Non-small Cell Lung Carcinoma Research Articles

Characterization of Nonsmall Cell Lung Carcinoma in Limited Biopsy Samples and Identifying Optimal Immunohistochemical Marker Combinations in Resource-Constrained Setup: An Institutional Experience

Abstract Background The incorporation of immunohistochemical markers in the analysis of small biopsy samples, as outlined in the fourth edition of the World Health Organization Blue books, represents a noteworthy advancement in the diagnosis of advanced-stage lung carcinoma. This improved the histological classification for poorly differentiated nonsmall cell lung carcinomas (NSCLCs), especially in small biopsy specimens. Despite challenges in obtaining viable cells from diminutive tumor samples, a focused immunohistochemical panel effectively distinguishes histological types in most NSCLC. This preserves tissue for subsequent molecular testing. Material and Methods This study examined 130 consecutive lung biopsy cases initially diagnosed as NSCLC, including various biopsy types (transbronchial, endobronchial, ultrasound-guided, computed tomography-guided). Carcinomas were categorized based on specific characteristics, such as glands and/or mucin for adenocarcinomas, keratinization and/or intercellular bridges for squamous cell carcinomas, and recognition of poorly differentiated NSCLC. Cases lacking clear morphological attributes underwent reclassification using immunohistochemical markers (TTF1, Napsin A, p63, and p40). Results TTF1 exhibited superior sensitivity (97.56%) and specificity (96.77%) for adenocarcinoma compared with Napsin A, with sensitivity and specificity at 90.24 and 93.3%, respectively. p63 and p40 demonstrated 100% sensitivity for squamous cell carcinoma, with p40 being more specific than p63 (100% vs. 82.92%). Using TTF1 and p63 as a conventional panel, 87% of cases were subtyped. However, the combination of TTF1 and p40 achieved accurate classification in 94.66% (71/75) of cases, and all four markers allowed subtype identification in 97.2% (73/75) of cases. Conclusion In a resource-constrained setting, subtyping NSCLC in small biopsy can be effectively accomplished using a minimal panel consisting of TTF1 and p40 immunohistochemical markers.

Stephania tetrandra and Its Active Compound Coclaurine Sensitize NSCLC Cells to Cisplatin through EFHD2 Inhibition

Background: Adjuvant chemotherapy, particularly cisplatin, is recommended for non-small cell lung carcinoma (NSCLC) patients at high risk of recurrence. EF-hand domain-containing protein D2 (EFHD2) has been recently shown to increase cisplatin resistance and is significantly associated with recurrence in early-stage NSCLC patients. Natural products, commonly used as phytonutrients, are also recognized for their potential as pharmaceutical anticancer agents. Result: In this study, a range of Chinese herbs known for their antitumor or chemotherapy-enhancing properties were evaluated for their ability to inhibit EFHD2 expression in NSCLC cells. Among the herbs tested, Stephania tetrandra (S. tetrandra) exhibited the highest efficacy in inhibiting EFHD2 and sensitizing cells to cisplatin. Through LC-MS identification and functional assays, coclaurine was identified as a key molecule in S. tetrandra responsible for EFHD2 inhibition. Coclaurine not only downregulated EFHD2-related NOX4-ABCC1 signaling and enhanced cisplatin sensitivity, but also suppressed the stemness and metastatic properties of NSCLC cells. Mechanistically, coclaurine disrupted the interaction between the transcription factor FOXG1 and the EFHD2 promoter, leading to a reduction in EFHD2 transcription. Silencing FOXG1 further inhibited EFHD2 expression and sensitized NSCLC cells to cisplatin. Conclusions: S. tetrandra and its active compound coclaurine may serve as effective adjuvant therapies to improve cisplatin efficacy in the treatment of NSCLC.

Deferasirox's Anti-Chemoresistance and Anti-Metastatic Effect on Non-Small Cell Lung Carcinoma.

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal's body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action's molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect.

The EXO1/Polη/Polι axis as a promising target for miR-3163-mediated attenuation of cancer stem-like cells in non-small cell lung carcinoma.

Cancer stem-like cells (CSLCs) drive tumour progression and chemoresistance. The concerted efforts of EXO1 and TLS polymerases safeguard DNA integrity against chemotherapeutic drugs. In absence of potential drug targets, non-small cell lung carcinoma (NSCLC) patients have few therapeutic options. In current scenario, microRNAs offer a potential avenue for eradicating CSLCs. EXO1 downregulation impact on CSLCs expansion was assessed via flow cytometry. Co-localisation of EXO1, Polη and Polι was validated through co-immunoprecipitation and confocal-imaging. The effects of co-downregulation of Polη and Polι on CSLC survival, repair synthesis, and mutagenesis were evaluated using flow cytometry and immunohistochemistry in cell lines and xenografts. MicroRNA targeting EXO1 was studied for its role in CSLCs regulation. EXO1 downregulation in NSCLC CSLCs induces DNA lesions, triggering apoptosis and enhances cisplatin sensitivity. It collaborates with Polη and Polι in DNA repair, contributing to cisplatin resistance in CSLCs. Absence of Polη and Polι impairs repair and reduces cisplatin-induced mutagenesis. Co-downregulation of Polη and Polι in xenografts reduces tumour proliferation significantly. MiR-3163 overexpression sensitises CSLCs to cisplatin via targeting EXO1/Polη/Polι axis, as shown in mechanistic studies. This study unveils a novel regulatory pathway involving EXO1/Polη/Polι axis and miR-3163, providing insights into CSLCs regulation in NSCLC. EXO1/Polη/Polι axistargeted by miR-3163, resulting in the inhibition of cell growth and induction of apoptosis inNSCLC CSLCs.

Stereologic consequences of iatrogenic collapse: The morphology of adenocarcinoma in situ overlaps with invasive patterns. Proposal for a necessary modified classification of pulmonary adenocarcinomas

Recognizing non-invasive growth patterns is necessary for correct diagnosis, invasive size determination and pT-stage in resected non-small cell lung carcinoma. Due to iatrogenic collapse after resection, the distinction between adenocarcinoma in-situ (AIS) and invasive adenocarcinoma may be difficult. The aim of this study is to investigate the complex morphology of non-mucinous non-invasive patterns of AIS in resection specimen with iatrogenic collapse, and to relate this to follow-up.The effects of iatrogenic collapse on the morphology of collapsed AIS were simulated in a mathematical model. Three dimensional related criteria applied in a modified classification, using also cytokeratin 7 and elastin as additional stains, in two independent retrospective cohorts of primary pulmonary adenocarcinomas ≤3 cm resection specimen with available follow-up information.The model demonstrated that infolding of alveolar walls occurs during iatrogenic collapse and lead to a significant increase in tumor cell heights in maximal collapse areas, compared to less collapsed areas. The morphology of infolded AIS overlaps with patterns described as papillary and acinar adenocarcinoma according to the WHO classification, necessitating an adaptation.The modified classification incorporates recognition of iatrogenic and biologic collapse, tangential cutting effect true invasion and surrogate markers of invasion i.e. grey zone, covering a multilayering falling short of micropapillary, cribriform and solid alveolar filling growth. The use of elastin and CK7 staining aids in the morphologic recognition of iatrogenic collapsed AIS and the distinction from invasive adenocarcinoma. Out of a total of 70 resection specimens 1 case was originally classified as AIS and 9 were reclassified as iatrogenic collapsed AIS. Patients with collapsed AIS showed a 100 % recurrence-free survival after a mean follow-up time of 69.5 months.With the current WHO classification, AIS is overdiagnosed as invasive adenocarcinoma due to infolding. The modified classification facilitates the diagnosis of AIS.

Deep learning to estimate response of concurrent chemoradiotherapy in non-small-cell lung carcinoma

BackgroundConcurrent chemoradiotherapy (CCRT) is a crucial treatment for non-small cell lung carcinoma (NSCLC). However, the use of deep learning (DL) models for predicting the response to CCRT in NSCLC remains unexplored. Therefore, we constructed a DL model for estimating the response to CCRT in NSCLC and explored the associated biological signaling pathways.MethodsOverall, 229 patients with NSCLC were recruited from six hospitals. Based on contrast-enhanced computed tomography (CT) images, a three-dimensional ResNet50 algorithm was used to develop a model and validate the performance in predicting response and prognosis. An associated analysis was conducted on CT image visualization, RNA sequencing, and single-cell sequencing.ResultsThe DL model exhibited favorable predictive performance, with an area under the curve of 0.86 (95% confidence interval [CI] 0.79–0·92) in the training cohort and 0.84 (95% CI 0.75–0.94) in the validation cohort. The DL model (low score vs. high score) was an independent predictive factor; it was significantly associated with progression-free survival and overall survival in both the training (hazard ratio [HR] = 0.54 [0.36−0.80], P = 0.002; 0.44 [0.28−0.68], P < 0.001) and validation cohorts (HR = 0.46 [0.24−0.88], P = 0.008; 0.30 [0.14−0.60], P < 0.001). The DL model was also positively related to the cell adhesion molecules, the P53 signaling pathway, and natural killer cell-mediated cytotoxicity. Single-cell analysis revealed that differentially expressed genes were enriched in different immune cells.ConclusionThe DL model demonstrated a strong predictive ability for determining the response in patients with NSCLC undergoing CCRT. Our findings contribute to understanding the potential biological mechanisms underlying treatment responses in these patients.

Endoscopic Ultrasound-guided Transesophageal Fine-Needle Biopsy of Lung Masses: Diagnostic Performance and Safety

Pulmonary masses are a diagnostic challenge in the field of endoscopic ultrasound(EUS) tissue acquisition, especially through transesophageal EUS-FNB(fine needle biopsy). Our study evaluated the feasibility, diagnostic performance, and safety of EUS-FNB of pulmonary lesions. Fifty-three patients were enrolled in a prospective registry. All of the EUS procedures were performed by experienced endosonographers. Outcomes were specimen adequacy, diagnostic accuracy, diagnostic sensibility, diagnostic specificity, and safety. The mean age was 70±10.4, and 71.7% were male. The mean lesion size was 52.4±23.3 mm, and patients had mostly a single lesion(86.8%). Most of the patients had advanced stage at diagnosis(stage IV, 41.82%), and the most common lung cancer was non-small cell lung carcinoma(69.4%). Diagnostic adequacy rate was 92.86%, and diagnostic accuracy was 87.5%. Adverse events were reported in 3 procedures. Transesophageal EUS-FNB is a feasible and safe diagnostic method of tissue sampling for lung masses reachable by EUS.

Adagrasib in KRYSTAL-12has Broken the KRAS G12C Enigma Code in Non-Small Cell Lung Carcinoma.

Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C-mutant non-small cell lung carcinoma (NSCLC) accounts for approximately 10-13% of advanced nonsquamous NSCLC cases in Western populations, presenting a significant therapeutic challenge owing to the difficulty of directly targeting KRAS. Adagrasib, an oral small-molecule covalent inhibitor, irreversibly and selectively targets KRASG12C in its inactive state. It received accelerated Food and Drug Administration (FDA) approval on December 12, 2022, following the KRYSTAL-1 Phase II trial. The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45-0.76; P<0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRAS G12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS G12C enigma code in NSCLC.

508LBA (PB-508) LBA Posters: Deferasirox’s anti-chemoresistance and anti-metastatic effect on nonsmall cell lung carcinoma

508LBA (PB-508) LBA Posters: Deferasirox’s anti-chemoresistance and anti-metastatic effect on nonsmall cell lung carcinoma

P1.02A.01 ADAR1 Regulates Tumorigenesis and Stem Cell Properties in Non-Small Cell Lung Carcinoma

P1.02A.01 ADAR1 Regulates Tumorigenesis and Stem Cell Properties in Non-Small Cell Lung Carcinoma

Searching for the key factor in nutritional deterioration of non-small cell lung carcinoma (NSCLC) patients (PTS): A prospective observational study

Searching for the key factor in nutritional deterioration of non-small cell lung carcinoma (NSCLC) patients (PTS): A prospective observational study

P1.09B.02 Double Lung Transplantation in Patients with Metastatic Lung-limited Non-Small Cell Lung Carcinoma (NSCLC)

P1.09B.02 Double Lung Transplantation in Patients with Metastatic Lung-limited Non-Small Cell Lung Carcinoma (NSCLC)

IL-12 encoding oNDV synergizes with CAR-T cells in orthotopic models of non-small cell lung cancer

Systemic administration of oncolytic viruses (OVs) is a promising approach for targeting metastatic solid tumors, but their anti-tumor activity is limited by pre-existing neutralizing antibodies against common human viruses. Therefore, investigators have developed OVs derived from non-human host viruses. Successful implementation of this strategy requires that the viral vector selectively infects and replicates within human cancer cells. Newcastle disease virus (NDV) is an avian paramyxovirus that as NDV-based OVs (oNDVs) have demonstrated safety and activity against multiple human tumors in clinical trials. Their use as a single agent, however is insufficient to cure tumors. Similarly, CAR-T cells enable systemic targeting of cancer cells but have limited anti-tumor effects against bulky solid tumors, in part due to the immunosuppressive tumor environment. In this study, we evaluated the anti-tumor effects of combining systemic oNDV and CAR-T cell treatments. In models of non-small cell lung carcinoma (NSCLC), we found that oNDV itself and IL-12 derived from oNDV enhance HER2-directed CAR-T cell anti-tumor activity and persistence in vitro and in vivo, leading to superior control of NSCLC tumors compared with either agent alone in vivo. Our data indicate that oNDV enhances the anti-tumor effects of HER2.CAR-T cells, thus controlling the growth of orthotopic NSCLC tumors.

EP.03F.04 Treatment of Non-Small Cell Lung Carcinoma (NSCLC) Cells with Tumor Treating Fields (TTFields) And DNA-Dependent Protein Kinase (PK) Inhibitors

EP.03F.04 Treatment of Non-Small Cell Lung Carcinoma (NSCLC) Cells with Tumor Treating Fields (TTFields) And DNA-Dependent Protein Kinase (PK) Inhibitors

EP.06B.05 Ultra-Stat Idylla EGFR Testing for Non-Small Cell Lung Carcinomas: Patient Selection and Impact on Clinical Outcomes

EP.06B.05 Ultra-Stat Idylla EGFR Testing for Non-Small Cell Lung Carcinomas: Patient Selection and Impact on Clinical Outcomes

Association of rs401681 (C > T) and rs402710 (C > T) polymorphisms in the CLPTM1L region with risk of lung cancer: a systematic review and meta-analysis.

Although many genome-wide association studies (GWAS) have confirmed the negative associations between rs401681[T] / rs402710[T] in the Cleft lip and cleft palate transmembrane protein 1 (CLPTM1L) region and lung cancer (LC) susceptibility in Caucasian and Asian populations, some other studies haven't found these negative associations. The purpose of this study is to clarify the associations between them and LC, as well as the differences in these associations between patients of different ethnicities (Caucasians and Asians), LC subtypes and smoking status. Relevant literatures published before July 7, 2023 in PubMed, EMbase, Web of Science, MEDLINE were searched through the Internet. Statistical analysis of data was performed in Revman 5.3, including drawing forest plots, funnel plots and so on. Sensitivity and publication bias were performed in Stata 14.0. TSA software was performed for the trial sequential analysis (TSA) tests to assess the stability of the results. Registration number: CRD42023407890. A total of 41 literatures (containing 44 studies: 16 studies in Caucasians and 28 studies in Asians) were included in this meta-analysis, including 126476 LC patients and 191648 healthy controls. The results showed that the T allele variants of rs401681 and rs402710 were negatively associated with the risk of LC (rs401681[T]: [OR] = 0.87, 95% CI [0.86, 0.88]; rs402710[T]: [OR] = 0.88, 95% CI [0.86, 0.89]), and the negative associations were stronger in Caucasians than in Asians (Subgroup differences: I2 > 50%). In LC subtypes, the rs401681[T] was negatively associated with the risk of Non-small-cell lung carcinoma (NSCLC), Lung adenocarcinoma (LUAD) and Lung squamous cell carcinoma (LUSC) (P < 0.05), and these negative associations were stronger in Caucasians than in Asians (Subgroup differences: I2 > 50%). The rs402710[T] was negatively associated with the risk of NSCLC, LUAD and LUSC (P < 0.05), and these negative associations in Caucasians were the same as in Asians (Subgroup differences: I2 < 50%). The rs401681[T] was negatively associated with the risk of LC in both smokers and non-smokers (P < 0.05), and the negative association for smokers equals to that of non-smokers (Subgroup differences: P = 0.25, I2 = 24.2%). In LC subtypes, the rs401681[T] was negatively associated with the risks of NSCLC and LUAD in both Caucasian smokers and Asian non-smokers (P < 0.05). The rs402710[T] was negatively associated with the risk of LC in both smokers and non-smokers (P < 0.05), and there was no difference in the strength of this negative risk association between them in Caucasians (Subgroup differences: I2 = 0%). In Asians, this negative association was found to be predominantly among smokers ([OR] = 0.80, 95%CI [0.65, 0.99]). In LC subtypes, the rs402710[T]was negatively associated with the risk of NSCLC in non-smokers, and this negative association was found to be predominantly among non-smokers in Asians ([OR] = 0.75, 95%CI [0.60, 0.94]). The T allele variants of rs401681 and rs402710 are both negatively associated with the risk of developing LC, NSCLC (LUAD, LUSC) in the Caucasian and Asian populations, and the negative associations with the risk of LC are higher in Caucasians. Smoking is an important risk factor for inducing the rs401681 and rs402710 variants and causes LC development in both populations. Other factors like non-smoking are mainly responsible for inducing the development of NSCLC in Asians, and is concentrated in LUAD among Asian non-smoking women.

Perioperative immunotherapy for nonsmall cell lung cancer.

Recent years have witnessed significant advancements in the treatment of lung cancer with immunotherapy, primarily centered on immune checkpoint inhibitors (ICIs). Numerous clinical studies have evaluated or are currently evaluating the clinical benefits of neoadjuvant, adjuvant, and perioperative use of ICIs. These findings have notably reshaped the landscape of perioperative treatment for nonsmall cell lung carcinoma (NSCLC). Comparing different treatment modes, adding ICIs in the adjuvant phase to neoadjuvant treatment with ICIs and chemotherapy may not improve survival outcomes for patients with resectable NSCLC and may be associated with increased adverse events. For prognostic factors, ctDNA minimal residual disease (MRD) status might serve as an early predictor of achieving pathological remission. For study endpoints, a positive result with PFS as the primary endpoint may not necessarily translate into overall survival benefits. For perioperative immunotherapy, challenges persist, including the current lack of sensitive and reliable biomarkers, the effect of neoadjuvant therapy on surgical risk as well as the selection of the appropriate study endpoint. In this review, we discuss recent and ongoing trials investigating strategies of neoadjuvant, adjuvant and perioperative immunotherapy in NSCLC, while also proposing considerations for future directions in this continuously evolving field.

ASPYRE-Lung: validation of a simple, fast, robust and novel method for multi-variant genomic analysis of actionable NSCLC variants in FFPE tissue.

Genomic variant testing of tumors is a critical gateway for patients to access the full potential of personalized oncology therapeutics. Current methods such as next-generation sequencing are costly and challenging to interpret, while PCR assays are limited in the number of variants they can cover. We developed ASPYRE® (Allele-Specific PYrophosphorolysis REaction) technology to address the urgent need for rapid, accessible and affordable diagnostics informing actionable genomic target variants of a given cancer. The targeted ASPYRE-Lung panel for non-small cell carcinoma covers 114 variants in 11 genes (ALK, BRAF, EGFR, ERBB2, KRAS, RET, ROS1, MET & NTRK1/2/3) to robustly inform clinical management. The assay detects single nucleotide variants, insertions, deletions, and gene fusions from tissue-derived DNA and RNA simultaneously. We tested the limit of detection, specificity, analytical accuracy and analytical precision of ASPYRE-Lung using FFPE lung tissue samples from patients with non-small cell lung carcinoma, variant-negative FFPE tissue from healthy donors, and FFPE-based contrived samples with controllable variant allele fractions. The sensitivity of ASPYRE-Lung was determined to be ≤ 3% variant allele fraction for single nucleotide variants and insertions or deletions, 100 copies for fusions, and 200 copies for MET exon 14 skipping. The specificity was 100% with no false positive results. The analytical accuracy test yielded no discordant calls between ASPYRE-Lung and expected results for clinical samples (via orthogonal testing) or contrived samples, and results were replicable across operators, reagent lots, runs, and real-time PCR instruments with a high degree of precision. The technology is simple and fast, requiring only four reagent transfer steps using standard laboratory equipment (PCR and qPCR instruments) with analysis via a cloud-based algorithm. The ASPYRE-Lung assay has the potential to be transformative in facilitating access to rapid, actionable molecular profiling of tissue for patients with non-small cell carcinoma.

Very Rare Case of Pulmonary Lepidic Adenocarcinoma at a Young Age Man

Introduction: Lung cancer remains one of the higher prevalence of cancer and leading cause of death in the world. Smoking and genetic factors are two important etiologies in lung cancer. Adenocarcinoma is the most common type of non-small cell lung carcinoma. Lepidic predominant adenocarcinoma is one type of adenocarcinoma that has a good prognosis. Case Illustration: A 24-year-old male came with chronic cough and chest pain. He had a history of smoking and no prior family history of cancer. Plain chest Xray and Thorax computed tomography (CT) showed pleural effusion and presence of lung mass with suggestion of bone and liver involvement, respectively. The cytology from pleural effusion and bronchial lavage initially found no malignancy cell. Later thoracostomy biopsy and pathology study suggested lepidic adenocarcinoma. Discussion: Lung cancer is still one of the leading causes of death in men. Even though rarely found in young male, patients with a history of smoking or genetic factor with clinical manifestation suggestive chronic respiratory condition with weight loss should be suspected of the diagnosis. Adenocarcinoma, as the most common non-small cell lung carcinoma, could be later divided into several subtypes. Lepidic adenocarcinoma is distinguished by the pathology finding of a large invasion focus of stromal, lymphatic, vascular, or pleural space. Considered one of the most favorable, lepidic predominant adenocarcinoma has a very high rate of 5 year survival when diagnosed early and responds well to lobe resection. Advanced state however has poor outcome due to limited choice of therapy. Promising trial of targeted chemotherapy have been reported and could improve outcome in the future. Conclusion: Lung cancer in young male is a rare disease but should be suspected in those with chronic cough, chest pain and weight loss. The history of smoking and family history are crucial for this suspicion. Lepidic predominant adenocarcinoma has a good prognosis when diagnosed early. Studies in the future could enhance overall survival in these patients.

Expression of Carbonic Anhydrase IX as a Novel Diagnostic Marker for Differentiating Pleural Mesothelioma from Non-small Cell Lung Carcinoma

Expression of Carbonic Anhydrase IX as a Novel Diagnostic Marker for Differentiating Pleural Mesothelioma from Non-small Cell Lung Carcinoma