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I. Opitz
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OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
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OA02.03 - Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study (ID 5988)
11:20 - 11:30 | Author(s): I. Opitz
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare but devastating malignancy. Despite the search for new promising treatment approaches, the outcome for most MPM patients remains dismal. Therefore, the identification of novel biomarkers is urgently needed in order to identify patients with a better prognosis and to support personalized therapeutic decisions. In our previously published study, we were able to show that fibroblast growth factor 18 (FGF18) is overexpressed in MPM tissue specimens and cell models. The objective of this study was the evaluation of FGF18 as a circulating biomarker in MPM.
Methods:
Plasma was collected from 107 MPM patients at the time of diagnosis or before surgical resection. Samples were included from the Medical University of Vienna, University Hospital Center in Zagreb and from The Concord Repatriation General Hospital and Strathfield Private Hospital in Sydney. Samples from 49 healthy volunteers and from 8 patients with non-malignant pleural diseases served as controls. Circulating FGF18 was measured by enzyme-linked immunosorbent assay and correlated to clinical, pathologic and radiologic parameters.
Results:
Plasma FGF18 level was significantly elevated in MPM patients vs. healthy controls (P<0.0001). A slight increase of circulating FGF18 level was also detected in patients with pleuritis or fibrosis (vs. control, P=0.0067). Sarcomatoid (n=7) morphology was associated with high FGF18 levels when compared to the epithelioid (n=77) histology (P=0.0064). Importantly, MPM patients presenting with FGF18 levels below the median had a significantly longer overall survival when compared to those with high FGF18 levels (median survival 625 versus 382 d, P=0.0038). Data on multivariate analysis, disease-free survival, correlation with other biomarkers and tumor volume will be presented at the conference.
Conclusion:
Our findings reveal that FGF18 is a promising blood-derived candidate biomarker in MPM. Furthermore FGF18 may support the histological classification of MPM and the identification of MPM patients with poor prognosis. .
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OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 2
- Moderators:H. Pass, N. Van Zandwijk
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 3
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OA22.06 - Refinement of the Prognostic miR-Score for Use in Diagnostic Specimens from Chemo-Naïve Malignant Pleural Mesothelioma Patients (ID 5045)
15:05 - 15:15 | Author(s): I. Opitz
- Abstract
- Presentation
Background:
A 6-microRNA signature (miR-Score, Kirschner et al 2015) was previously demonstrated to show high prognostic accuracy in a series of surgical specimens (with and without induction chemotherapy). In the present study we investigated these microRNAs in an independent cohort of MPM patients all treated with induction chemotherapy followed by extrapleural pneumonectomy (EPP). The main focus of the study was to evaluate the possible effects of induction chemotherapy on microRNA expression and to refine and validate the miR-Score for use in chemo-naïve diagnostic specimens.
Methods:
We identified a cohort of 120 MPM patients who received chemotherapy followed by EPP between 1999 and 2014 at University Hospital Zurich. At present microRNA analysis (RT-qPCR) has been carried out in 34 pairs of chemo-naïve (diagnostic biopsy) and chemo-treated (EPP) specimens. Paired-samples t-test was employed to determine differences in microRNA expression pre- and post-chemotherapy. Accuracy of the miR-Score in predicting a good prognosis (>20 months survival post-surgery) was evaluated by ROC curve analysis. In addition, binary logistic regression modelling was used to build a refined miR-Score.
Results:
Applying the miR-Score to chemo-naïve diagnostic specimens revealed an area under the ROC curve (AUC) of 0.65 (95% CI: 0.46-0.84), and the same analysis on the EPP specimens gave an AUC of 0.57 (95% CI: 0.37-0.77). Therefore, the accuracy of the miR-Score was lower than observed in the previous study. However, pairwise comparison of microRNA expression before and after chemotherapy showed that although not reaching statistical significance, the levels of several microRNAs were lower following induction chemotherapy. We next employed binary logistic regression modelling on microRNA levels in chemo-naïve tissue to determine whether a refined microRNA signature less susceptible to chemotherapy-induced changes could be created. A refined miR-Score consisting of miR-221 and miR-30e, the two microRNAs least affected by chemotherapy, achieved AUCs of 0.77 (95% CI: 0.61-0.94) and 0.80 (95% CI: 0.64-0.96) in diagnostic and EPP specimens, respectively. When applied to samples from the previous study, the refined score resulted in an AUC of 0.72 (95% CI: 0.54-0.90).
Conclusion:
This validation and refinement study has shown that the expression of several miR-Score microRNAs appears to be affected by standard chemotherapy. A refined miR-Score was generated which is less susceptible to the effect of chemotherapy and may have prognostic value when applied to diagnostic specimens. Further validation in additional paired samples and investigation of the effect of cisplatin, pemetrexed and gemcitabine on microRNA expression are ongoing.
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OA22.07 - Correlation of CT Scan Based Tumor Volume Measurement to Actual Resected Tumor Volume - A New T-Factor? (ID 5958)
15:15 - 15:25 | Author(s): I. Opitz
- Abstract
- Presentation
Background:
Tumor volume has been reported to be a valuable prognosticator for malignant pleural mesothelioma (MPM) survival. We wanted to assess the precision of CT scan based preoperatively measured tumor volume when correlated to the actual resected tumor weight and tumor volume after pleurectomy/decortication.
Methods:
From 10/2012 – 06/2016 the tumor weight of surgery specimens was measured in 32 patients undergoing macroscopic complete resection by (extended) pleurectomy/decortication ((e)P/D). The median tumor weight of all patients was (n=32) 443g (95-783g). In all patients tumor volume was measured in the CT or PET-CT scans performed before surgery as described previously (Frauenfelder 2011). Tumor volume of the resected specimen was additionally measured in 21 patients. Relations between tumor weight, tumor volume at surgery, CT-volume, cT stage and pT stage were analyzed using Spearman rank correlation.
Results:
Median time between CT scan and surgery was 18 days (range 1-48). The analysis revealed a moderate correlation between CT tumor volume and weight (p=0.001, correlation coefficient 0.58, CT volume and tumor volume at surgery showed strong correlation (p=0.001, correlation coefficient 0.65). No significant correlation was observed between cT stage and tumor weight (p=0.1, correlation coefficient 0.31), but a moderate correlation between cT stage and CT volume (p=0.001, correlation coefficient 0.58) as well as specimen volume (p=0.008, correlation coefficient 0.58). There was a moderate correlation of tumor weight with pT stage (p=0.02, correlation coefficient 0.42), but no correlation of CT volume (p=0.1, correlation coefficient 0.31) as well as specimen volume with the pT stage (p=0.2, correlation coefficient 0.32). Figure 1
Conclusion:
The correlation between preoperatively assessed CT tumor volume and volume of the resected specimen showed a strong correlation. To assess the prognostic role of CT measured tumor volume a correlation to prognosis has to be performed before implementation as a new T-factor.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-001 - Targeting Cullin Ubiquitin Ligase Leads to Growths Arrest in Malignant Pleural Mesothelioma Cells (ID 5486)
14:30 - 14:30 | Author(s): I. Opitz
- Abstract
Background:
Mutation of the tumor suppressor gene NF2 was detected in 30-40% of malignant pleural mesothelioma (MPM) patients. NF2 suppresses tumorigenesis in part by inhibiting Cullin4 ubiquitin ligase. Cullin4A (CUL4A) gene amplification and its’ overexpression has been detected in MPM cell lines and tumors. We hypothesized that cullin4 is a potential treatment target for MPM. Cullins’ activity can be blocked by the inhibition of neddylation, a post-translational modification for cullins. In this study we assessed the efficacy of pevonedistat, an inhibitor of protein neddylation.
Methods:
Thirteen MPM cell lines and 3 MPM primary cells grown in monolayer (2D) were employed to assess the efficacy of pevonedistat in vitro compared to normal mesothelial cells, using MTT assay. The expression of cullins was assessed by quantitative real time PCR and western blot. Cell cycle was analyzed by flow cytometry. Four cell lines were cultured in multicellular spheroid (3D) format and measured for viability by acid phosphatase assay.
Results:
Five MPM cell lines overexpressing CUL4A are highly sensitive to pevonedistat (figure1). The treatment induced G2 cell cycle arrest and accumulation of cells containing >4N DNA content, representing cells undergoing DNA re-replication. DNA re-replication is known to be mediated by the accumulation of a DNA replication licensing factor, CDT1. Indeed, higher CDT1 accumulation was detected in the sensitive compared to the resistant cell lines. All primary cells showed no CUL4A overexpression compared to normal mesothelial cells, nonetheless 2 of them were sensitive to pevonedistat. Interestingly, these cells exhibited higher levels of neddylated (activated) CUL4A and higher CTD1 accumulation following the treatment. Cells lines overexpressing CUL4A remained sensitive to pevonedistat when grown in 3D spheroids. Figure 1
Conclusion:
Inhibition of cullins by pevonedistat induced growth arrest preferentially in MPM cells overexpressing CUL4A in 2D and 3D cultures. The major mechanism seems to be mediated by DNA re-replication induced by CDT1 accumulation.
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P3.03-044 - Is Toxicity Increased by Adding Intraoperative Chemotherapy to Preoperative Induction Chemotherapy for Mesothelioma Patients? (ID 5945)
14:30 - 14:30 | Author(s): I. Opitz
- Abstract
Background:
Intracavitary application of chemotherapy after mesothelioma resection is intended to prevent local recurrence. In the present study, we compared hematological and renal toxicity of patients treated with or without additional intracavitary cisplatin-fibrin after (extended) pleurectomy/decortication ((e)P/D) and previous i.v. induction chemotherapy with cisplatin/pemetrexed (CTX).
Methods:
Hemoglobin values, platelet count as well as urea, creatinine, sodium, potassium and magnesium values of 32 patients treated with (e)P/D were compared to the first five patients receiving 44mg/m[2] BSA intracavitary cisplatin-fibrin in our INFLuenCe-Meso phase II trial (www.clinicaltrial.gov NCT01644994). The median time between last cycle of CTX and surgery was 6 weeks (1-14 weeks). The blood values were measured on postoperative day (POD) 1 to 5, 7, 10 and 14 if available. For statistical comparison Mann-Whitney U test was used.
Results:
No significant difference between the 2 groups was observed in the preoperative baseline blood samples. On POD3 hemoglobin dropped significantly more in patients with cisplatin-fibrin application (Figure 1A). However, the use of blood transfusion was not significantly different in both groups. Also sodium, potassium (Figure 1B) and magnesium levels were significantly lower in the study patient group. Disorders in electrolytes were however never reflected in clinical symptoms and reached only in 3 patients a CTCAE level ≥3. There was no significant difference in platelet count, urea and creatinine levels. Figure 1
Conclusion:
The present analysis shows that additional intracavitary cisplatin-fibrin after eP/D and previous i.v. induction chemotherapy with cisplatin/pemetrexed can lead to electrolyte disorders and drop in hemoglobin concentration. However, none of the mentioned laboratory findings had a clinically significant impact on the patients’ postoperative course.
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SC06 - Novel Therapies in Malignant Pleural Mesothelioma and Thymic Malignancies (ID 330)
- Event: WCLC 2016
- Type: Science Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
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SC06.03 - Intraoperative Therapies in Malignant Pleural Mesothelioma (ID 6623)
15:10 - 15:30 | Author(s): I. Opitz
- Abstract
- Presentation
Abstract:
Intraoperative Therapies in Malignant Pleural Mesothelioma The rational of localized / intracavitary treatment is to eliminate microscopic residual disease (MRD) after macroscopic complete resection (MCR) for mesothelioma patients. The advantage of the treatment is that local effects can be enhanced whereas systemic side effects of the therapeutic agents applied might be reduced. Several approaches have been investigated over the past decades in preclinical and clinical trials, such as intracavitary chemotherapy (iCTX), immunotherapy (iIT), photodynamic therapy (PDT) and gene therapy (iGT). Intracavitary chemotherapy (iCTX) iCTX has been studied after mesothelioma resection, not only after extrapleural pneumonectomy (EPP) but also after (extended) pleurectomy/decortication ((e)P/D). The main therapeutic agent used is cisplatin. In some trials hyperthermia was additionally added with the aims to enhance the penetration of cisplatin into tissues and maximize its cytotoxicity in tumor cells [1]. Hyperthermic intrapleural perfusion had a maximum tolerated dose of 225-250 mg Cisplatin/m[2] BSA [2]. The morbidity ranges from 13 to 85% and the mortality from 0 to 29% [2, 3]. Some complications are related to renal toxicity which was the dose limiting adverse event [2]. Median survival time reaches up to 35.3 months in low-risk MPM patients receiving hyperthermic intraplueral cisplatin chemotherapy following MCR [4]. This treatment is only considered for well-designed clinical trials. In vivo preclinical model using intrapleural administration of cisplatin-mixed loaded to a fibrin carrier improved the local drug concentration and prolonged the exposure of tissue to high cisplatin concentration [5]. Our phase I dose escalation trial (INFLuenCe – Meso; see figure) has proven the safety of this treatment approach (manuscript in preparation). This treatment regimen is now being tested in a phase II trial (NCT01644994). Figure 1 In addition to chemotherapy, other substances have also been tested for intracavitary treatment. Recently, Tada, et. al. reported study plan for a phase I trial for intrapleural treatment with zoledronic acid, a third generation of bisphosphonates, in inoperable MPM, after having successfully proven the efficacy of zoledronic in a pre-clinical model [6]. Intracavitary immunotherapy (iIT) MPM is not a classical “immunogenic” tumor. Intrapleural instillation of cytokines such as interleukin (IL)-2, interferon (IFN)-α and IFN-γ provided a good control of malignant pleural effusion (MPE) and MPM with minimal toxicity [7, 8]. To prolong and increase local exposure of IFNs, recent studies implemented immuno-gene therapy approach using adenoviral vector expressing human IFNs. Four out of 10 patients with MPM and metastatic pleural effusions showed stable disease following a single dose of intrapleural adenoviral vector expressing IFN-β [9]. Nevertheless due to rapid production of neutralizing antibody against adenovirus, no improvement of gene transfer efficacy was achieved after the second dose [10]. The same research group conducted a clinical trial assessing the safety of adenoviral-mediated IFN-α2b in combination with chemotherapy. Recent data from this trial showed that the treatment is well tolerated and 25% of patients had partial response [11]. An intrapleural treament with re-directed T cells genetically engineered to express chimeric antigen receptor (CAR) that specifically recognizes tumor antigens is an attractive therapeutic option. A clinical phase I trial for intrapleural administration of fibroblast activation protein (FAP)-specific re-directed T cells is currently being conducted (NCT01722149). Photodynamic therapy (PDT) PDT is a light based cancer therapy. Most modern PDT applications involve three key components: a photosensitizer, a light source and tissue oxygen. The photosensitizing agent accumulates in tumor cells and is activated by light of a specific wavelength to produce reactive singlet oxygen that mediates cellular toxicity. The tumor cells are killed through both apoptosis and necrosis and by damaging tumor vasculature. It may also induce inflammatory reaction capable of stimulating a tumor directed host immune response. The advantages of this treatment are that its efficacy is not influenced by chemo- or radio-resistance of tumor cells, that it can be repeated at the same site without compromising its efficacy and that it does not compromise the ability to administer other treatment modalities in patients with recurrent or residual disease. PDT should be combined with macroscopic complete resection due to limited depth of penetration. Localized inflammation and fluid accumulation after treatment can modestly extend hospital stay. PDT appears promising and may improve local control and potentially prolong survival in properly selected patients who are able to undergo MCR, with clinical outcomes appearing best when PDT is combined with lung-sparing definitive surgery [12]. Friedberg reported a median survival of 31.7 months (41.2 months in patients with epithelioid histological subtype), but the progression free survival was only 9.6 months [13]. Intracavitary gene therapy (iGT) Gene therapy is based upon transfer of genetic material, including complementary DNA, full-lengths genes, small interfering RNA or oligonucleotids into cells for therapeutic purposes. For sufficient gene delivery, adenovirus is the most widely used in clinical trials among a variety of viral and non-viral vectors. In addition to delivering cytokine expressing vectors or re-directed T cells (see iIT part), several different cancer gene therapy approaches are currently used including the so called suicide gene therapy wherein a neoplasm is transduced with a cDNA encoding for an enzyme rendering tumor cells sensitive to a benign agent by converting the product to a toxic metabolite. The Herpes Simplex Virus 1- thymidine kinase (HSVtk) gene encodes for an enzyme that converts ganciclovir, an antiviral drug, to its cytotoxic metabolite. Intrapleural adenovirus HSVtk/ganciclovir administration was safe in MPM and two patients survived >6.5 years. Nevertheless, due to the fact that transgenes HSVtk were only detected at the surface of tumor tissues, the authors suggested that the treatment efficacy may be a result of antitumor immune response stimulation [14]. MPM tumor genome is characterized by frequent mutations in tumor suppressor genes such NF2, BAP1 or p53, thus the delivery of tumor suppressor gene expressing vectors into tumor cells can serve as an attractive treatment approach. The delivery of adenovirus expressing p53 has been tested in clinical trials for lung cancer but did not show better clinical benefit over chemotherapy [15]. This may be due to limited transfection efficiency of the vector and the stimulation of neutralizing antibody, therefore an improvement of transfection is still needed for the further development of gene therapy. References: 1. Sugarbaker, P.H., et al., Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist, 2005. 10(2): p. 112-22. 2. Richards, W.G., et al., Phase I to II Study of Pleurectomy/Decortication and Intraoperative Intracavitary Hyperthermic Cisplatin Lavage for Mesothelioma. J Clin Oncol, 2006. 24(10): p. 1561-1567. 3. de Bree, E., et al., Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma. Chest, 2002. 121(2): p. 480-7. 4. Sugarbaker, D.J., et al., Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg, 2013. 145(4): p. 955-63. 5. Lardinois, D., et al., Intrapleural topical application of cisplatin with the surgical carrier Vivostat increases the local drug concentration in an immune-competent rat model with malignant pleuromesothelioma. J Thorac Cardiovasc Surg, 2006. 131(3): p. 697-703. 6. Tada, Y., et al., An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol. Springerplus, 2016. 5: p. 195. 7. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 8. Antoniou, K.M., E. Ferdoutsis, and D. Bouros, Interferons and their application in the diseases of the lung. Chest, 2003. 123(1): p. 209-16. 9. Sterman, D.H., et al., A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res, 2007. 13(15 Pt 1): p. 4456-66. 10. Sterman, D.H., et al., A phase I trial of repeated intrapleural adenoviral-mediated interferon-beta gene transfer for mesothelioma and metastatic pleural effusions. Mol Ther, 2010. 18(4): p. 852-60. 11. Sterman, D.H., et al., Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNalpha Combined with Chemotherapy. Clin Cancer Res, 2016. 22(15): p. 3791-800. 12. Simone, C.B., 2nd and K.A. Cengel, Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin Oncol, 2014. 41(6): p. 820-30. 13. Friedberg, J.S., et al., Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann Thorac Surg, 2012. 93(5): p. 1658-65; discussion 1665-7. 14. Sterman, D.H., et al., Long-term Follow-up of Patients with Malignant Pleural Mesothelioma Receiving High-Dose Adenovirus Herpes Simplex Thymidine Kinase/Ganciclovir Suicide Gene Therapy. Clin Cancer Res, 2005. 11(20): p. 7444-7453. 15. Schuler, M., et al., Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol, 2001. 19(6): p. 1750-8.
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