, CXCL12, CXCR4, CCR7, IL-7R, and IL-12Rβ2. Overall survival (OS) was analyzed using the log-rank test and the Cox proportional hazards model.
Analysis of single immune cell infiltration revealed that high tumor-infiltrating CD10+ neutrophils were associated with worse prognoses in the training cohort (P = 0.021). Analysis of biologically relevant immune cell combinations identified that patients with high CD10+ neutrophil and low CD20+ lymphocyte had a significantly worse OS (5-year OS, 42%) than those with other combinations of CD10 and CD20 (5-year OS, 62%; P < 0.001); this was confirmed in the validation cohort (P = 0.032). For the multivariate analysis, high CD10/low CD20 immune cell infiltration was an independent predictor of OS in both the training cohort (HR = 1.61, P = 0.006) and validation cohort (HR = 1.75; P = 0.043).
High CD10+/low CD20+ immune cell infiltration ratio is a significant prognostic factor of lung squamous cell carcinoma. Immunomodulatory therapy of tumor-specific neutrophil and B lymphocyte responses may have applicability in the treatment of lung squamous cell carcinoma.
PMCID: PMC4545576  PMID: 26291010
tumor infiltrating lymphocytes; immune response; non-small cell lung cancer; survival
17.  Reevaluation and reclassification of resected lung carcinomas originally diagnosed as squamous cell carcinoma using immunohistochemical analysis 
Currently, non-small cell lung carcinomas are primarily classified by light microscopy. However, recent studies have shown that poorly-differentiated tumors are more accurately classified by immunohistochemistry. In this study, we investigated the use of immunohistochemical analysis in reclassifying lung carcinomas that were originally diagnosed as squamous cell carcinoma. Tumor slides and blocks were available for histologic evaluation, and tissue microarrays were constructed from 480 patients with resected lung carcinomas originally diagnosed as squamous cell carcinoma between 1999 and 2009. Immunohistochemistry for p40, p63, thyroid transcription factor-1 (TTF-1; clone SPT24 and 8G7G3/1), Napsin A, Chromogranin A, Synaptophysin, and CD56 were performed. Staining intensity (weak, moderate, or strong) and distribution (focal or diffuse) were also recorded. Of all, 449 (93.5%) patients were confirmed as having squamous cell carcinomas; the cases were mostly diffusely positive for p40 and negative for TTF-1 (8G7G3/1). Twenty cases (4.2%) were reclassified as adenocarcinoma since they were positive for TTF-1 (8G7G3/1 or SPT24) with either no or focal p40 expression, and all of them were poorly-differentiated with squamoid morphology. In addition, 1 case was reclassified as adenosquamous carcinoma, 4 cases as large cell carcinoma, 4 cases as large cell neuroendocrine carcinoma, and 2 cases as small cell carcinoma. In poorly-differentiated non-small cell lung carcinomas, an accurate distinction between squamous cell carcinoma and adenocarcinoma cannot be reliably determined by morphology alone and requires immunohistochemical analysis, even in resected specimens. Our findings suggest that TTF-1 8G7G3/1 may be better suited as the primary antibody in differentiating adenocarcinoma from squamous cell carcinoma.
PMCID: PMC4537681  PMID: 25871623
squamous cell carcinoma; lung; immunohistochemistry; classification
18.  Chylothorax and Recurrent Laryngeal Nerve Injury Associated with Robotic Video-Assisted Mediastinal Lymph Node Dissection 
Innovations (Philadelphia, Pa.)  2015;10(3):170-173.
Although the technical aspects of robotic video-assisted thoracic surgery (RVATS) for lung resections may be advantageous, compared with standard thoracoscopy, complications of chylothorax and recurrent laryngeal nerve injury (RLNI) associated with mediastinal lymph node dissection (MLND) may be significant.
Consecutive patients who underwent RVATS anatomic lung resection for suspected or confirmed cancer and experienced RLNI or chylothorax were identified and reviewed from a prospectively maintained database. Complications were graded according to the Common Terminology Criteria for Adverse Events version 3.0.
From July 28, 2010, to December 20, 2013, 251 patients underwent RVATS segmentectomy, lobectomy, or bilobectomy with mediastinal lymph node dissection (MLND). Eleven patients (4.4%) experienced MLND-related complications and composed the study group; 81.8% were right-sided resections, and median lymph node counts in right station IV and station VII were 9 (range, 1–23) and 5.5 (range, 1–10); 72.7% of cases were performed for early-stage I and II lung cancers. Chylothorax (6/251 [2.4%]) and RLNI (6/251 [2.4%]) were significantly more common in the RVATS group than in the open thoracotomy and standard VATS groups. Complications requiring procedural intervention (Grade 3) are as follows: 4 cases of RLNI in patients undergoing percutaneous vocal cord medialization and 3 cases of chylothorax in patients undergoing image-guided thoracic duct embolization or maceration. No operative interventions were required.
RVATS MLND may be associated with increased rates of chylothorax and RLNI. Attention must be paid to identifying potential technical pitfalls with RVATS lung resections, adjusting surgical techniques accordingly, and minimizing patient morbidity.
PMCID: PMC4981881  PMID: 26165562
Robotic surgery; VATS; lung cancer; mediastinal lymph node dissection; complications
19.  Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer 
Cell Reports  2016;16(7):2032-2046.
Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we integrated with whole genomes from 23 breast cancers. Using X-inactivation analyses, we found that cancer cells are more transcriptionally active than intermixed stromal cells. This is especially true in estrogen receptor (ER)-negative tumors. Overall, 59% of substitutions were expressed. Nonsense mutations showed lower expression levels than expected, with patterns characteristic of nonsense-mediated decay. 14% of 4,234 rearrangements caused transcriptional abnormalities, including exon skips, exon reusage, fusions, and premature polyadenylation. We found productive, stable transcription from sense-to-antisense gene fusions and gene-to-intergenic rearrangements, suggesting that these mutation classes drive more transcriptional disruption than previously suspected. Systematic integration of transcriptome with genome data reveals the rules by which transcriptional machinery interprets somatic mutation.
Graphical Abstract
•Greater transcriptional activity in cancer than stromal cells, particularly when ER-ve•Intron mutations only infrequently affect splicing, even at essential splice sites•Distinctive RNA effects of sense-to-antisense and gene-to-intergenic rearrangements•Exhaustive pipeline for identifying aberrant transcripts from RNA-sequencing data
Shlien et al. quantify first-order transcriptional consequences across all classes of somatic mutation in well-annotated breast cancers. They find that cancer cells are more transcriptionally active than stromal cells, especially in ER-negative cancers. Rearrangements that break genes or place them in opposite orientation are an unexpectedly potent source of fusions.
PMCID: PMC4987284  PMID: 27498871
20.  A decision analytic model to investigate the cost-effectiveness of poisoning prevention practices in households with young children 
BMC Public Health  2016;16:705.
Systematic reviews and a network meta-analysis show home safety education with or without the provision of safety equipment is effective in promoting poison prevention behaviours in households with children. This paper compares the cost-effectiveness of home safety interventions to promote poison prevention practices.
A probabilistic decision-analytic model simulates healthcare costs and benefits for a hypothetical cohort of under 5 year olds. The model compares the cost-effectiveness of home safety education, home safety inspections, provision of free or low cost safety equipment and fitting of equipment. Analyses are conducted from a UK National Health Service and Personal Social Services perspective and expressed in 2012 prices.
Education without safety inspection, provision or fitting of equipment was the most cost-effective strategy for promoting safe storage of medicines with an incremental cost-effectiveness ratio of £2888 (95 % credible interval (CrI) £1990–£5774) per poison case avoided or £41,330 (95%CrI £20,007–£91,534) per QALY gained compared with usual care. Compared to usual care, home safety interventions were not cost-effective in promoting safe storage of other household products.
Education offers better value for money than more intensive but expensive strategies for preventing medicinal poisonings, but is only likely to be cost-effective at £30,000 per QALY gained for families in disadvantaged areas and for those with more than one child. There was considerable uncertainty in cost-effectiveness estimates due to paucity of evidence on model parameters. Policy makers should consider both costs and effectiveness of competing interventions to ensure efficient use of resources.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-3334-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4973049  PMID: 27488449
Economic evaluation; Public health; Injury prevention; Poisonings; Children; Decision models
21.  Results of the National Lung Cancer Screening Trial: Where Are We Now? 
Thoracic surgery clinics  2015;25(2):145-153.
The National Lung Screening Trial (NLST) was a large, multicenter, randomized, controlled trial published in 2011. It found that annual screening with low-dose computed tomography (LDCT) in a high-risk population was associated with a 20% reduction in lung cancer–specific mortality, compared with conventional chest radiography. Several leading professional organizations have since put forth lung cancer screening guidelines that include the use of LDCT, largely on the basis of this study. Broad adoption of these screening recommendations, however, remains a challenge.
PMCID: PMC4817217  PMID: 25901558
lung cancer; screening; low-dose computed tomography; NLST
22.  Comparing Surgical Infections in NSQIP and an Institutional Database 
The Journal of surgical research  2015;196(2):416-420.
Surgical quality improvement requires accurate tracking and benchmarking of postoperative adverse events. We track surgical-site infections (SSIs) with two systems, our in-house Surgical Secondary Events (SSE) database and the National Surgical Quality Improvement Project (NSQIP). The SSE database, a modification of the Clavien-Dindo classification, categorizes SSIs by their anatomic site while NSQIP categorizes by their level. Our aim was to directly compare these different definitions.
Materials and Methods
NSQIP and the SSE database entries for all surgeries performed in 2011 and 2012 were compared. To match NSQIP definitions, and while blinded to NSQIP results, entries in the SSE database were categorized as either incisional (superficial or deep) or organ space infections. These categorizations were compared with NSQIP records; agreement was assessed with Cohen’s kappa.
The 5,028 patients in our cohort had a 6.5% SSI in the SSE database and a 4% rate in NSQIP, with an overall agreement of 95% (kappa = 0.48, p <0.0001). The rates of categorized infections were similarly well matched; incisional rates of 4.1% and 2.7% for the SSE database and NSQIP, and organ space rates of 2.6% and 1.5%. Overall agreements was 96% (kappa = 0.36, p <0.0001) and 98% (kappa = 0.55, p < 0.0001), respectively. Over 80% of cases recorded by the SSE database but not NSQIP did not meet NSQIP criteria.
The SSE database is an accurate, real-time, record of post-operative SSIs. Institutional databases that capture all surgical cases can be used in conjunction with NSQIP with excellent concordance.
PMCID: PMC4667735  PMID: 25840487
Surgical Quality Improvement; Surgical Site Infection; Wound Classification; Surgical Complications; Surgical Secondary Events; Secondary Event Grading System
23.  Cell cycle progression score is a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma  
Oncotarget  2016;7(23):35241-35256.
The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes.
Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer–specific mortality as the primary outcome.
In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer–specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14–2.24; P=0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer–specific mortality (HR=1.77; 95% CI, 1.18–2.66; P=0.006). Five-year lung cancer–specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P<0.001). In patients with intermediate-grade lung ADC of acinar and papillary subtypes, high mPS was associated with worse 5-year lung cancer–specific survival (P<0.001 and 0.015, respectively), compared with low mPS.
This study validates CCP score and mPS as independent prognostic markers for lung cancer–specific mortality and provides quantitative risk assessment, independent of known high-risk features, for stage I lung ADC patients treated with surgery alone.
PMCID: PMC5085225  PMID: 27153551
molecular prognostic score; CCP score; chemotherapy; adjuvant therapy; overall survival
24.  Nicotine and Cotinine Exposure from Electronic Cigarettes: A Population Approach 
Clinical pharmacokinetics  2015;54(6):615-626.
Background and Objectives
Electronic cigarettes (e-cigarettes) are a recent technology that has gained rapid acceptance. Still, little is known about them in terms of safety and effectiveness. A basic question is how effectively they deliver nicotine, however the literature is surprisingly unclear on this point. Here, a population pharmacokinetic (PK) model was developed for nicotine and its major metabolite cotinine with the aim to provide a reliable framework for the simulation of nicotine and cotinine concentrations over time, based solely on inhalation airflow recordings and individual covariates (i.e. weight and breath carbon monoxide CO levels).
This study included 10 adults self-identified as heavy smokers (at least one pack per day). Plasma nicotine and cotinine concentrations were measured at regular 10-minute intervals for 90 minutes while human subjects inhaled nicotine vapor from a modified e-cigarette. Airflow measurements were recorded every 200 milliseconds throughout the session. A population PK model for nicotine and cotinine was developed based on previously published PK parameters and the airflow recordings. All the analyses were performed with the nonlinear mixed-effect modelling software NONMEM 7.2.
The results show that e-cigarettes deliver nicotine effectively, although the pharmacokinetic profiles are lower than those achieved with regular cigarettes. Our PK model effectively predicts plasma nicotine and cotinine concentrations from the inhalation volume, and initial breath CO.
E-cigarettes are effective at delivering nicotine. This new PK model of e-cigarette usage might be used for pharmacodynamic analysis where the PK profiles are not available.
PMCID: PMC4450108  PMID: 25503588
nicotine; cotinine; NONMEM
25.  Tumor Spread Through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences Following Limited Resection for Small Stage I Lung Adenocarcinomas 
Tumor invasion in lung adenocarcinoma is defined as infiltration of stroma, blood vessels, or pleura. Based on observation of tumor spread through air spaces (STAS), we considered whether this could represent new patterns of invasion and investigated whether it correlated with locoregional versus distant recurrence according to limited resection versus lobectomy.
We reviewed resected small (≤2 cm) stage I lung adenocarcinomas (n=411; 1995–2006). Tumor STAS was defined as tumor cells—micropapillary structures, solid nests, or single cells—spreading within air spaces in the lung parenchyma beyond the edge of the main tumor. Competing risks methods were used to estimate risk of disease recurrence and its associations with clinicopathological risk factors.
STAS was observed in 155 cases (38%). In the limited resection group (n=120), the risk of any recurrence was significantly higher in patients with STAS-positive tumors than that of patients with STAS-negative tumors (5-year cumulative incidence of recurrence [CIR], 42.6% vs. 10.9%; P<0.001); the presence of STAS correlated with higher risk of distant (P=0.035) and locoregional recurrence (P=0.001). However, in the lobectomy group (n=291), presence of STAS was not associated with either any (P=0.50) or distant recurrence (P=0.76). In a multivariate analysis, presence of tumor STAS remained independently associated with the risk of developing recurrence (hazard ratio, 3.08; P=0.014).
Presence of STAS is a significant risk factor of recurrence in small lung adenocarcinomas treated with limited resection. These findings support our proposal that STAS should formally be recognized as a pattern of invasion in lung adenocarcinoma.
PMCID: PMC4500042  PMID: 25629637
lung; adenocarcinoma; invasion; spread through air spaces; recurrence

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