Non-neoplastic Lung Research Articles

Solitary Capillary Hemangioma of the Lung: A Report of Two Cases

It has long been recognized that tumors of capillary vessels in the lung are extremely rare. While pulmonary capillary hemangiomatosis, which is a rare cause of pulmonary hypertension, is relatively well known, there have been only a few reports of solitary capillary hemangioma (SCH) of the lung. Herein we report two cases of SCH. Both cases were first detected as a solitary nodule of the lung in chest computed tomography images. Both lesions were recognized as early lung cancer and surgical resections were performed. At low power view, one was not encapsulated but was well delineated from the non-neoplastic lung and the other was pseudo-capsulated. Both tumors consisted of uniform capillaries with cuboidal or flattened endothelial cells. There was no cytologic atypia. Endothelial cells were highlighted by CD31 stain. Awareness of this entity is important for pathologists for differential diagnosis of a solitary pulmonary nodule. (J Lung Cancer 2012;11(2):102�� 104)

Overexpression of Periostin Protein in Non-Small Cell Lung Carcinoma is Not Related with Clinical Prognostic Significance

Background: Periostin is preferentially expressed in periosteum, indicating a potential role in bone formation. Recently, there have been emerging controversies about its role in invasion and metastasis of human malignancies. We attempted to determine the clinicopathological significance of periostin expression in non-small cell lung carcinoma (NSCLC). Methods: Immunohistochemical staining of periostin protein from 91 cases of NSCLCs was performed using tissue microarray blocks. The results were correlated with clinicopathological parameters. Results: Positive reaction to periostin was predominantly noted in the tumor stroma. The strongest reaction presented as a band-like pattern just around the tumor nests. Non-neoplastic lung tissue and most in-situ carcinomas did not show a positive reaction in their stroma. With respect to tumor differentiation, moderate to poor differentiated tumors (47/77) revealed even higher periostin expression than the well-differentiated ones (4/14) (p=0.024). High periostin expression was positively correlated with E-cadherin and p53 expression, but was not related with patient age, sex, tumor type, PCNA index, b-catenin, cyclin D1, pTNM-T, pTNM-N, stage, and patient survival (p>0.05). Conclusion: These results suggest that periostin might play a role during the biological progression of NSCLC, but may not be related to the clinical prognostic parameters.

Variable DNA Methylation Is Associated with Chronic Obstructive Pulmonary Disease and Lung Function

Chronic obstructive pulmonary disease (COPD) is associated with local (lung) and systemic (blood) inflammation and manifestations. DNA methylation is an important regulator of gene transcription, and global and specific gene methylation marks may vary with cigarette smoke exposure. To perform a comprehensive assessment of methylation marks in DNA from subjects well phenotyped for nonneoplastic lung disease. We conducted array-based methylation screens, using a test-replication approach, in two family-based cohorts (n = 1,085 and 369 subjects). We observed 349 CpG sites significantly associated with the presence and severity of COPD in both cohorts. Seventy percent of the associated CpG sites were outside of CpG islands, with the majority of CpG sites relatively hypomethylated. Gene ontology analysis based on these 349 CpGs (330 genes) suggested the involvement of a number of genes responsible for immune and inflammatory system pathways, responses to stress and external stimuli, as well as wound healing and coagulation cascades. Interestingly, our observations include significant, replicable associations between SERPINA1 hypomethylation and COPD and lower average lung function phenotypes (combined P values: COPD, 1.5 × 10(-23); FEV(1)/FVC, 1.5 × 10(-35); FEV(1), 2.2 × 10(-40)). Genetic and epigenetic pathways may both contribute to COPD. Many of the top associations between COPD and DNA methylation occur in biologically plausible pathways. This large-scale analysis suggests that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis.

Bayesian probit regression model for the diagnosis of pulmonary fibrosis: proof-of-principle

BackgroundThe accurate diagnosis of idiopathic pulmonary fibrosis (IPF) is a major clinical challenge. We developed a model to diagnose IPF by applying Bayesian probit regression (BPR) modelling to gene expression profiles of whole lung tissue.MethodsWhole lung tissue was obtained from patients with idiopathic pulmonary fibrosis (IPF) undergoing surgical lung biopsy or lung transplantation. Controls were obtained from normal organ donors. We performed cluster analyses to explore differences in our dataset. No significant difference was found between samples obtained from different lobes of the same patient. A significant difference was found between samples obtained at biopsy versus explant. Following preliminary analysis of the complete dataset, we selected three subsets for the development of diagnostic gene signatures: the first signature was developed from all IPF samples (as compared to controls); the second signature was developed from the subset of IPF samples obtained at biopsy; the third signature was developed from IPF explants. To assess the validity of each signature, we used an independent cohort of IPF and normal samples. Each signature was used to predict phenotype (IPF versus normal) in samples from the validation cohort. We compared the models' predictions to the true phenotype of each validation sample, and then calculated sensitivity, specificity and accuracy.ResultsSurprisingly, we found that all three signatures were reasonably valid predictors of diagnosis, with small differences in test sensitivity, specificity and overall accuracy.ConclusionsThis study represents the first use of BPR on whole lung tissue; previously, BPR was primarily used to develop predictive models for cancer. This also represents the first report of an independently validated IPF gene expression signature. In summary, BPR is a promising tool for the development of gene expression signatures from non-neoplastic lung tissue. In the future, BPR might be used to develop definitive diagnostic gene signatures for IPF, prognostic gene signatures for IPF or gene signatures for other non-neoplastic lung disorders such as bronchiolitis obliterans.

Promoter methylation of ASPP1 and ASPP2 genes in non-small cell lung cancers

To investigate the methylation status of CpG islands in the promoter region and the protein expression of ASPP1 and ASPP2 genes in non-small-cell lung cancer (NSCLC) and their relationship with cellular apoptosis and p53 gene expression. The 5'CpG island methylation patterns of ASPP1 and ASPP2 were evaluated by methylation specific polymerase chain reaction (MSP) followed by confirmation of sequencing. Immunohistochemistry was used to detect the expression of ASPP1, ASPP2 and p53 in lung carcinoma tissue samples (n = 90) and adjacent non-neoplastic lung tissue samples (n = 25). TUNEL assay was used to detect the apoptotic activity. The presence of ASPP1 methylation was significantly higher in NSCLC than that in the adjacent non-neoplastic lung tissue [42.2% (38/90) vs. 16.0% (4/25), P = 0.019]. ASPP1 promoter methylation had a close relationship with TNM stage and lymph node metastasis (P = 0.031, P = 0.030), but was not related to the age, sex, histological types and the grades of tumor differentiation (P = 0.389, P = 0.278, P = 0.570, and P = 0.103). Tumors with ASPP1 promoter methylation demonstrated a lower expression of ASPP1 as compared with those without the methylation (P = 0.002). ASPP1 expression was associated with a higher apoptotic index (AI) (P = 0.022) and a decreased p53 expression (r = -0.259, P < 0.01). Methylation in the promoter region of ASPP2 gene was not detected in lung cancer (n = 90) or adjacent non-neoplastic lung tissue (n = 25). Expression of ASPP2 protein did not correlate with AI (P = 0.282) and p53 status in NSCLC. High methylation of ASPP1 gene promoter regions is one of the important mechanisms that down-regulate its protein expression in NSCLC. ASPP1 promoter methylation may be associated with the malignant progression of the tumor, and ASPP1 expression promotes cellular apoptosis.

Reply to Letter to Editor re: usefulness of FDG PET/CT in determining benign from malignant endobronchial obstruction

Dear Sir, We agree with the author’s comment that delineation of the malignant tumour extent within the collapsed lung is critical in determining the radiation field. However, our research [1] focused on the differentiation between malignancy and benign obstruction at the obstruction site itself. Nevertheless, it is important to delineate the accurate tumour volume within the atelectatic lung to reduce unnecessary radiation. One of the main difficulties in delineating malignant foci within the atelectatic lung would be increased FDG uptake due to inflammatory cells accumulated within the atelectatic lung [2, 3]. However, the investigators point out that there might be a difference of vascularity between the neoplastic areas and adajacent non-neoplastic atelectatic lung. In fact, this result was shown in their recent parametric imaging study using 15O-H2O perfusion technique [4]. We agree that the use of 15O-H2O could be useful in defining tumour within the atelectatic lung, however, routine use of 15O-H2O may be difficult in the clinical setting, due to its very short halflife. A possible alternative to bring this perfusion studies in the clinical setting might be to perform a perfusion computed tomography using contrast media, or initial dynamic study using 18F-FDG as a perfusion tracer immediately after injection, instead of using 15O-H2O [5, 6]. Correlation between the previous dynamic study with 15O-H2O with dynamic 18F-FDG PET in the atelectatic lung could lead to an interesting result.

Morphometrical analysis of transbronchial cryobiopsies

The recent introduction of bronchoscopically recovered cryobiopsy of lung tissue has opened up new possibilities in the diagnosis of neoplastic and non-neoplastic lung diseases in various aspects. Most notably the morphological diagnosis of peripheral lung biopsies promises to achieve a better yield with a high quality of specimens. To better understand this phenomenon, its diagnostic options and perspectives, this study morphometrically compares 15 cryobiopsies and 18 transbronchial forceps biopsies of peripheral lung tissue a priori without considering clinical hit ratio or integration of results in the clinical diagnostic processing. Cryotechnically harvested specimens were significantly larger (mean: 17.1 ± 10.7 mm2 versus 3.8 ± 4.0 mm2) and contained alveolar tissue more often. If present, the alveolar part in cryobiopsies exceeded the one of forceps biopsies. The alveolar tissue of crybiopsy specimens did not show any artefacts. Based on these results cryotechnique seems to open up new perspectives in bronchoscopic diagnosis of lung disease.

Activity-based proteomics: Identification of ABHD11 and ESD activities as potential biomarkers for human lung adenocarcinoma

Lung cancer is the leading cause of all cancer related deaths with a worldwide mortality of 1.2 million each year. The 5-year survival rate ranges from 80% in early stages to a dismal 5% in advanced disease. Prognosis is currently mostly determined based on the extension of disease at diagnosis. Thereby it has become evident that predicted and real outcomes can vary significantly, even for patients with the same stage of disease. Novel biomarkers with a reliable predictive significance are therefore clearly needed. In this study we implemented an activity-based, solely mass spectrometry dependent biomarker discovery platform. We investigated the role of serine hydrolase activities as potential biomarkers for human lung adenocarcinoma, the most common lung cancer subtype. Forty pairs of fresh frozen malignant and matching non-neoplastic lung tissues were analyzed and enzymatic activities linked to clinical follow-up data. We found that the activities of Abhydrolase domain-containing protein 11 and Esterase D predict the development of distant metastases and the presence of aggressive lung adenocarcinomas, respectively, in a statistically significant model. We conclude that serine hydrolase activities bear a predictive potential for human lung adenocarcinoma and that activity-based proteomics represents a powerful methodology in the search for novel disease biomarkers.

CXCL13 and CXCR5 expression by Non-Small Cell Lung Carcinoma (149.15)

Abstract Lung cancer is the leading cause of cancer deaths worldwide. Chemokines and their corresponding receptor have been shown to play important role in tumor progression, including lung cancer. In this regard, we have previously shown that the chemokine receptor CXCR5 is involved in metastatic dissemination in breast and prostate cancers. In this study we show CXCR5 is highly expressed by lung cancer cell lines and non-small cell lung carcinomas (NSCLC) tissues, than compared to non-neoplastic lung tissue. CXCL13, which is the only natural ligand for CXCR5, is also expressed within the lung tumors. Retrospective analysis of CXCR5 expression in 45 patients specimens showed significantly higher expression of CXCR5 in squamous cell carcinoma and adenocarcinoma samples. Interestingly, the nuclei of advanced tumor cells from these tissues were also positive for CXCR5 in more than 50% of these cases. Furthermore, ELISA showed significantly higher serum levels of CXCL13 by serum of patients with either adenocarcinoma or squamous cell carcinoma (n = 31), than compared to normal controls (n = 9). The mechanism underlying these clinically and biologically important findings need to be further explored.

CYP24A1Is an Independent Prognostic Marker of Survival in Patients with Lung Adenocarcinoma

The active form of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25-D(3)), exerts antiproliferative effects in cancers, including lung adenocarcinoma (AC). CYP24A1 is overexpressed in many cancers and encodes the enzyme that catabolizes 1,25-D(3). The purpose of our study was to assess CYP24A1 as a prognostic marker and to study its relevance to antiproliferative activity of 1,25-D(3) in lung AC cells. Tumors and corresponding normal specimens from 86 patients with lung AC (stages I-III) were available. Affymetrix array data and subsequent confirmation by quantitative real time-PCR were used to determine CYP24A1 mRNA expression. A subsequent validation set of 101 lung AC was used to confirm CYP24A1 mRNA expression and its associations with clinical variables. The antiproliferative effects of 1,25-D(3) were examined using lung cancer cell lines with high as well as low expression of CYP24A1 mRNA. CYP24A1 mRNA was elevated 8- to 50-fold in lung AC (compared to normal nonneoplastic lung) and significantly higher in poorly differentiated cancers. At 5 years of follow-up, the probability of survival was 42% (high CYP24A1, n = 29) versus 81% (low CYP24A1, n = 57) (P = 0.007). The validation set of 101 tumors showed that CYP24A1 was independently prognostic of survival (multivariate Cox model adjusted for age, gender, and stage, P = 0.001). A549 cells (high CYP24A1) were more resistant to antiproliferative effects of 1,25-D(3) compared with SKLU-1 cells (low CYP24A1). CYP24A1 overexpression is associated with poorer survival in lung AC. This may relate to abrogation of antiproliferative effects of 1,25-D(3) in high CYP24A1 expressing lung AC.

Analysis of 2-[Fluorine-18]-Fluoro-2-deoxy-D-glucose Uptake Kinetics in PET Studies of Pulmonary Inflammation

Dynamic positron emission tomography (PET) imaging of the lung using the radiotracer 2-[fluorine-18]-fluoro-2-deoxy-D-glucose ((18)F-FDG) is an emerging method to assess noninvasively the metabolic activity of pulmonary inflammatory cells. Nevertheless, because of the distinct functional and structural characteristics of inflamed lung tissue standard methods of (18)F-FDG analysis can be substantially limited and there is no consensus about the best method for quantification of the (18)F-FDG signal for acute or chronic inflammatory lung diseases. This article gives an overview on recent advances in quantitative analysis of (18)F-FDG uptake kinetics in non-neoplastic inflamed lung tissue.

Relationship of aquaporin 1, 3, and 5 expression in lung cancer cells to cellular differentiation, invasive growth, and metastasis potential

An oncogenic capacity of aquaporins, transmembrane channels for water, was recently proposed. This study seeks to elucidate the involvement of aquaporin 1, 3, and 5 in the development and progression of lung cancer. Expression of aquaporin 1, 3, and 5 was examined by immunohistochemistry, Western blot, and laser-captured microdissection/real-time reverse transcription polymerase chain reaction in 160 lung cancers of various histologic subtypes; and its correlation with clinicopathological factors and survival was analyzed. Aquaporin 1, 3, and 5 were expressed in tumor cells in 71%, 40%, and 56% of lung cancers, respectively. Aquaporin expressions were frequent in adenocarcinomas, whereas aquaporin 1 and 5 were negative in squamous cell carcinomas. Bronchioloalveolar carcinoma cells exhibited an apicolateral aquaporin 1 and apicolateral or basolateral aquaporin 3 localization in nonmucinous type, and apical aquaporin 1 and 5 and basolateral aquaporin 3 expression in mucinous type, which corresponded to aquaporins expression of nonneoplastic lung tissue. Basolateral aquaporin 5 expression was acquired during tumorigenesis of nonmucinous bronchioloalveolar carcinoma. In contrast, invasive adenocarcinoma tumor cells overexpressed aquaporin 1 and 5 with loss of subcellular polarization and with an intracytoplasmic distribution. Overexpression of aquaporin 1 correlated with high postoperative adenocarcinoma metastasis ratios and unfavorable disease-free survival rates (P = .031). We conclude that expression patterns of aquaporin 1, 3, and 5 in lung cancer cells are mostly associated with cellular differentiation. However, the expression of aquaporin 1 and 5 is up-regulated in invading lung cancer cells, particularly in adenocarcinomas; and the overexpression of aquaporin 1 with loss of subcellular polarization is suggested to be involved in their invasive and metastatic potential.

On-the-spot lung cancer differential diagnosis by label-free, molecular vibrational imaging and knowledge-based classification

We report the development and application of a knowledge-based coherent anti-Stokes Raman scattering (CARS) microscopy system for label-free imaging, pattern recognition, and classification of cells and tissue structures for differentiating lung cancer from non-neoplastic lung tissues and identifying lung cancer subtypes. A total of 1014 CARS images were acquired from 92 fresh frozen lung tissue samples. The established pathological workup and diagnostic cellular were used as prior knowledge for establishment of a knowledge-based CARS system using a machine learning approach. This system functions to separate normal, non-neoplastic, and subtypes of lung cancer tissues based on extracted quantitative features describing fibrils and cell morphology. The knowledge-based CARS system showed the ability to distinguish lung cancer from normal and non-neoplastic lung tissue with 91% sensitivity and 92% specificity. Small cell carcinomas were distinguished from nonsmall cell carcinomas with 100% sensitivity and specificity. As an adjunct to submitting tissue samples to routine pathology, our novel system recognizes the patterns of fibril and cell morphology, enabling medical practitioners to perform differential diagnosis of lung lesions in mere minutes. The demonstration of the strategy is also a necessary step toward in vivo point-of-care diagnosis of precancerous and cancerous lung lesions with a fiber-based CARS microendoscope.

Downregulation of Signaling-active IGF-1 by Dipeptidyl Peptidase IV (DPP-IV)

Functioning as an extracellular protease, dipeptidyl peptidase IV (DPP-IV) preferentially cleaves the peptide bond after the penultimate proline residue. We report here that DPP-IV cleaves the first two amino acids from insulin-like growth factor 1 (IGF-1), revealed by mass spectrometry. The kinetic parameters of the proteolytic cleavage indicate that this reaction is physiologically relevant. Interestingly, truncated IGF-1 is less potent than the full-length protein in activating the IGF-1R, but binds more readily to IGF-binding protein 3 (IGFBP3). Quantitative RT-PCR showed that the level of DPP-IV mRNA is dramatically lower in lung squamous cell carcinoma tissues than in adjacent nonneoplastic lung tissues. However, this reduction was not observed in lung adenocarcinoma tissues. Our study suggests a possible link between IGF-1 and DPP-IV in cancer development in a specific tumor niche. A DPP-IV-related pathway may be important in mitigating IGF-1 signaling. Consequently, a robust IGF signaling pathway may accelerate early carcinogenesis in environments lacking DPP-IV.

Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer

The identification of prognostic tumor biomarkers that also would have potential as therapeutic targets, particularly in patients with early stage disease, has been a long sought-after goal in the management and treatment of lung cancer. The nuclear receptor (NR) superfamily, which is composed of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of these biomarkers. In fact, many members of this family are the targets of already identified selective receptor modulators, providing a direct link between individual tumor NR quantitation and selection of therapy. The goal of this study, which begins this overall strategy, was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome for patients with lung cancer, and to test whether a tumor NR gene signature provided useful information (over available clinical data) for patients with lung cancer. Using quantitative real-time PCR to study NR expression in 30 microdissected non-small-cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients' tumor and non-involved lung epithelium, found a strong association between NR expression and clinical outcome, and identified an NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. The NR signature derived from the initial 30 NSCLC samples was validated in two independent microarray datasets derived from 442 and 117 resected lung adenocarcinomas. The NR gene signature was also validated in 130 squamous cell carcinomas. The prognostic signature in tumors could be distilled to expression of two NRs, short heterodimer partner and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium and matched tumors identified expression in normal (but not tumor) epithelium of NGFIB3 and mineralocorticoid receptor as single gene predictors of good prognosis. NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. This study highlights the potential use of NRs as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer. Please see later in the article for the Editors' Summary.

A multi-analyte serum test for the detection of non-small cell lung cancer

Background:In this study, we appraised a wide assortment of biomarkers previously shown to have diagnostic or prognostic value for non-small cell lung cancer (NSCLC) with the intent of establishing a multi-analyte serum test capable of identifying patients with lung cancer.Methods:Circulating levels of 47 biomarkers were evaluated against patient cohorts consisting of 90 NSCLC and 43 non-cancer controls using commercial immunoassays. Multivariate statistical methods were used on all biomarkers achieving statistical relevance to define an optimised panel of diagnostic biomarkers for NSCLC. The resulting biomarkers were fashioned into a classification algorithm and validated against serum from a second patient cohort.Results:A total of 14 analytes achieved statistical relevance upon evaluation. Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-α, CYFRA 21-1, interleukin-1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. When tested against a second patient cohort, the panel successfully classified 75 of 88 patients.Conclusions:Here, we report the development of a serum algorithm with high specificity for classifying patients with NSCLC against cohorts of various ‘high-risk’ individuals. A high rate of false positives was observed within the cohort in which patients had non-neoplastic lung nodules, possibly as a consequence of the inflammatory nature of these conditions.

ADAM28 is a serological and histochemical marker for non-small-cell lung cancers

ADAM28 (a disintegrin and metalloproteinase 28) is over-expressed in non-small-cell lung cancer (NSCLC) with correlation to cancer cell proliferation, tumor size and lymph node metastasis. The present study was aimed to develop an enzyme-linked immunosorbent assay (ELISA) system for diagnosis and monitoring of NSCLC. Our ELISA specifically measured ADAM28, showing negligible cross-reactivity with other metalloproteinases. The ADAM28 level in the NSCLC tissue was remarkably 36.9-fold higher than that in the non-neoplastic lung tissue (p < 0.001). The serum level was significantly 4.6-fold higher in the NSCLC patients (5.41 +/- 8.62 ng/ml; n = 102) than in the control subjects (1.17 +/- 0.93 ng/ml; n = 20) (p < 0.001), and increased with progress of tumor stage (p < 0.001). The level was also significantly higher in the patients with recurrent carcinoma than the control (p < 0.001) and in the patients with lymph node metastasis than those without metastasis (p < 0.001). The sensitivity, false-negative rate and AUC for ADAM28 were better than those for carcinoembryonic antigen. The combination of both assays improved the sensitivity, specificity, false-positive and false-negative rates for NSCLC. There was a positive correlation between the ADAM28 level measured by ELISA system and the degree of immunostaining in the lung adenocarcinomas with a size of <or=20 mm in diameter. The adenocarcinoma patients showing the high immunohistochemical reaction exhibited a poorer disease-free survival than those with the lower immunoreactivity (n = 102; p < 0.05). These data demonstrate that our ELISA is specific and sensitive to monitor the levels of ADAM28 in the samples from NSCLC patients and suggest that ADAM28 is a useful serological and histochemical marker for NSCLC.

Zone of transition: a potential source of error in tumor volume estimation.

To measure the width of the zone of transition (ZOT) between nonaerated solid tumor and surrounding nonneoplastic lung parenchyma and determine the extent to which ZOT influences computer-derived estimates of tumor volume based on computed tomographic (CT) images. This HIPAA-compliant study was approved by the institutional research board. The histologic slide containing the maximum tumor area was digitized for 20 consecutive patients with solid adenocarcinoma. The outer border of the tumor (A2) was marked; it included all lung parenchyma having any tumor cells. The inner border of the tumor (A1) was marked; it included only solid tumor where lung parenchyma was no longer preserved. Assuming two circles with areas of A2 and A1, the corresponding two radii, R2 and R1, were calculated. The average width of the ZOT was defined as R2 minus R1. The relationship between ZOT and tumor diameter on the CT images prior to surgery was assessed by using regression analysis. The relationship between ZOT and tumor volume was assessed by using a theoretical model of idealized spheres with varying diameters. The mean width of the ZOT was 0.78 mm (median, 0.48 mm). The proportional effect of ZOT on tumor volume estimates decreased with increasing tumor diameter and increased with increasing width of ZOT. Correlation between ZOT and tumor diameter was not significant (P = .87). The average width of ZOT is about a single pixel width on a full field of view CT scan; thus, the ZOT can have a large effect on volume estimates, particularly for small tumors.

Metastasis-Associated Protein 1 Nuclear Expression is Associated with Tumor Progression and Clinical Outcome in Patients with Non-small Cell Lung Cancer

Little research has been done to test the usefulness of metastasis-associated protein 1 (MTA1) as a prognostic marker for non-small cell lung cancer (NSCLC). In this study, we investigated MTA1 expression and its prognostic value for NSCLC. NSCLC surgical tissue samples were taken from 100 patients with NSCLC who had been followed up for more than 2 years. The expression of MTA1 protein was evaluated by immunohistochemistry, and the correlations between the expression of MTA1 and clinical features and the prognosis were analyzed. The difference of MTA1 protein expression between NSCLCs and their adjacent nonneoplastic lung tissues was analyzed in a tissue microarray. The change of MTA1 mRNA expression and protein expression after RNA interference (RNAi) was detected by real-time polymerase chain reaction, Western blot, and immunocytochemistry in NSCLC cell line 95D. Overexpression of MTA1 (immunoreactivity scoring >4) was shown in 61.0% of the NSCLC cases but only in 9.4% of their adjacent nonneoplastic lung tissues (p < 0.001). The MTA1 expression level was correlated with lymph node metastasis (p = 0.013) and clinical stage (p = 0.002). Survival analysis showed that the MTA1 overexpression group had a significantly shorter overall survival time than the MTA1 downexpression group (p = 0.003). However, multivariate analysis showed that MTA1 expression was not a significant and independent prognostic parameter for patients with NSCLC. After RNAi, the 95D cells exhibit consistent reduction in MTA1 mRNA expression and MTA1 protein expression. MTA1 protein expression is associated with tumor progression and clinical outcome in patients with NSCLC. Further molecular, cellular, and animal model studies on MTA1 gene will provide new clues for exploring the mechanism of carcinogenesis and tumor progression in patients with NSCLC.

Sarcoidosis development during induction chemotherapy for lung cancer mimicked progressive disease

We report a rare case of sarcoidosis that developed during induction chemotherapy for primary lung cancer, mimicking progressive disease. A 63-year-old man had an abnormal shadow in the right upper lung, and a bronchoscopic examination revealed a squamous cell carcinoma. Swelling of a pretracheal lymph node was also noted. Thus, we gave induction chemotherapy consisting of paclitaxel (days 1, 8) + carboplatin (days 1, 8) for two cycles under clinical staging of T2N2M0. After induction chemotherapy, (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed positive accumulation of FDG in mediastinal and bilateral hilar lymph nodes that had been negative in a previous FDG-PET examination, which led us to suspect disease progression. Transbronchial lymph node biopsy results showed sarcoid granulomas in the specimens. Following complete resection of the lung cancer, sarcoid granulomas were revealed in both nonneoplastic lung tissue and lymph nodes, which resulted in a diagnosis of lung cancer accompanied with sarcoidosis.