Effects of EGFR driver mutations on pathologic regression in resectable locally advanced non-small cell lung cancer treated with neoadjuvant chemoradiation and completion surgery.

OBJECTIVE: We hypothesized that driver mutations in epidermal growth factor receptor (EGFR) are associated with decreased pathologic response to neoadjuvant chemoradiation (NA-ChRT) in locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Patients with Stage IIB-IIIA NSCLC treated with NA-ChRT, completion surgery, and underwent molecular profile testing were identified in a lung cancer database. Pathologic response was quantified using: (i) major pathologic response (MPR), (ii) complete pathologic response (pCR), and (iii) mean residual viable tumor cells (MRTC). Two groups were formed based on the presence or absence of driver mutations. Clinical and pathological correlations between the groups were studied. RESULTS: Forty-seven patients underwent tumor molecular profile testing, NA-ChRT, and completion surgery. Compared to the no-driver mutation group, the driver mutation group had lower MPR (23% vs 71%, p = 0.003), pCR (0% vs 26%, p = 0.02), and higher MRTC (43.4% vs 15.8%, p = 0.009). Univariate analysis showed an increased MPR rate for smokers, squamous cell histology, ChRT-surgery interval >65 days, and no-driver mutations. Multivariate analysis showed that only no-driver mutations (OR 0.39, p = 0.02) remained significant for MPR. PD-L1 status did not affect MPR. At 2 years, the driver mutation group had lower rates of local control (Hazard ration [HR] 0.67, p = 0.17) and disease-free survival (HR 0.5, p = 0.001). Overall survival was similar for both groups (HR = 1.04, p = 0.86). CONCLUSION: Following 60 Gray NA-ChRT, tumors with a driver mutation had lower MPR and pCR rates than tumors without a driver mutation. PD-L1 was not associated with tumor regression. ADVANCES IN KNOWLEDGE: Patients with resectable LA-NSCLC and an EGFR driver mutation treated with neoadjuvant-ChRT and completion surgery have reduced pathologic regression, lower local control rates, and shorter disease-free survival than patients without a driver mutation. Evaluation of molecular testing should be introduced in LA-NSCLC intended for prognostication and treatment decisions.

Rising Incidence of Lung Cancer in Arab Females, Jewish Females, and Arab Males from 1990 to 2014 in Israel.

BACKGROUND: Lung cancer is the most common cause of cancer-related death. OBJECTIVES: To identify changing patterns of lung cancer and its histologic subtypes among different population groups in Israel over a 25 year period. METHODS: Primary lung cancers, all types and all stages, diagnosed during 1990-2014 were recorded in the Israel National Cancer Registry database. Demographic information was retrieved from the National Population Register. Age-standardized rates for the different subgroups were calculated for each year. Joinpoint software was used to analyze trends in incidence. RESULTS: We identified 42,672 lung cancer cases. The most common histology was adenocarcinoma (34%), followed by squamous cell carcinoma (19%), large cell/not-otherwise-specified (19%), other histologies (15%), and small cell lung cancer (11%). The adenocarcinoma incidence rose from 25.7% to 48.2% during the examined period. Large cell/not-otherwise-specified incidence peaked around 2005-2006 and declined after. Lung cancer incidence increased significantly for the population overall and specifically in Arab females, followed by Jewish females and by Arab males. Adenocarcinoma and small cell lung cancer increased in Jewish females and in Arab males. A younger age of diagnosis was seen in Arab compared to Jewish patients. CONCLUSIONS: Jewish females and Arab males and females living in Israel demonstrated a constant increase in lung cancer incidence, mostly in adenocarcinoma and small cell lung cancer incidence. In addition, a younger age of diagnosis in Arabs was noted. Smoking reduction interventions and screening should be implemented in those populations.

Predicting brain metastasis in early stage non-small cell lung cancer patients by gene expression profiling.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-death due to early metastatic spread, in many cases primarily to the brain. Organ-specific pattern of spread of disease might be driven by the activity of a specific signaling pathway within the primary tumors. We aimed to identify an expression signature of genes and the relevant signaling associated with the development of brain metastasis (BM) after surgical resection of NSCLC. METHODS: Rapidly frozen NSCLC surgical specimens were procured from tumor banks. RNA was extracted and analyzed by RNA-sequencing (Illumina HiSeq 2500). Clinical parameters and gene expression were examined for differentiating between patients with BM, patients with metastases to sites other than brain, and patients who did not develop metastatic disease at a clinically significant follow up. Principal component analysis and pathway enrichments studies were done. RESULTS: A total of 91 patients were included in this study, 32 of which developed BM. Stage of disease at diagnosis (P=0.004) and level of differentiation (P=0.007) were significantly different between BM and control group. We identified a set of 22 genes which correlated specifically with BM, and not with metastasis to other sites. This set achieved 93.4% accuracy (95% CI: 86.2-97.5%), 96.6% specificity and 87.5% sensitivity of correctly identifying BM patients in a leave-one-out internal validation analysis. The oxidative phosphorylation pathway was strongly correlated with BM risk. CONCLUSIONS: Expression level of a small set of genes from primary tumors was found to predict BM development, distinctly from metastasis to other organs. These genes and the correlated oxidative phosphorylation pathway require further validation as potentially clinically useful predictors of BM and possibly as novel therapeutic targets for BM prevention.

Stromal-MDM2 Promotes Lung Cancer Cell Invasion through Tumor-Host Feedback Signaling.

Tumor-host interactions play a major role in malignancies' initiation and progression. We have reported in the past that tumor cells attenuate genotoxic stress-induced p53 activation in neighboring stromal cells. Herein, we aim to further elucidate cancer cells' impact on signaling within lung cancer stroma. Primary cancer-associated fibroblasts were grown from resected human lung tumors. Lung cancer lines as well as fresh cultures of resected human lung cancers were used to produce conditioned medium (CM) or cocultured with stromal cells. Invasiveness of cancer cells was evaluated by transwell assays, and in vivo tumor growth was tested in Athymic nude mice. We found CM of a large variety of cancer cell lines as well as ex vivo-cultured lung cancers to rapidly induce protein levels of stromal-MDM2. CM of nontransformed cells had no such effect. Mdm2 induction occurred through enhanced translation, was mTORC1-dependent, and correlated with activation of AKT and p70 S6 Kinase. AKT or MDM2 knockdown in fibroblasts reduced the invasion of neighboring cancer cells, independently of stromal-p53. MDM2 overexpression in fibroblasts enhanced cancer cells' invasion and growth of inoculated tumors in mice. Our results indicate that stromal-MDM2 participates in a p53-independent cancer-host feedback mechanism. Soluble cancer-originated signals induce enhanced translation of stromal-MDM2 through AKT/mTORC1 signaling, which in turn enhances the neighboring cancer cells' invasion ability. The role of these tumor-host interactions needs to be further explored. IMPLICATIONS: We uncovered a novel tumor-stroma signaling loop, which is a potentially new therapeutic target in lung cancer and possibly in additional types of cancer.

MiR-21, EGFR and PTEN in non-small cell lung cancer: an in situ hybridisation and immunohistochemistry study.

AIMS: To analyse microRNA (miR)-21 distribution and expression at the cellular level in non-small cell lung cancer (NSCLC). MiR-21 is an oncogenic microRNA overexpressed in NSCLC. In previous studies, overexpression of miR-21 was evaluated from the tumour bulk by quantitative reverse transcription PCR with results expressed on average across the entire cell population. METHODS: We used in situ hybridisation and immunohistochemistry to assess the correlation between miR-21 levels and the expression of markers that may be possible targets (epidermal growth factor reaction) or may be involved in its upregulation (phosphatase and tensin homolog (PTEN), p53). The Pearson's χ2 tests was used to assess correlation with clinicopathological data and with miR-21 expression both in tumour and tumour stroma. RESULTS: Cytoplasmic staining and expression of Mir-21 were detected in the tumours and in associated stromal cells. Expression was highest in the stroma immediately surrounding the tumour cells and decreased as the distance from the tumour increased. No expression of miR-21 was found in normal lung parenchyma and a significant association was found between tumour localised miR-21 and PTEN. CONCLUSIONS: Presence of miR-21 in both cell tumour and stromal compartments of NSCLC and the relationship with PTEN confirms miR-21 as a microenvironment signalling molecule, possibly inducing epithelial mesenchymal transition and invasion by targeting PTEN in the stromal compartment possibly through exosomal transport. In situ immunohistochemical studies such as ours may help shed light on the complex interactions between miRNAs and its role in NSCLC biology.

Transformation to small cell lung cancer as a mechanism of resistance to immunotherapy in non-small cell lung cancer.

OBJECTIVES: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death world-wide. Immune checkpoint inhibitors (ICI) have become the most promising type of treatment in oncology in general, and significantly so in NSCLC. Limited data is available about mechanisms of primary resistance. Data is lacking about mechanisms involved in acquired resistance or mixed responses in NSCLC. We aimed to identify mechanisms of resistance by studying biopsies taken from sites of secondary progression. MATERIALS AND METHODS: We identified all cases of NSCLC that have received ICI for advanced disease in our institute. Of these cases, those that have demonstrated acquired resistance or mixed responses, and have underwent a biopsy from a progressive lesion were analyzed. Selected specimens were subjected to next-generation sequencing (NGS; Oncomine™ Solid Tumour Fusion Transcript Kit). RESULTS: Out of 664 lung cancer cases, 249 were NSCLC that have received ICI. Of these, eight cases matched our search criteria. Two of them demonstrated transformation to small cell lung cancer (SCLC; 2/8, 25%). NGS verified a common origin to a matched pre-treatment NSCLC specimen and an on-treatment progressive SCLC specimen. In two cases no tumor cells were found and in the remaining four the pathology was similar to the initial biopsy. In one of the cases of SCLC transformation platinum-etoposide chemotherapy was administered, with short-term benefit only and further disease progression. CONCLUSION: Mechanisms of acquired resistance to ICI include SCLC transformation. Repeat biopsies of progressing lesions after initial response or in cases of mixed response can shed light on mechanisms of resistance.

Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies.

BACKGROUND: Systemic lupus erythematosus (SLE) comprise a diverse range of clinical manifestations. To date, more than 30 single gene causes of lupus/lupus like syndromes in humans have been identified. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to phenotypic and genetic heterogeneity. METHODS: We employed whole exome sequencing (WES) in patients presenting with childhood-onset lupus with severe and/or atypical presentations to identify cases that are explained by a single-gene (monogenic) cause. RESULTS: From January 2015 to June 2018 15 new cases of childhood-onset SLE were diagnosed in Edmond and Lily Safra Children's Hospital. By WES we identified causative mutations in four subjects in five different genes: C1QC, SLC7A7, MAN2B1, PTEN and STAT1. No molecular diagnoses were established on clinical grounds prior to genetic testing. CONCLUSIONS: We identified a significant fraction of monogenic SLE etiologies using WES and confirm the genetic locus heterogeneity in childhood-onset lupus. These results highlight the importance of establishing a genetic diagnosis for children with severe or atypical lupus by providing accurate and early etiology-based diagnoses and improving subsequent clinical management.

Comparative effectiveness of intensity modulated radiation therapy to 3-dimensional conformal radiation in locally advanced lung cancer: pathological and clinical outcomes.

OBJECTIVE: Intensity-modulated radiotherapy (IMRT) has better normal-tissue sparing compared with 3-dimensional conformal radiation (3DCRT). We sought to assess the impact of radiation technique on pathological and clinical outcomes in locally advanced non-small cell lung cancer (LANSCLC) treated with a trimodality strategy. METHODS: Retrospective review of LANSCLC patients treated from August 2012 to August 2018 at Sheba Medical Center, Israel. The trimodality strategy consisted of concomitant chemoradiation to 60 Gray (Gy) followed by completion surgery. The planning target volume (PTV) was defined by co-registered PET/CT. Here we compare the pathological regression, surgical margin status, local control rates (LC), disease free (DFS) and overall survival (OS) between 3DCRT and IMRT. RESULTS: Our cohort consisted of 74 patients with mean age 62.9 years, male in 51/74 (69%), adenocarcinoma in 46/74 (62.1%), stage 3 in 59/74 (79.7%) and chemotherapy in 72/74 (97.3%). Radiation mean dose: 59.2 Gy (SD ± 3.8). Radiation technique : 3DCRT in 51/74 (68.9%), IMRT in 23/74 (31%). Other variables were similar between groups.Major pathological response (including pathological complete response or less than 10% residual tumor cells) was similar: 32/51 (62.7%) in 3DCRT and 15/23 (65.2%) in IMRT, p=0.83. Pathological complete response (pCR) rates were similar: 17/51 (33.3%) in 3DCRT and 8/23 (34.8%) in IMRT, p=0.9. Surgical margins were negative in 46/51 (90.1%) in 3DCRT vs. 17/19 (89.4%) in IMRT (p=1.0).The 2-year LC rates were 81.6% (95% CI 69-89.4%); DFS 58.3% (95% CI 45.5-69%) and 3-year OS 70% (95% CI57-80%). Comparing radiation techniques, there were no significant differences in LC (p=0.94), DFS (p=0.33) and OS (p=0.72). CONCLUSION: When used to treat LANSCLC in the neoadjuvant setting, both IMRT and 3DCRT produce comparable pathological and clinical outcomes. ADVANCES IN KNOWLEDGE: This study validates the real-world effectiveness of IMRT compared to 3DCRT.

Metastatic cardiac tumors: from clinical presentation through diagnosis to treatment.

BACKGROUND: To evaluate the prevalence of metastatic tumors involving the myocardium and study their presentation in order to increase awareness to their existence. METHODS: Pathological reports from Sheba Medical Center (Israel, January 1, 2010 through December 31, 2015) and medical records from The Institute for Cardiovascular Diseases of Vojvodina, Sremska Kamenica (Serbia, 23 years period) were screened for cases of metastatic cardiac tumors. Medical, radiological and pathological data of identified cases was retrieved and reviewed. RESULTS: Out of thousands of registered cardiac surgeries we found less than a dozen cases of metastatic cardiac tumors classified as melanoma, carcinomas of lung, colon and kidney and sarcomas of uterine origin. We found that metastatic cardiac tumors comprised 15.8% of all the cardiac tumors. CONCLUSIONS: Metastatic cardiac tumors are extremely rare. As new diagnostic technologies and improved survival of oncological patients may increase the incidence of metastatic cardiac tumors in the future, awareness to their existence and knowledge of their presentation are key factors in their timely recognition.

Neo-adjuvant Chemo-Radiation to 60 Gray Followed by Surgery for Locally Advanced Non-Small Cell Lung Cancer Patients: Evaluation of Trimodality Strategy.

BACKGROUND: Neoadjuvant chemo-radiation therapy (CRT) dosages in locally advanced non-small cell lung cancer (NSCLC) were traditionally limited to 45 Gray (Gy). OBJECTIVES: To retrospectively analyze outcomes of patients treated with 60 Gy CRT followed by surgery. METHODS: A retrospective chart review identified patients selected for CRT to 60 Gy followed by surgery between August 2012 and April 2016. Selection for surgery was based on the extent of disease, cardiopulmonary function, and response to treatment. Pathological response after neoadjuvant CRT was scored using the modified tumor regression grading. Local control (LC), disease free survival (DFS), and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS: Our cohort included 52 patients: 75% (39/52) were stage IIIA. A radiation dose of 60 Gy (range 50-62Gy) was delivered in 82.7%. Surgeries performed included: lobectomy, chest-wall resection, and pneumonectomy in 67.3%, 13.4%, and 19.2%, respectively. At median follow-up of 22.4 months, the 3 year OS was 74% (95% confidence interval [CI] 52-87%), LC was 84% (95%CI 65-93), and DFS 35% (95%CI 14-59). Grade 4-5 postoperative complications were observed in 17.3% of cases and included chest wall necrosis (5.7%), bronco-pleural fistula (7.7%), and death (3.8%). A major pathologic regression with < 10% residual tumor occurred in 68.7% of patients (36/52) and showed a trend to improved OS (P = 0.1). Pneumonectomy cases had statistically worse OS (P = 0.01). CONCLUSIONS: Major pathologic regression was observed 68.7% with 60 Gy neoadjuvant CRT with a trend to improved survival. Pneumonectomy correlated with worse survival.

New ARCHITECT plasma pro-gastrin-releasing peptide assay for diagnosing and monitoring small-cell lung cancer.

BACKGROUND: Progastrin-releasing peptide (ProGRP) is a potential marker for small-cell lung cancer (SCLC) in serum; however, it may be more stable in plasma. We investigated a new plasma assay (ProGRPp) and its usefulness in diagnosing and monitoring SCLC. METHODS: The marker concentrations were determined on the ARCHITECT i system. RESULTS: The assay could distinguish SCLC from non-small-cell lung cancer (NSCLC: area under the curve 0.931, 95% CI 0.893-0.969; cross-validated accuracy 0.813; sensitivity 84.0%, specificity 96.3%; at 140 pg ml(-1) cutoff). The probability of SCLC when ProGRPp was >140 pg ml(-1) was 91.8%, after adjusting for age, gender, and renal dysfunction. The NSCLC patients with ProGRPp >140 pg ml(-1) were at high risk (odds ratio=37.0, P<0.001) for tumours with neuroendocrine features. False negatives in SCLC were associated with a lack of thyroid transcription factor-1 (P<0.001). A decrease of ProGRPp to <140 pg ml(-1) during chemotherapy was significantly associated with the image-based response (P<0.001), and independently affected progression-free survival (PFS, relative risk=2.51, P=0.04) and overall survival (OS, relative risk=4.38, P=0.003), after adjustment for imaging response, performance status, and stage. CONCLUSIONS: The ProGRPp assay is specific and sensitive for diagnosing SCLC. Changes in ProGRPp during chemotherapy are significantly associated with image-based response, PFS, and OS.

IgG4-Related Lung Disease - Three Untreated Cases with a Benign Outcome.

IgG4-related disease is a fibroinflammatory disease in which the organs involved share similar pathological findings. Chest disease has been recently clinically and radiologically characterized. Most reports advocate prompt immunosuppressive therapy and describe a fast and good response. We report 3 cases of untreated IgG4-related lung disease that on follow-up have been clinically asymptomatic and radiologically stable or improved. In some cases of IgG4-related lung disease immunosuppressive therapy may not be warranted.

The unique clinical features and outcome of infectious endocarditis and vertebral osteomyelitis co-infection.

OBJECTIVE: The clinical significance of vertebral osteomyelitis and infectious endocarditis co-infection is unclear. This study investigates the rate, clinical features, and outcome of vertebral osteomyelitis with and without concomitant infectious endocarditis. METHODS: A retrospective study of all cases of osteomyelitis with spinal imaging (n = 176), from January 2007 to April 2013, that were diagnosed as vertebral osteomyelitis. Sixty-two patients with spontaneous vertebral osteomyelitis were identified after excluding postsurgical, decubitus ulcers and spinal metastases. Seventeen (27%) were identified with concomitant infectious endocarditis. RESULTS: All patients presented with back pain and 59% were diagnosed with infectious endocarditis subsequent to vertebral osteomyelitis. Distinguishing features among the co-infection group include the increased use of transesophageal echocardiography (94% vs 58%, P = .004), predisposing cardiac conditions (59% vs 16%, P = .001), and Gram-positive bacteremia, of which Streptococcus sp. and Enterococcus sp. were more common (35% vs 11%, P = .026). Adverse neurologic events were increased significantly in the co-infection group (59% vs 22%, P = .006). On transesophageal echocardiography, 88% of co-infection patients had highly mobile vegetations, 9 of which measured 10 mm or more. The overall mortality was 41% and 29% in the co-infection and lone vertebral osteomyelitis groups, respectively (P = .356). One-year mortality was identical for both groups at 24% (P = .999), and higher than previously reported (11.3% for lone vertebral osteomyelitis). CONCLUSIONS: Patients with vertebral osteomyelitis, in whom infectious endocarditis is not excluded, are at increased risk for adverse neurologic events and mortality. The prompt diagnosis of infectious endocarditis, and associated high-risk features that may benefit from surgical intervention, require early evaluation by transesophageal echocardiography.

Genetic mutation screen in early non--small-cell lung cancer (NSCLC) specimens.

BACKGROUND: Testing for genetic abnormalities in epithelial growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and potentially additional genes is a critical tool in the care of advanced NSCLC. There is conflicting evidence for the role of such tests in early NSCLC. We report a single-institute Sequenom testing for a wide range of mutations and their clinical correlations in early-resected NSCLC specimens. MATERIALS AND METHODS: Early NSCLC paraffin-embedded, formalin-fixed (FFPE) specimens were collected, DNA extracted, and using Sequenom-based matrix-assisted laser desorption/ionization-time of flight analysis, mutations in 22 oncogenes and tumor suppressor genes were evaluated. Clinical data was collected retrospectively. RESULTS: The technique was found to be feasible. Thirty-six of 96 patients (37.5%) had any genetic abnormality identified, and 8 (8.3%) had 2 or more mutations. Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR were the most common genes to appear mutated (15.6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) was the gene to be found most commonly in tumors with co-mutations. Transversions were found mostly in KRAS gene mutations and to be nonprognostic. No difference in the spectrum of mutations was found between squamous-cell and non-squamous-cell lung cancers. Ever-smokers showed a trend for worse prognosis, with a similar spectrum of mutations. CONCLUSION: Sequenom-based mutation screen is feasible using FFPE samples. More than a third of the patients were found to harbor some genetic abnormality, and 8% were found to have more than a single mutated gene. Wide-range gene screens using large sample depositories are required for further insight into the important genes at play in early NSCLC.

Resection and heated pleural chemoperfusion in patients with thymic epithelial malignant disease and pleural spread: a single-institution experience.

OBJECTIVE: Our objective was to evaluate whether resection and heated pleural chemoperfusion (HPCP) is an effective treatment for de novo stage IVa thymoma (DNT) and thymic carcinoma (TC) and for thymoma with pleural relapse (TPR). METHODS: A retrospective study was conducted of patients undergoing resection and HPCP in 1 center. HPCP with cisplatinum ± doxorubicin (adriamycin) was performed for 60 minutes using a standard roller pump and a modified heat exchanger to a maximal intrapleural temperature of 43°C. Follow-up included at least 1 annual computed tomographic scan until death or March 2012. RESULTS: Thirty-five patients, 17 DNT, 14 TPR, and 4 TC, completed 42 intended treatments and were followed up for 4 to 202 months (median, 62 months). Seven patients had repeated HPCP at an interval of 2 to 12 years. There was no systemic toxicity. Ninety-day mortality was 2.5%. Major and minor morbidity occurred in 12% each. Five-, 10-, and 15-year overall survivals for DNT, TPR, and TC were 81%, 73%, 58% (DNT), 67%, 56%, 28% (TPR), and 0%, 0%, 0% (TC). Five- and 10-year progression-free survival was 61%, 43% for DNT and 48%, 18% for TPR. Presently, 11 of 17 DNT patients are alive (6, no evidence of disease), and 8 of 14 TPR are alive (6, no evidence of disease). Median survival for thymoma was 157 months. Overall survival was unrelated to any preoperative or intraoperative variable. Progression-free survival was improved in R0 compared with R1-2 resection (P < .001). Local control achieved in 21 (57%) of 37 procedures in thymoma patients was related only to completeness of resection (P = .015). CONCLUSIONS: (1) Lung-sparing resection and HPCP is feasible and safe. (2) In thymoma with pleural spread it offers excellent survival despite moderate pleural control. (3) Preliminary results with stage IVa TC are disappointing.

Mesothelioma and asbestosis in a young woman following occupational asbestos exposure: Short latency and long survival: Case Report.

A 27-year-old female white-collar worker was diagnosed in 1998 with mesothelioma eight and one-half years following first exposure as a bystander to debris in a site in which asbestos-containing building materials were being dismantled and rebuilding work took place. Prodromal back pain had been present for a year and a half. She underwent extrapleural pneumectomy and received an intrapleural infusion of cisplatin post-operatively. Exposure to asbestos was verified by contemporary reports and lung biopsy, which demonstrated asbestos bodies and microscopic interstitial fibrosis -conforming evidence for asbestosis. The patient is alive and well 12 years after diagnosis and 14 years after onset of symptoms. The combination of an extremely short latency period and long survival following occupational exposure to asbestos dust is unique.

A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesothelioma.

The definitive identification of malignant pleural mesothelioma (MPM) has significant clinical implications, yet other malignancies often involve the lung pleura, confounding the diagnosis of MPM. In the absence of accurate markers, MPM can be difficult to distinguish from peripheral lung adenocarcinoma and metastatic epithelial cancers. MicroRNA expression is tissue-specific and highly informative for identifying tumor origin. We identified microRNA biomarkers for the differential diagnosis of MPM and developed a standardized microRNA-based assay. Formalin-fixed, paraffin-embedded samples of 33 MPM and 210 carcinomas were used for assay development. Using microarrays, we identified microRNAs differentially expressed between MPM and various carcinomas. Hsa-miR-193-3p was overexpressed in MPM, while hsa-miR-200c and hsa-miR-192 were overexpressed in peripheral lung adenocarcinoma and carcinomas that frequently metastasize to lung pleura. We developed a standardized diagnostic assay based on the expression of these microRNAs. The assay reached a sensitivity of 100% and a specificity of 94% in a blinded validation set of 68 samples from the lung and pleura. This diagnostic assay can provide a useful tool in the differential diagnosis of MPM from other malignancies in the pleura.

MicroRNA expression differentiates between primary lung tumors and metastases to the lung.

For surgical pathologists, distinguishing whether a pulmonary neoplasm is primary or metastatic can be challenging, and current biomarkers do not always aid lung tumor classification. The tissue-associated expression of microRNA likely explains the remarkable finding that many tumors can be classified based solely on their microRNA expression signature. Here we show that microRNAs can serve as biomarkers for lung tumor classification. Using microRNA microarray data generated from 76 formalin-fixed, paraffin-embedded (FFPE) samples of either primary lung cancer or metastatic tumors to the lung, we have identified a set of microRNAs expressed differentially between these two groups. This set includes hsa-miR-182, which was most strongly over-expressed in the lung primary tumors, and hsa-miR-126, which was over-expressed in the metastatic tumors. The differential expression of this set of microRNAs was confirmed using qRT-PCR on a set of 54 samples. In light of our data, microRNA expression should be considered as a potential clinical biomarker for surgical pathologists faced with discerning the tumor type of an inscrutable lung neoplasm.