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1.  Occult Metastases in Lymph Nodes Predict Survival in Resectable Non–Small-Cell Lung Cancer: Report of the ACOSOG Z0040 Trial 
Journal of Clinical Oncology  2011;29(32):4313-4319.
Purpose
The survival of patients with non–small-cell lung cancer (NSCLC), even when resectable, remains poor. Several small studies suggest that occult metastases (OMs) in pleura, bone marrow (BM), or lymph nodes (LNs) are present in early-stage NSCLC and are associated with a poor outcome. We investigated the prevalence of OMs in resectable NSCLC and their relationship with survival.
Patients and Methods
Eligible patients had previously untreated, potentially resectable NSCLC. Saline lavage of the pleural space, performed before and after pulmonary resection, was examined cytologically. Rib BM and all histologically negative LNs (N0) were examined for OM, diagnosed by cytokeratin immunohistochemistry (IHC). Survival probabilities were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazards regression model were used to compare survival of groups of patients. P < .05 was considered significant.
Results
From July 1999 to March 2004, 1,047 eligible patients (538 men and 509 women; median age, 67.2 years) were entered onto the study, of whom 50% had adenocarcinoma and 66% had stage I NSCLC. Pleural lavage was cytologically positive in only 29 patients. OMs were identified in 66 (8.0%) of 821 BM specimens and 130 (22.4%) of 580 LN specimens. In univariate and multivariable analyses OMs in LN but not BM were associated with significantly worse disease-free survival (hazard ratio [HR], 1.50; P = .031) and overall survival (HR, 1.58; P = .009).
Conclusion
In early-stage NSCLC, LN OMs detected by IHC identify patients with a worse prognosis. Future clinical trials should test the role of IHC in identifying patients for adjuvant therapy.
doi:10.1200/JCO.2011.35.2500
PMCID: PMC3221530  PMID: 21990404
2.  Clinical Impact of Immune Microenvironment in Stage I Lung Adenocarcinoma: Tumor Interleukin-12 Receptor β2 (IL-12Rβ2), IL-7R, and Stromal FoxP3/CD3 Ratio Are Independent Predictors of Recurrence 
Journal of Clinical Oncology  2012;31(4):490-498.
Purpose
Mounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC).
Patients and Methods
Using tissue microarray and immunohistochemistry, we investigated eight types of tumor-infiltrating immune cells in the tumor nest and tumor-associated stroma as well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts).
Results
Although a high density of stromal forkhead box P3 (FoxP3) –positive cells was associated with shorter recurrence-free probability (RFP; P = .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P = .004). High expression of tumor interleukin-12 receptor β2 (IL-12Rβ2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P = .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for high v 86% for low expression; P = .001). In multivariate analysis, these immune markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors ≤ 2 cm.
Conclusion
Our investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.
doi:10.1200/JCO.2012.45.2052
PMCID: PMC3731922  PMID: 23269987
3.  Do we need a revised staging system for malignant pleural mesothelioma? Analysis of the IASLC database 
Annals of Cardiothoracic Surgery  2012;1(4):438-448.
Introduction
A number of staging systems have been proposed for malignant pleural mesothelioma (MPM) in the past, but few have utilized a TNM (tumor, node, metastasis) system. The International Association for the Study of Lung Cancer (IASLC) and the International Mesothelioma Interest Group (IMIG) previously developed a TNM-staging system which has been accepted by the International Union Against Cancer (UICC) and the American Joint Commission on Cancer (AJCC). The present study examines this staging system by analysing the updated IASLC database for patients with MPM.
Methods
De-identified data from participating centres dated from 1995 to 2009 were submitted to the IASLC Statistical Center. Surgical procedures included those with a curative or palliative intent. Survival was measured from the date of pathologic diagnosis to the most recent contact or death. Endpoints included overall survival and analysis of potential prognostic factors.
Results
Data was available for 3,101 patients from 15 centers, mostly from North America and Europe. After a median follow-up of 15 months, a number of clinicopathological and treatment-related prognostic factors were found to significantly influence overall survival. These included overall tumor stage based on the proposed TNM staging system, T category, N category, tumor histology, gender, age, and type of operation.
Conclusions
The IASLC database represents the largest, multicenter and international database on MPM to date. Analyses demonstrate that the proposed TNM staging system effectively distinguishes the T and N categories, but also highlight areas for potential revision in the future.
doi:10.3978/j.issn.2225-319X.2012.11.10
PMCID: PMC3741785  PMID: 23977534
Pleural mesothelioma; extrapleural pneumonectomy; pleurectomy; decortication; trimodality therapy; multi-institutional database; survival; staging
4.  Video-atlas of extrapleural pneumonectomy 
This is a step-by-step video demonstration of a left extrapleural pneumonectomy for malignant pleural mesothelioma, including thoracotomy incision, extrapleural mobilization of tumor, resection of diaphragm, mediastinal nodal dissection and division of hilar vessels followed by reconstruction of diaphragm and closure of the thoracotomy.
doi:10.3978/j.issn.2225-319X.2012.11.02
PMCID: PMC3741793  PMID: 23977548
Extrapleural pneumonectomy (EPP); malignant pleural mesothelioma
6.  Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-free and Overall Survival in Early-Stage Lung Adenocarcinoma 
Purpose
In an effort to identify molecular markers of tumor aggressiveness and therapeutic targets in lung adenocarcinoma (ADC), we investigated the expression of mesothelin (MSLN) in lung ADC, as well as its biological and clinical relevance.
Experimental Design
In a training and validation set of patients with early-stage (I–III) lung ADC (n=1209), a tissue microarray consisting of tumors and normal lung tissue was used to examine the association between MSLN expression and recurrence-free survival (RFS) and overall survival (OS). The influence of MSLN overexpression on lung ADC was investigated in vitro and in vivo by use of clinically relevant orthotopic and metastatic xenogeneic and syngeneic mouse models.
Results
MSLN was expressed in 69% of lung ADC tumors, with one in five patients strongly expressing MSLN and no expression in normal lung tissue. Increased MSLN expression was associated with reduced OS (HR, 1.78 [95% CI, 1.26–2.50]; P<0.01) and RFS (HR, 1.67 [95% CI, 1.21–2.27]; P<0.01) in multivariate analyses, even after adjustment for currently known markers of tumor aggressiveness in lung ADC: male sex, smoking history, increasing stage, morphologic pattern, visceral pleural invasion, lymphatic or vascular invasion, and mutation status. In vitro, lung ADC cells overexpressing MSLN demonstrated increased cell proliferation, migration, and invasion; in vivo, mice with MSLN(+) tumors demonstrated decreased survival (P=0.001).
Conclusions
MSLN expression in patients with early-stage lung ADC is associated with increased risk of recurrence and reduced OS, indicating that MSLN expression is a molecular marker of tumor aggressiveness and a potential target for therapy.
doi:10.1158/1078-0432.CCR-13-1862
PMCID: PMC3944669  PMID: 24334761
Mesothelin; lung adenocarcinoma; prognosis; targeted therapy; non-small cell lung cancer
7.  Esophageal Cancer Recurrence Patterns and Implications for Surveillance 
Introduction
After definitive treatment of esophageal cancer, patients are at high risk for recurrence. Consistent follow-up is important for detection and treatment of recurrence. The optimal surveillance regimen remains undefined. We investigated posttreatment recurrence patterns and methods of detection in survivors of esophageal cancer.
Methods
We retrospectively studied a cohort of patients who had undergone surgical resection for esophageal cancer at our institution between 1996 and 2010. Routine computed tomography (CT) scan and upper endoscopy were performed for surveillance.
Results
In total, 1147 patients with resected esophageal adenocarcinoma or squamous cell carcinoma were included (median follow-up, 46 months). Of these, 723 (63%) had received neoadjuvant therapy before surgery. During follow-up, there were 595 deaths (52%) and 435 recurrences (38%) (distant [55%], locoregional [28%], or both [17%]). Half of recurrences were detected as a result of symptoms (n = 217), 45% by routine chest and abdominal CT scan (n = 194), and 1% by surveillance upper endoscopy (n = 6). The recurrence rate decreased from 27 per 100 person-years in posttreatment year 1 to 4 per 100 person-years in year 6. In the first 2 years, the rate of recurrence was higher among patients who had received neoadjuvant therapy (35 per 100 person-years) than among those who had not (14 per 100 person-years) (p < 0.001).
Conclusions
The incidence of recurrence is high after esophagectomy for cancer. Surveillance endoscopy has limited value for detection of asymptomatic local recurrence. The yield from follow-up scans diminishes significantly after the sixth year; surveillance scans after that point are likely unnecessary.
doi:10.1097/01.JTO.0000437420.38972.fb
PMCID: PMC4066875  PMID: 24389438
Esophageal Cancer; Surveillance; Endoscopy
8.  Comparison of Patterns of Relapse in Thymic Carcinoma and Thymoma 
Objective
Thymic carcinomas (TC) are considered to be more aggressive than thymomas and carry a worse prognosis. We reviewed our recent experience with the surgical management of thymic tumors and compared the outcomes and patterns of relapse between TC and thymoma.
Methods
Single institution retrospective cohort study. Data included patient demographics, stage, treatment, pathologic findings, and postoperative outcomes.
Results
During the period 1995–2006, 120 patients with thymic tumors underwent surgery, including 23 patients with TC and 97 patients with thymoma by the WHO 2004 histologic classification. The overall 5 year survival was significantly different between TC and thymoma (TC 53%, thymoma 89%, p=0.01). Data on relapse was available for 112 patients. The progression-free 5 year survival was also significantly different between TC and thymoma (TC 36%, thymoma 75%, p<0.01). By multivariate analysis, thymic carcinoma and incomplete resection were found to be independent predictors of progression-free survival. Relapses in TC tended to occur earlier, and occurred signficantly more frequently at distant sites than in thymoma (60% vs. 13%, p=0.01).
Conclusions
Patterns of relapse differ significantly between TC and thymoma with lower progression-free survival, earlier onset and more distant relapses in TC. Given the greater propensity for distant failures, the inclusion of systemic therapy in the treatment of TC may take on greater importance. Despite significantly higher rates of distant relapse, good overall survival in TC can be achieved.
doi:10.1016/j.jtcvs.2009.03.033
PMCID: PMC4151511  PMID: 19577051
9.  Impact of Micropapillary Histologic Subtype in Selecting Limited Resection vs Lobectomy for Lung Adenocarcinoma of 2cm or Smaller 
Background
We sought to analyze the prognostic significance of the new International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) lung adenocarcinoma (ADC) classification for patients undergoing resection for small (≤2cm) lung ADC and to investigate whether histologic subtyping can predict recurrence after limited resection (LR) vs lobectomy (LO).
Methods
Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification on all consecutive patients who underwent LR or LO for small lung ADC between 1995 and 2009 at Memorial Sloan-Kettering Cancer Center. Clinical characteristics and pathologic data were retrospectively evaluated for 734 consecutive patients (LR: 258; LO: 476). Cumulative incidence of recurrence (CIR) was calculated using competing risks analysis and compared across groups using Grey’s test. All statistical tests were two-sided.
Results
Application of IASLC/ATS/ERS lung ADC histologic subtyping to predict recurrence demonstrates that, in the LR group but not in the LO group, micropapillary (MIP) component of 5% or greater was associated with an increased risk of recurrence, compared with MIP component of less than 5% (LR: 5-year CIR = 34.2%, 95% confidence interval [CI] = 23.5% to 49.7% vs 5-year CIR = 12.4%, 95% CI = 6.9% to 22.1%, P < .001; LO: 5-year CIR = 19.1%, 95% CI = 12.0% to 30.5% vs 15-year CIR = 12.9%, 95% CI = 7.6% to 21.9%, P = .13). In the LR group, among patients with tumors with an MIP component of 5% or greater, most recurrences (63.4%) were locoregional; MIP component of 5% or greater was statistically significantly associated with increased risk of local recurrence when the surgical margin was less than 1cm (5-year CIR = 32.0%, 95% CI = 18.6% to 46.0% for MIP ≥ 5% vs 5-year CIR = 7.6%, 95% CI = 2.3% to 15.6% for MIP < 5%; P = .007) but not when surgical margin was 1cm or greater (5-year CIR = 13.0%, 95% CI = 4.1% to 22.1% for MIP ≥ 5% vs 5-year CIR = 3.4%, 95% CI = 0% to 7.7% for MIP < 5%; P = .10).
Conclusions
Application of the IASLC/ATS/ERS classification identifies the presence of an MIP component of 5% or greater as independently associated with the risk of recurrence in patients treated with LR.
doi:10.1093/jnci/djt166
PMCID: PMC3748005  PMID: 23926067
10.  Supplementary Prognostic Variables for Pleural Mesothelioma 
Journal of Thoracic Oncology  2014;9(6):856-864.
Introduction:
The staging system for malignant pleural mesothelioma is controversial. To revise this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. This report analyzes prognostic variables in a surgical population, which are supplementary to previously published CORE variables (stage, histology, sex, age, and type of procedure).
Methods:
Supplementary prognostic variables were studied in three scenarios: (1) all data available, that is, patient pathologically staged and other CORE variables available (2) only clinical staging available along with CORE variables, and (3) only age, sex, histology, and laboratory parameters are known. Survival was analyzed by Kaplan–Meier, prognostic factors by log rank and stepwise Cox regression modeling after elimination of nonsignificant variables. p value less than 0.05 was significant.
Results:
A total of 2141 patients with best tumor, node, metastasis (TNM) stages (pathologic with/without clinical staging) had nonmissing age, sex, histology, and type of surgical procedure. Three prognostic models were defined. Scenario A (all parameters): best pathologic stage, histology, sex, age, type of surgery, adjuvant treatment, white blood cell count (WBC) (≥15.5 or not), and platelets (≥400 k or not) (n = 550). Scenario B (no surgical staging): clinical stage, histology, sex, age, type of surgery, adjuvant treatment, WBC, hemoglobin (<14.6 or not), and platelets (n = 627). Scenario C (limited data): histology, sex, age, WBC, hemoglobin, and platelets (n = 906).
Conclusion:
Refinement of these models could define not only the appropriate patient preoperatively for best outcomes after cytoreductive surgery but also stratify surgically treated patients after clinical and pathologic staging who do or do not receive adjuvant therapy.
doi:10.1097/JTO.0000000000000181
PMCID: PMC4132031  PMID: 24807157
Mesothelioma; Surgery; Prognosis; Registry; Staging
11.  A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma 
Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival = 28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.
doi:10.1038/modpathol.2011.146
PMCID: PMC4080411  PMID: 21983936
epithelioid mesothelioma; MIB-1; mitosis; nuclear atypia; nuclear grade; survival
12.  FDG-PET SUVmax Combined with IASLC/ATS/ERS Histologic Classification Improves the Prognostic Stratification of Patients with Stage I Lung Adenocarcinoma 
Annals of surgical oncology  2012;19(11):3598-3605.
Background
We investigated the association between the newly proposed International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), and whether the combination of these radiologic and pathologic factors can further prognostically stratify patients with stage I lung adenocarcinoma.
Methods
We retrospectively evaluated 222 patients with pathologic stage I lung adenocarcinoma who underwent FDG-PET scanning before undergoing surgical resection between 1999 and 2005. Patients were classified by histologic grade according to the IASLC/ATS/ERS classification (low, intermediate, or high grade) and by maximum standard uptake value (SUVmax) (low <3.0, high ≥3.0). The cumulative incidence of recurrence (CIR) was used to estimate recurrence probabilities.
Results
Patients with high-grade histology had higher risk of recurrence (5-year CIR, 29 % [n = 25]) than those with intermediate-grade (13 % [n = 181]) or low-grade (11 % [n = 16]) histology (p = 0.046). High SUVmax was associated with high-grade histology (p < 0.001) and with increased risk of recurrence compared to low SUVmax (5-year CIR, 21 % [n = 113] vs. 8 % [n = 109]; p = 0.013). Among patients with intermediate-grade histology, those with high SUVmax had higher risk of recurrence than those with low SUVmax (5-year CIR, 19 % [n = 87] vs. 7 % [n = 94]; p = 0.033). SUVmax was associated with recurrence even after adjusting for pathologic stage (p = 0.037).
Conclusions
SUVmax on FDG-PET correlates with the IASLC/ATS/ERS classification and can be used to stratify patients with intermediate-grade histology, the predominant histologic subtype, into two prognostic subsets.
doi:10.1245/s10434-012-2414-3
PMCID: PMC4049004  PMID: 22644511
13.  Morphologic Features of Adenocarcinoma of the Lung Predictive of Response to the Epidermal Growth Factor Receptor Kinase Inhibitors Erlotinib and Gefitinib 
Context
A subset of lung adenocarcinomas appears preferentially sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). EGFR-activating mutations and never smoking are associated with response to TKIs.
Objectives
To describe the morphology of adenocarcinomas responsive to TKIs, compare it to tumors in nonresponding patients, and correlate findings with EGFR mutations, gene copy number, and protein expression.
Design
Material from 52 EGFR TKI-treated patients was studied: 29 responders and 23 nonresponders. Adenocarcinoma subtypes and morphologic features were defined in histologic and cytologic material. EGFR mutations were detected by sequencing, copy number by chromogenic in situ hybridization, and expression by immunohistochemistry.
Results
Tumors from TKI responders tended to be better-differentiated adenocarcinomas with bronchioloalveolar carcinoma components. Nonresponders showed more heterogeneous morphology, higher grade, and more subtypes, and were more likely to show solid growth. In nonresponders, the only pure bronchioloalveolar carcinoma was mucinous, a subtype known to be negative for EGFR mutations. Using World Health Organization criteria, all tumors in both groups other than pure bronchioloalveolar carcinomas would be classified as adenocarcinomas, mixed subtype, thereby obscuring some of these distinctions. EGFR mutations were significantly more common in responders (22/29 vs 0/23; P < .001). Immunohistochemistry and chromogenic in situ hybridization results were not significantly correlated with EGFR mutations or response to TKIs in this study.
Conclusions
Overall, histologic differences exist between tumors that respond to TKIs and those that do not, although sampling affects classification, and there is significant histologic overlap between the 2 groups. Response is strongly associated with EGFR mutations.
doi:10.1043/1543-2165-133.3.470
PMCID: PMC4016915  PMID: 19260752
14.  Thyroid Transcription Factor–1 Expression Is an Independent Predictor of Recurrence and Correlates with the IASLC/ATS/ERS Histologic Classification in Patients with Stage I Lung Adenocarcinoma 
Cancer  2012;119(5):931-938.
BACKGROUND
We investigated whether thyroid transcription factor–1 (TTF-1) expression correlates with the IASLC/ATS/ERS classification and whether it stratifies patients with stage I lung adenocarcinoma with respect to recurrence.
METHODS
Patients with stage I lung adenocarcinoma were classified according to the IASLC/ATS/ERS classification. We constructed tissue microarrays and performed immunostaining for TTF-1; 452 cases were available for analysis. Tumors were dichotomized by intensity of nuclear TTF-1 expression: negative (score 0) or positive (score 1–3). Cumulative incidence of recurrence (CIR) was used to estimate recurrence probabilities.
RESULTS
TTF-1 expression was identified in 92% of all patients, including 100% of patients with minimally invasive or lepidic-predominant adenocarcinoma, 94% of acinar-predominant, 98% of papillary-predominant, 93% of micropapillary-predominant, 86% of solid-predominant, 67% of colloid-predominant, and 47% of invasive-mucinous. The CIR for patients with negative TTF-1 expression (n = 34; 5-year CIR, 40%) was significantly higher than that for patients with positive TTF-1 (n = 418; 5-year CIR, 15%; p < 0.001). Among the intermediate-grade tumors, the CIR for patients with negative TTF-1 expression (n = 16; 5-year CIR, 45%) was significantly higher than that for patients with positive TTF-1 (n = 313, 5-year CIR, 14%; p < 0.001). In multivariate analysis, negative TTF-1 expression significantly correlated with increased risk of recurrence (hazard ratio, 2.55; p = 0.009).
CONCLUSIONS
TTF-1 expression is an independent predictor of recurrence, stratifying intermediate-grade tumors into 2 prognostic subsets, and it correlates with the IASLC/ATS/ERS classification.
doi:10.1002/cncr.27863
PMCID: PMC3691693  PMID: 23096929
lung adenocarcinoma; thyroid transcription factor–1; histologic subtype; recurrence
15.  Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients 
Purpose
Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biological function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases.
Experimental Design
Human and murine MPM cells with MSLN forced expression and shRNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples.
Results
MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, co-localized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n=139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n=72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors.
Conclusions
Our data provide evidence elucidating a biological role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN-expressing MPM. As regional invasion is the characteristic feature in MSLN-expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target.
doi:10.1158/1078-0432.CCR-11-2614
PMCID: PMC3759995  PMID: 22371455
Mesothelin; mesothelioma; matrix metalloproteinase; tumor invasion; locoregional aggressiveness
16.  High-SUVmax on FDG-PET indicates pleomorphic subtype in epithelioid malignant pleural mesothelioma: Supportive evidence to reclassify pleomorphic as non-epithelioid histology 
Background
We have recently proposed to reclassify the pleomorphic subtype of epithelioid malignant pleural mesothelioma (MPM) as non-epithelioid (biphasic/sarcomatoid) histology due to its similarly poor prognosis. We sought to investigate whether preoperative maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) correlates with histologic subtype in MPM.
Methods
Clinical data was collected for 78 patients with MPM who underwent preoperative FDG-PET. We retrospectively classified the epithelioid tumors into five subtypes: trabecular, tubulopapillary, micropapillary, solid and pleomorphic. Tumors were categorized by SUVmax into two groups: low (<10.0) and high (≥10.0).
Results
The median overall survival of epithelioid tumors with high-SUVmax (n=12) was significantly shorter (7.1 months) than that of epithelioid tumors with low-SUVmax (n=54, 18.9 months, p<0.001) and comparable to non-epithelioid tumors (n=12, 7.2 months). Epithelioid tumors with pleomorphic subtype (n=9) had marginally higher SUVmax (mean±SD: 10.6±5.9) than epithelioid non-pleomorphic subtype (n=57, 6.5±3.2, p=0.050), and were comparable to that of non-epithelioid tumors (n=12, 9.1±4.8). Among the epithelioid tumors with high-SUVmax (n=12), 50% (n=6) showed pleomorphic subtype. In contrast, among epithelioid tumors with low-SUVmax (n=54), 6% (n=3) showed epithelioid pleomorphic subtypes (p=0.001). A positive correlation between mitotic count and SUVmax was observed (r=0.30, p=0.010).
Conclusions
Pleomorphic subtype of epithelioid MPM showed higher SUVmax than epithelioid non-pleomorphic subtype and was similar to non-epithelioid histology. Preoperative SUVmax on FDG-PET in epithelioid MPM can indicate patients with pleomorphic subtype with poor prognosis, supporting their reclassification as non-epithelioid.
doi:10.1097/JTO.0b013e3182519d96
PMCID: PMC3691682  PMID: 22617244
Mesothelioma; Pleural neoplasm; Positron emission tomography; Pleomorphic
17.  Core Needle Lung Biopsy Specimens: Adequacy for EGFR and KRAS Mutational Analysis 
OBJECTIVE
The purpose of this study was to prospectively compare the adequacy of core needle biopsy specimens with the adequacy of specimens from resected tissue, the histologic reference standard, for mutational analysis of malignant tumors of the lung.
SUBJECTS AND METHODS
The first 18 patients enrolled in a phase 2 study of gefitinib for lung cancer in July 2004 through August 2005 underwent CT- or fluoroscopy-guided lung biopsy before the start of gefitinib therapy. Three weeks after gefitinib therapy, the patients underwent lung tumor resection. The results of EGFR and KRAS mutational analysis of the core needle biopsy specimens were compared with those of EGFR and KRAS mutational analysis of the surgical specimens.
RESULTS
Two specimens were unsatisfactory for mutational analysis. The results of mutational assay results of the other 16 specimens were the same as those of analysis of the surgical specimens obtained an average of 31 days after biopsy.
CONCLUSION
Biopsy with small (18- to 20-gauge) core needles can yield sufficient and reliable samples for mutational analysis. This technique is likely to become an important tool with the increasing use of pharmacotherapy based on the genetics of specific tumors in individual patients.
doi:10.2214/AJR.09.2858
PMCID: PMC3676673  PMID: 20028932
biopsy; lung cancer; molecular typing; personalized medicine; targeted therapy
18.  Tissue and serum mesothelin are potential markers of neoplastic progression in Barrett’s–associated esophageal adenocarcinoma 
Background
Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett’s esophagus (BE) and in esophageal adenocarcinoma (EAC).
Methods
Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum.
Results
Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean, 0.89 nM; range, 0.03-3.77 nM), but not in patients with acid reflux and/or BE.
Conclusions
Mesothelin is commonly expressed in BE-associated esophageal adenocarcinoma. Based on this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin are potential markers of neoplastic progression in BE and in EAC (NCT01393483).
Impact
Current surveillance methods in Barrett’s esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation.
doi:10.1158/1055-9965.EPI-11-0993
PMCID: PMC3297720  PMID: 22237988
Mesothelin; SMRP; Barrett’s esophagus; esophageal cancer; screening
19.  Clinicopathological features and the impact of the new TNM classification of malignant tumors in patients with pulmonary large cell neuroendocrine carcinoma 
Molecular and Clinical Oncology  2013;1(3):437-443.
The prognosis of patients with large-cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor and the optimal treatment for these patients has yet to be determined. In this study, we described the clinicopathological characteristics of LCNECs and compared the prognoses of corresponding stages determined by the guidelines of the 6th and 7th editions of the TNM classification of malignant tumors. Clinical data from 42 patients diagnosed with primary LCNEC who underwent treatment at Kitasato University Hospital between 1991 and 2009 were retrospectively analyzed. On follow-up of 42 patients, 22 (52.4%) had confirmed recurrent tumors, including 8 patients with mediastinal lymph node recurrences and 19 with distant metastases. The sites of distant metastases included the brain in 8, bone in 8, liver in 7, lungs in 5 and adrenal glands in 4 patients. For all the patients, the 5-year overall survival rate was 34.7% and the 5-year disease-free survival rate was 32.9%. The 5-year overall survival rates of patients with stage I cancers according to the 6th and 7th staging editions was 51.3% (6th n=18, 7th n=16). Thirteen of 42 patients (31.0%) also had metachronous or synchronous primary cancers. Patients with LCNEC had poor outcomes, even those with stage I tumors classified according to the 7th edition of the TNM classification. Therefore, frequent recurrences in addition to metachronous or synchronous primary cancers in patients with LCNEC should be treated.
doi:10.3892/mco.2013.80
PMCID: PMC3916090  PMID: 24649189
large cell; neuroendocrine; TNM stage; prognosis; outcome
20.  Preface 
doi:10.3978/j.issn.2225-319X.2012.11.01
PMCID: PMC3741792
21.  Incidence of EGFR Exon 19 Deletions and L858R in Tumor Specimens From Men and Cigarette Smokers With Lung Adenocarcinomas 
Journal of Clinical Oncology  2011;29(15):2066-2070.
Purpose
EGFR mutations underlie the sensitivity of lung cancers to erlotinib and gefitinib and can occur in any patient with this illness. Here we examine the frequency of EGFR mutations in smokers and men.
Methods
We determined the frequency of EGFR mutations and characterized their association with cigarette smoking status and male sex.
Results
We tested 2,142 lung adenocarcinoma specimens for the presence of EGFR exon 19 deletions and L858R. EGFR mutations were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13% to 17%), 6% from current smokers (20 of 344; 95% CI, 4% to 9%), and 52% from never smokers (302 of 580; 95% CI, 48% to 56%; P < .001 for ever v never smokers). EGFR mutations in former or current smokers represented 40% of all those detected (201 of 503; 95% CI, 36% to 44%). EGFR mutations were found in 19% (157 of 827; 95% CI, 16% to 22%) of tumors from men and 26% (346 of 1,315; 95% CI, 24% to 29%) of tumors from women (P < .001). EGFR mutations in men represented 31% (157 of 503; 95% CI, 27% to 35%) of all those detected.
Conclusion
A large number of EGFR mutations are found in adenocarcinoma tumor specimens from men and people who smoked cigarettes. If only women who were never smokers were tested, 57% of all EGFR mutations would be missed. Testing for EGFR mutations should be considered for all patients with adenocarcinoma of the lung at diagnosis, regardless of clinical characteristics. This strategy can extend the use of EGFR tyrosine kinase inhibitors to the greatest number individuals with the potential for substantial benefit.
doi:10.1200/JCO.2010.32.6181
PMCID: PMC3296671  PMID: 21482987
22.  Frequency of EGFR and KRAS Mutations in Lung Adenocarcinomas in African-Americans 
Journal of Thoracic Oncology  2011;6(1):28-31.
Structured Abstract
Introduction
The detection of mutations in the epidermal growth factor receptor (EGFR) gene, which predict sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs), represents a major advance in the treatment of lung adenocarcinoma. KRAS mutations confer resistance to EGFR -TKIs. The prevalence of these mutations in African-American patients has not been thoroughly investigated.
Methods
We collected formalin-fixed, paraffin-embedded material from resected lung adenocarcinomas from African-American patients at three institutions for DNA extraction. The frequencies of EGFR exon 19 deletions, exon 21 L858R substitutions and KRAS mutations in tumor specimens from African-American patients were compared to data in Caucasian patients (n=476).
Results
EGFR mutations were detected in 23 of the 121 specimens from African-American patients (19%, 95% CI 13–27%), while KRAS mutations were found in 21 (17%, 95% CI 12−25%). There was no significant difference between frequencies of EGFR mutations comparing African-American and Caucasian patients, 19% vs. 13% (61/476, 95% CI 10–16%) (p=0.11). KRAS mutations were more likely among Caucasians, 26% (125/476, 95% CI 23−30%) (p=0.04).
Conclusions
This is the largest study to date examining the frequency of mutations in lung adenocarcinomas in African-Americans. Although KRAS mutations were somewhat less likely, there was no difference between the frequencies of EGFR mutations in African-American patients as compared to Caucasians. These results suggest that all patients with advanced lung adenocarcinomas should undergo mutational analysis prior to initiation of therapy.
doi:10.1097/JTO.0b013e3181fb4fe2
PMCID: PMC3337520  PMID: 21107288
EGFR mutation; KRAS; African-Americans; racial differences
23.  An In Vivo Platform for Tumor Biomarker Assessment 
PLoS ONE  2011;6(10):e26722.
Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers – serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response – a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research.
doi:10.1371/journal.pone.0026722
PMCID: PMC3202552  PMID: 22046338
24.  Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma 
The prognosis for patients with large-cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor, and an optimal treatment has not yet been established. It has been recently reported that molecular-targeted therapies, such as tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR), are effective in patients with lung carcinoma. In efforts to improve the prognosis of patients with LCNEC, we analyzed gene expression, gene mutations and immunohistochemical (IHC) expression of known molecular targets in LCNECs, and compared the expression to that of lung adenocarcinomas (ACs). Thirteen patients with primary LCNEC and 14 patients with AC were analyzed. We evaluated IHC expression for c-KIT, human epidermal growth factor receptor type 2 (HER2) and vascular endothelial growth factor (VEGF), gene mutations for EGFR, K-ras and c-kit, and gene expression using fluorescence in situ hybridization for EGFR. In cases with LCNEC, the IHC expression of c-KIT, HER2 and VEGF was 76.9, 30.8 and 100%, respectively. There was a significant difference in the IHC expression of c-KIT and HER2 between the LCNEC and AC cases. Two cases of LCNEC had overexpression of HER2, and the frequency of EGFR gene mutations was higher in the the AC group, with only a single EGFR mutation (exon 18) identified in the LCNEC group. Although LCNEC had a higher rate of expression of c-KIT by IHC, no c-kit gene mutations were found. These findings suggest a potential role for anti-VEGF-, anti-c-KIT- and possibly anti-HER2-targeted agents in the treatment of LCNEC.
doi:10.3892/etm.2011.343
PMCID: PMC3440793  PMID: 22977617
large-cell neuroendocrine carcinoma; molecular-targeted therapy; vascular endothelial growth factor; c-KIT; human epidermal growth factor receptor type 2
25.  Fluorescence-Assisted Cytological Testing (FACT): Ex Vivo Viral Method for Enhancing Detection of Rare Cancer Cells in Body Fluids 
Molecular Medicine  2011;17(7-8):628-634.
Cytological analysis of body fluids is currently used for detecting cancer. The objective of this study was to determine if the herpes virus carrying an enhanced green fluorescent protein (EGFP) could detect rare cancer cells in body fluids against millions of normal cells. Human cancer cells suspended with normal murine cells were infected with NV1066 at a multiplicity of infection (MOI) of 0.5 and 1.0 for 18 h. Fluorescent microscopy and flow cytometry were used for EGFP detection of cancer cells. EGFP-expressing cells were confirmed as cancer cells with specific markers by immunohistochemistry staining. Limits of detection of cancer cells in body fluid were measured by serial dilutions. Applicability of technique was confirmed with samples from patients with malignant pleural effusions. NV1066 expressed EGFP in 111 human cancer cell lines detected by fluorescent microscopy at an MOI of 0.5. NV1066 selectively infected cancer cells and spared normal cells as confirmed by immunohistochemistry. Sensitivity of detecting fluorescent green cells was 92% (confidence interval [CI] 83% to 97%) at a ratio of 1 cancer cell to 1 million normal cells. EGFP-positive cells were detected by fluorescent microscopy in patients’ malignant pleural effusion samples. Our data show proof of the concept that NV1066-induced EGFP expression allows detection of a single cancer cell against a background of 1 million normal cells. This method was demonstrated to be a reliable screening tool for human cancer cells in a suspension of normal murine cells as well as clinical specimens of malignant pleural effusions.
doi:10.2119/molmed.2011.00078
PMCID: PMC3146608  PMID: 21487639

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