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V.L. Capelozzi



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    MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MINI23.12 - HAases and HAS in Lung/Bronchial Pre-Neoplastic Lesions: Impact on Prognosis (ID 395)

      16:45 - 18:15  |  Author(s): V.L. Capelozzi

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the result of a multi-step accumulation of genetic and/or epigenetic alterations; therefore, a better understanding of the molecular mechanism, by which these alterations affect lung cancer pathogenesis, would provide new diagnostic procedures and prognostic factors for early detection of recurrence. In this regard, many have studied molecular or other markers in pre-neoplastic and neoplastic lesions to discover what might relate to tumor recurrence and shortened survival.

      Methods:
      A series of 136 lung/bronchial and lung parenchyma tissue samples from 136 patients consisting of basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma were analyzed for the distribution of hyaluronidase 1 (HYAL1) and 3 (HYAL3), and hyaluronan synthases 1 (HAS1), 2 (HAS2) and 3 (HAS3) by immunohistochemistry.

      Results:
      HYAL 1 was significantly more expressed in basal cell hyperplasia compared to moderate dysplasia (p=0.01), atypical adenomatous hyperplasia (p=0.0001) and severe dysplasia (p=0.03). A lower expression of HYAL 3 was found in atypical adenomatous hyperplasia compared to basal cell hyperplasia (p=0.01) and moderate dysplasia (p=0.02). HAS 2 was significantly higher in severe dysplasia compared to basal cell hyperplasia (p=0.002), and equally higher in squamous metaplasia compared to basal cell hyperplasia (p=0.04). HAS 3 was significantly expressed in basal cell hyperplasia compared to atypical adenomatous hyperplasia (p=0.05) and severe dysplasia (p=0.02). A lower expression of HAS 3 was found in severe dysplasia compared to squamous metaplasia (p=0.01) and moderate dysplasia (p=0.01). Epithelial HYAL 1 and 3 and HAS 1, 2 and 3 expressions were significantly increased in pre neoplastic lesions compared to neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic types of tumors showed a significant association between poor survival and high pre neoplastic cell associated to HAS3 (HR=1.19; p=0.04).

      Conclusion:
      We concluded that localization of HYALs and HASs in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, these factors emerging as potentially important diagnostic markers in patients with suspicion of lung cancer.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 2
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      P1.04-008 - Tissue Hyaluronan and Its Relationship with Angiogenesis Are Indicators of Lung Cancer Malignancy (ID 1049)

      09:30 - 17:00  |  Author(s): V.L. Capelozzi

      • Abstract

      Background:
      Cell-extracellular matrix interactions participate in several steps required for tumor cell invasion and because of that, a group of glycosaminoglycans have been targeted as potentially useful tumor markers. Hyaluronan has shown promise, but still there is uncertainty about its localization in tumor tissue and its relationship with histological types and angiogenesis. Regarding that, we evaluated the association between HA and degree of malignancy through its expression in lung tumor tissue and association with angiogenesis.

      Methods:
      Forty-six lung specimens were evaluated. Hyaluronan and microvessel (CD34) quantification in situ was done in FFPE sections of nonneoplastic cells, lung cancer cells, and tumor stroma. Colocation was evaluated in tumor stroma using confocal microscopy. Cox proportional hazards model, MantelHaenszel test and Pearson’s x2 were used to evaluate the hyaluronan and microvessel staining inferences and the relationship between them.

      Results:
      Squamous cell carcinoma showed abundant hyaluronan on the cancer cell-stroma interface coincident with prominent microvessel staining and identical colocalization at confocal microscopy. Strong hyaluronan staining associated with cancer cells was significant in 32.1% of squamous cell carcinoma compared to 17.9% of adenocarcinoma and 0.0% in large cell carcinoma (P<0.001). Adenocarcinomas revealed strong stromal hyaluronan staining in contrast with the hyaluronan-poor tumor cells. The foci of hyaluronan stromal staining was coincident with foci of microvessel and colocalization. Furthermore, adenocarcinoma more often showed a lower percentage of hyaluronan-positive cancer cells (35.7% of cases) than large cell carcinoma (14.3% of cases) or squamous cell carcinoma (0% of cases; P<0.001). For large cell carcinoma, the hyaluronan signal in tumor cells was very poor and contrasted with the foci of staining in stroma, coincident with focal microvessel density and colocalization. All these results are shown in Figure 1. A significant direct association was found between tumors with a high percentage of HA and MVD in tumor stroma (R=0.6; P=0.02). Similarly significant was the direct association between tumors at the N1 stage and high levels of hyaluronan in cancer cells (R=0.31; P=0.05). In addition, tumors in the T4 stage presented positive association with a high percentage of hyaluronan-positive cancer cells (R=0.80; P=0.01).Figure 1



      Conclusion:
      Our findings showed that an elevated hyaluronan signal in tumor cells was associated with poor prognosis and its localization relationship with histological types and angiogenesis was related to malignancy of lung cancer. To realize these findings a greater larger scale study in a randomized trial will be required.

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      P1.04-029 - Detection of Sputum Cofilin-1 Protein for Diagnosis of Human Non-Small Cell Lung Carcinomas (ID 1269)

      09:30 - 17:00  |  Author(s): V.L. Capelozzi

      • Abstract
      • Slides

      Background:
      The high incidence and mortality rates of lung cancer reflect the need for new diagnostic and prognostic markers capable to early detect the disease and also predict its recurrence. The ideal biomarker should be evaluated in biological samples obtained by minimally invasive procedures. In this context, sputum is an attractive biological sample for these tests since it may represent the field of injury. Because cell–extracellular matrix interactions participate in several steps required for tumor cell invasion and formation of metastases, cofilin-1, hyaluronic acid (HA) and CD44 have been targeted as potential useful tumor markers. To our knowledge, cofilin-1 has never been evaluated in sputum from lung cancer patients. Objective: To evaluate the diagnostic and prognostic role of sputum cofilin-1 and to the relationship between this biomarker with HA and its receptor (CD44) in patients with non small cell lung cancer (NSCLC).

      Methods:
      Cofilin-1 and CD44 were analyzed by Elisa immunoassay and HA by "Elisa-like" fluorometric assay in the sputum of 74 NSCLC patients, 13 cancer-free patients with obstructive lung disease and 8 healthy individuals. Statistical analyses included ANOVA, ROC curves, Spearman correlation, and logistic regression.

      Results:
      Sputum cofilin-1 levels were increased in patients with lung cancer (1475.83 pg/ml ±145.35) when compared to cancer-free patients (662.63 pg/ml ±5.74) and volunteers (415.25 ±3.68 pg/ml). A significant association was found between cancer patients with high levels of cofilin-1 and CD44 (R=0.21; P=0.04) as well as between HA and CD44 (R=0.46; P<0.01). Cofilin-1 did not correlate with HA (P>0.4). Univariate analysis demonstrated that high expression of sputum cofilin-1 significantly correlated to T4 (P=0.01) and M stage (P=0.03), tobacco history (P=0.01) and squamous cell carcinoma histologic type (P=0.04). Logistic regression analysis controlled for tobacco history, histologic types, stage, HA and CD44 expression showed that cancer cell–associated cofilin-1 was an independent predictor of metastases [OR=5.77 (0.78-42.74)]. Patients with sputum cofilin-1 >1475.83pg/ml had a high risk for metastasis. In relating to diagnosis, sputum Cofilin-1, at a cut off value of 248.9pg/mL presented sensitivity and specificity of 0.80 and 0.67 respectively, in distinguish healthy volunteers from NSCLC patients with AUC of 0.787. Cofilin-1 was also able to distinguish cancer-free patients from cancer patients at a cut off of 802.5pg/mL with AUC of 0.693 and respective sensitivity and specificity of 0.60 and 0.54.

      Conclusion:
      Cofilin-1 presented moderate sensitivity as diagnostic biomarker for lung cancer in sputum. Cofilin-1 was associated with metastases, but its prognostic value was dependent on the histological type and tobacco history. The association between sputum cofilin-1 and CD44 in cancer patients suggests that during tumor development, high levels of cofilin-1 facilitate tumors growth and the penetration of capillaries into the tissue milieu. Thus, increased tumor expression of cofilin-1 seems to be more associated to primary events, while increased angiogenesis seems to be related to a secondary event. Regardless of the involved mechanism, detection of sputum cofilin-1 provides important prognostic information on cancer patients. Larger series of NSCLC patients still needs to be studied to confirm the usefulness of sputum cofilin-1 as diagnostic and/or prognostic biomarker.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-088 - Matrix Proteoglycans Gene Expression Predicts Lung Cancer Patients Outcome (ID 1463)

      09:30 - 17:00  |  Author(s): V.L. Capelozzi

      • Abstract

      Background:
      The relationship between the extracellular matrix (ECM) components and cancer cells have an important role on cancer development and progression. Between the most important molecules present on the ECM are the glycosaminoglycans(GAGs) and their respective proteoglycans (PGs). Studies have reported that they have different behaviours when in the presence of malignant tissues.The aim of this study was to analyse PGs gene expression in normal and tumoral areas of patients with lung cancer (LC) and to explore its association with GAGs concentration.

      Methods:
      Eighty-seven lung specimens were evaluated. Biglycan, glypican, perlecan, syndecan and versican gene expression were analysed by qRT-PCR and sulfated GAG chains(heparan, dermatan and chondroitin sulfate - HS, DS and CS)were obtained after incubation with a proteolytic enzyme.GAGs were precipitated with ethanol and the pellet was centrifugated, dried and dissolved in DNAse(5 l/mg).The different types of sulfated GAGs and their concentration in the lung samples were identified after gel electrophoresis in diaminopropane buffer. Statistical analyses included ANOVA, Paired-samples T Test, Spearman correlation, and logistic regression.

      Results:
      A significant increase of biglycan was found in tumor tissue compared to normal (52.30 ± 21.2 vs 11.28 ± 3.77; p=0.04). A significant association was found between biglycan vs glypican (R= 0.64; P<0.01), biglycan vs perlecan (R=0.70; P<0.01) and biglycan vs versican (R=0.68; P<0.01). Univariate analysis demonstrated that high expression of tumoral biglycan significantly related to squamous cell carcinoma histologic type (P=0.02) and death (P=0.03). Equally significant was the association between high syndecan expression, tobacco history (P<0.01) and tumoral recurrence (P=0.04). Logistic regression analysis controlled for age, gender, Tstage, Nstage, histologic types and proteoglycans expression showed that higher biglycan expression was and independent predictor of death [OR= 1.44 (0.88-2.36)]. Those with higher relative expression of biglycan had a high risk for death. In addition, we found that biglycan and glypican gene expression related significantly to tumoral heparan sulphate concentration in tumoral tissue (R=0.38; P=0.04 and R=0.41; P=0.03).

      Conclusion:
      Different expression of PGs in lung cancer samples, its relationship with histologic types and death suggest a possible role of these PGs in this malignancy, but more importantly provide a potential biomolecular marker to predict outcome.The correlation between the histologic types and the expression of biglycan provide a possible role of this PG on the development of tumor agressiveness considering that one of its functions is to bind itself to growth factors and regulate their action. Moreover, the relationship between heparan sulphate concentration, biglycan and glypican gene expression might indicate what sort of PGs are produced by tumoral tissue considering that heparan sulphate is the GAG chain in these PGs. Further studies are needed to determine whether or not these PGs gene expression are able to be predict prognosis and tumoral aggressiveness.