Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

M. Ganzinelli



Author of

  • +

    P2.02 - Biology/Pathology (ID 616)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • +

      P2.02-065 - RanBP9 is a Novel Prognostic and Predictive Biomarker for NSCLC and Affects Cellular Response to Cisplatin and PARP Inhibitors  (ID 10002)

      09:30 - 09:30  |  Author(s): M. Ganzinelli

      • Abstract

      Background:
      We have previously demonstrated the involvement of Ran Binding Protein 9 (RanBP9) in the DNA Damage Response (DDR) in Non Small Cell Lung Cancer (NSCLC) cells. Here, we investigate its role in response to DNA-damaging agents in vitro and as prognostic and predictive biomarker for NSCLC patients.

      Method:
      First, by IHC, we evaluated RanBP9 expression in tumor vs normal adjacent tissue (NAT). Then, we generated A549 RanBP9 WT and KO NSCLC cells using CRISPR/Cas9. We treated A549 RanBP9 WT and KO with cisplatin (CDDP) and PARP inhibitors. We assessed response to treatment by measuring cell toxicity, apoptosis and proliferation. Finally, we determined the expression of RanBP9 in cohort of NSCLC patients previously enrolled in the TAILOR trial.

      Result:
      In the present study, we report that significant overexpression of RanBP9 is a common event in lung cancer, as shown by an extensive immunohistochemical analysis of RanBP9 levels in 148 lung tumors of different histotypes and their normal adjacent tissue (p<0.02 - 0.001). RanBP9 expression was maintained/acquired in the nodal metastasis from 30 NSCLC patients, indicating its potential involvement in tumor aggressiveness. We also show that RanBP9 KO A549 NSCLC cell lines display a reduced DDR and higher levels of apoptosis upon cisplatin treatment both in vitro and in vivo. Accordingly, a retrospective analysis of 134 NSCLC patients revealed that higher levels of RanBP9 are associated with tumor stage (p<0.0001), and low response to platinum compounds as first-line treatment (PFS, HR~ (RanBP9 positive versus negative)~ 1.71, 95% CI 1.142 - 2.563, p = 0.0093; OS HR~ (RanBP9 + vs -) ~1.942, 95% CI 1.243-3.033, p=0.0036). Finally, we show that ablation of RanBP9 is associated with overactivation of Poly(ADP-ribose) Polymerase (PARP) and increases sensitivity to PARP inhibitors. Moreover, that use of PARP inhibitors enhances cisplatin anti-neoplastic efficacy in the absence of RanBP9.

      Conclusion:
      We identified RanBP9 as a novel predictive biomarker of response to genotoxic treatments in NSCLC patients. We also report that RanBP9 affects the response of NSCLC cells to PARP inhibitors in vitro. Our results open new avenues for the treatment of NSCLC patients based on their level of expression of RanBP9.

  • +

    P2.09 - Mesothelioma (ID 710)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
    • +

      P2.09-001a - TNM or Tumor Volume for Predicting Prognosis in Malignant Pleural Mesothelioma: Still an Open Debate (ID 10192)

      09:30 - 09:30  |  Author(s): M. Ganzinelli

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor. Age, stage (TNM) and histotype are the only recognized prognostic factors but the site of disease makes staging difficult to be defined. Pleural tumor volume (TV) was suggested as an alternative in prognostic evaluation but the evidence is limited. The aim of our study was to assess the prognostic role of TV compared to that of the TNM.

      Method:
      Fifty-two MPM patients (pts), diagnosed in 2002-012, were retrospectively collected. A baseline CT scan was performed. Stage was defined according to TNM (7th edition) and TV was calculated using a dedicated computer system. We divided pts in 2 groups according to mean value of baseline TV(483 cm3 ; range 18-2329 cm3). Information on age, sex, histology, and surgery were collected. We evaluated disease site based on the pleural localization: mediastinal-diaphragmatic-parietal. Kaplan-Meier analysis and log-rank test were performed on OS to determine significant prognostic factors. Cox regression analysis adjusted for the prognostic factors was used for investigating their effect on OS.

      Result:
      Thirty-five pts were men; mean age was 62 years (range:25-74). Forty-four pts had epithelioid and 8 had mixed histology. Twenty-five pts had radical surgery. Six pts were diagnosed in early stage(I-II), 20 in III stage and 26 in IV stage. Median overall survival(OS) was 20.8 months (range:0.3–94.3). OS was significantly associated to: TV, stage (I-II, III, IV), T (T1,1B;T2;T3;T4,4B). Cox models adjusted by age, histology, sex, surgery, were used for investigating the effect of stage group and T separately on OS to avoid multicollinearity. The effect of mean TV on OS was evaluated with the Cox regression adding the number of involved sites to the above covariates. Cox regression analysis showed that: stage III (HR 3.75,95%CI 0.99-14.18;p<0.05) and IV (HR 5.43, 95%CI 1.43-20.68; p<0.01) were predictive of survival. With respect to extent of tumor, T3 and T4 were associated with worse prognosis (HR 4.99, 95%CI 1.84-13.49; p<0.002; HR 4.65, 95%CI 1.61-13.47; p<0.005 respectively). Smaller TV was associated with better survival (HR=2.37, 95%CI 1.05-5.37; p<0.04) irrespective of tumor site.

      Conclusion:
      We reported a significant association between TV and prognosis. However, stage and T seem to be better prognostic factors compared to TV most likely because they provide information also on adjacent organs infiltration. Our results should be interpreted with caution, considering the retrospective nature of our series and the small sample. Further collaborative studies are needed.