Virtual Library
Start Your Search
M. Jakopovic
Moderator of
-
+
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: 8
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
-
+
OA02.01 - The microRNA-15/16 Family Regulates Tumour Cell Growth via Fibroblast Growth Factor Signals in Malignant Pleural Mesothelioma (ID 5395)
11:00 - 12:30 | Author(s): K. Schelch, M.B. Kirschner, M. Williams, R. Lin, Y.Y. Cheng, M. Grusch, W. Berger, N. Van Zandwijk, G. Reid
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive, asbestos-related malignancy characterized by poor outcome and limited therapeutic options. Fibroblast growth factor (FGF) signals play important roles in mesothelioma cell growth and malignant behavior and their inhibition leads to reduced tumor growth. MicroRNAs (miRNAs) are conserved noncoding RNAs controlling gene expression via translational repression of target mRNAs. The miR-15/16 family is downregulated in MPM and has tumor suppressor functions. Several FGFs/FGFRs are predicted miR-15/16 targets. The aim of this study was to explore the link between the miR-15/16 and the FGF/R family in MPM.
Methods:
Gene and microRNA expression was determined by RT-qPCR or Taqman Low Density Arrays (TLDAs). Mimics were used for restoring microRNA expression. Stimulation or inhibition of FGF signals or bcl-2 was achieved by recombinant FGF2, siRNAs, or small-molecule inhibitors, respectively. A SYBR green-based proliferation assay and colony formation assays were used to monitor effects on cell growth.
Results:
Expression analysis showed a consistent downregulation of target FGF/FGFR genes after transfection with miRNA mimics. Restoration of miR-15/16 led to dose-dependent growth inhibition, which significantly correlated with sensitivity to the specific FGFR1 inhibitor PD166866. Re-expression of microRNAs in combination with FGFR knock-down or pharmacological inhibition resulted in reduced activity, indicating target competition. Combined inhibition of the FGF-axis and bcl-2, another established target of miR-15/16, resulted in enhanced activity. Treatment with recombinant FGF2 further reduced mature as well as pri-microRNA levels and also could prevent/reduce growth inhibition by mimics, but only when added within 24 hours after transfection. TLDA screens after stimulation/inhibition of FGF signals identified regulation of several other miRNAs involved in pathways relevant for tumour growth and aggressiveness.
Conclusion:
Our data shows that the post-transcriptional repression of FGF-mediated signals contributes to the tumour-suppressor function of the microRNA-15/16 family. Impairing hyperactivated FGF signals as well as the anti-apoptotic protein bcl-2 through the restoration of this miRNA family might serve as a novel therapeutic strategy in mesothelioma.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA02.02 - Gremlin-1 is a Key Regulator of the Invasive Phenotype in Mesothelioma (ID 5424)
11:00 - 12:30 | Author(s): M. Yin, M. Tissari, J. Tamminen, I. Ylivinkka, M. Ronty, K. Lehti, M. Hyytiainen, M. Myllarniemi, K. Koli
- Abstract
- Presentation
Background:
Malignant mesothelioma is an aggressive cancer that develops from mesothelial cells, most often in the pleural lining of the lung. We have previously shown that the BMP inhibitor protein gremlin-1 is highly expressed in mesothelioma and induces a mesenchymal and chemoresistant phenotype in mesothelioma cells. Since mesothelioma tumors are locally highly invasive, we analyzed the role of gremlin-1 in mesothelioma cell migration and invasive growth.
Methods:
Primary mesothelioma cells isolated from patient pleural fluid as well as mesothelioma cell lines were used for in vitro studies. Cells were transfected with siRNAs or transduced with lentiviral expression vectors. Invasive growth was analyzed in 3D matrigel or collagen I matrices. mRNA expression was analyzed using a commercial PCR array and quantitative RT-PCR. Migration assays were performed using scratch wound assay or Transwell migration assay with fibronectin or collagen coating. TGF-β and BMP signaling activity was measured with reporter-luciferase assays. For in vivo mouse xenograft experiment cells were additionally transduced to express a luciferase marker. Subcutaneous cell injection with matrigel matrix was performed in the flank of nude mice.
Results:
Mesothelioma cells expressing gremlin-1 showed invasive sprouting when tumor cell spheroids were imbedded into 3D collagen matrix. Silencing of gremlin-1 expression significantly reduced invasive growth. In addition, cells overexpressing gremlin-1 gained invasive growth ability. This was associated with increased mRNA expression levels of Slug and matrix metalloproteinases (MMP) as well as reduced expression of E-cadherin. The cells were more migratory and exhibited increased expression of certain integrins, especially the α~v~ subunit. Gremlin-1 induced invasive growth was dependent on MMP activity and associated with increased TGF-β activity. Intrapleural injection of gremlin-1 overexpressing mesothelioma cells isolated from a patient with epithelioid mesothelioma, produced tumors in 2/4 mice over 4 months after injection. Cells transduced with vector only did not produced tumors (0/4). When cells were injected subcutaneously together with matrigel gremlin-1 overexpressing tumors appeared more slowly, but exhibited comparable luciferase signal 2.5 months after injection. However, gremlin-1 tumors showed more local spreading and in contrast to control tumors some also developed metastasis (2/6 mice).
Conclusion:
Mesothelioma invades locally and has poor prognosis. We have identified gremlin-1 as an important regulator of mesothelioma chemoresistance and invasive growth behavior. Blocking gremlin function may overcome drug resistance and reduce invasion of mesothelioma.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA02.03 - Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study (ID 5988)
11:00 - 12:30 | Author(s): Y. Dong, H. Zhang, K. Schelch, T. Klikovits, P. Stockhammer, M. Jakopovic, M. Samarzija, L. Brcic, G. Reid, M.B. Kirschner, S. Kao, I. Opitz, W. Weder, T. Frauenfelder, T.D.L. Nguyen-Kim, W. Klepetko, N. Van Zandwijk, B. Hegedus, W. Berger, B. Dome, V. Laszlo, M. Grusch, M.A. Hoda
- 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. .
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA02.04 - Discussant for OA02.01, OA02.02, OA02.03 (ID 6952)
11:00 - 12:30 | Author(s): M.B. Kirschner
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA02.05 - Expression of miR-223 in Mesothelioma Xenografts Originates from Stromal Cells in the Tumour Microenvironment (ID 5875)
11:00 - 12:30 | Author(s): K.H. Sarun, Y.Y. Cheng, M.B. Kirschner, N. Van Zandwijk, R. Lin, G. Reid
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive cancer caused by asbestos exposure with limited therapeutic options. Dysregulated microRNAs play an important role in MPM biology and candidate microRNAs have been investigated as diagnostic and prognostic biomarkers or as a potential treatment targets. The role of miR-223 has previously been investigated in MPM tumour cells and was shown to act as a tumour suppressor by regulating cell mobility. Previous research indicated miR-223 to be primarily expressed by myeloid progenitor derived cells during differentiation of granulocytes and monocytes. This suggests miR-223 might have a more significant role in the inflammatory response during tumourigenesis. In this study we aimed to investigate the origin of miR-223 using mesothelioma xenograft and syngraft models.
Methods:
Human and mouse mesothelioma cell line-derived xenograft (MSTO-H211 and H226) and syngraft (AB1) models were established. MicroRNA profiles of xenografts were compared against profiles of their corresponding in vitro cultured cells to determine candidates. RT-qPCR using TaqMan MicroRNA assays was used to validate expression levels of miR-143-3p, miR-214-3p and miR-223-3p in tumour xenografts and syngrafts with those in corresponding cell lines in vitro. Species-specific ddPCR analysis was performed on RNA from xenograft tumours to determine the expression of human and mouse pri-miR-223.
Results:
MicroRNA profiles of xenograft tumours showed significant upregulation (p < 0.05) of miR-143-3p, miR-214-3p and miR-223-3p compared to corresponding in vitro mesothelioma cell lines. Only miR-223 showed significant upregulation in both xenograft and syngraft tumours compared to corresponding in vitro mesothelioma cell lines (>10000-fold increase). Other microRNAs were not significantly different between cell lines and tumours. RNA isolated from xenograft tumours contained significantly more mouse pri-miR-223 than human pri-miR-223 (p < 0.001), with only minimal expression levels of human tumour pri-miR-223 within xenograft tumours.
Conclusion:
Mature miR-223 is significantly overexpressed in xenograft tumours compared to corresponding in vitro mesothelioma cell lines suggesting stromal contribution. Species-specific pri-miRNA confirmed miR-223 is almost exclusively expressed by the mouse stromal cells in xenograft tumours. Ultimately, localising the expression of miR-223 to specific cell types (such as myeloid derived cells) through in situ hybridisation should help identify a more biologically relevant role for miR-223 in the tumour microenvironment.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA02.06 - Converting Tumor-Mediated PD-L1 Inhibition into CAR T-Cell Costimulation to Potentiate Thoracic Cancers Immunotherapy (ID 6058)
11:00 - 12:30 | Author(s): A. Morello, N. Chen, L. Cherkassky, M. Sadelain, D. Jones, P.S. Adusumilli
- Abstract
- Presentation
Background:
To overcome tumor-mediated inhibition of chimeric antigen receptor (CAR) T cells, we herein investigated the impact of tumor PD-L1 upregulation on CAR T-cell exhaustion and anti-tumor efficacy, and further developed clinically translatable T-cell extrinsic as well as intrinsic strategies to overcome PD-L1 inhibition in models of lung cancer (LC) and malignant pleural mesothelioma (MPM).
Methods:
Human T cells were transduced with MSLN-specific CAR with CD28 and CD3zeta domains (M28z) were tested in vitro and in clinically-relevant LC and MPM mouse models by bioluminescence imaging, BLI of tumor burden progression. To counteract PD-1/PD-L1 inhibition in vivo, we evaluated the efficacy of PD-1 blocking antibody or cell-intrinsic genetic-engineering strategies by cotranducing M28z CAR T cells with a PD-1 dominant negative receptor (PD1-DNR) or with PD-1/4-1BB fusion protein.
Results:
A single, low-dose of M28z CAR T cells is able to resist the progression of established tumor for 40 days, but mice eventually died with progressing tumor. Tumor harvest analysis demonstrated the PD-1 and PD-L1 upregulation on CAR T cells and tumor cells (Figure panel A). We then confirmed in vitro that PD-L1 inhibits M28z T-cell effector functions (proliferation, cytotoxicity and cytokine secretion). The addition of PD-1 blocking potentiates CAR T-cell therapy in vivo but its efficacy requires multiple injections (Panel B). In contrast, a single dose of M28z T cells coexpressing PD1-DNR restore effector functions, enhance tumor burden control (Panel C) and prolong median survival (56 vs 82 days, p=0.001). Converting PD-L1 inhibition into a positive costimulatory signal by PD-1/4-1BB construct cotransduction into M28z CAR T cells enhanced cytokine secretion and T-cell accumulation (Panel D). Figure 1
Conclusion:
Our results demonstrate the therapeutic benefit of providing optimal costimulation and coinhibitory blockade to counteract PD-L1/PD-1 immunosuppression, thus potentiate CAR T-cell therapy for lung cancer and mesothelioma.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA02.07 - Characterization of the Tumor Microenvironment and Investigation of Immune Checkpoint Expression in Malignant Pleural Mesothelioma (ID 4437)
11:00 - 12:30 | Author(s): E. Marcq, V. Siozopoulou, J. De Waele, J. Van Audenaerde, K. Zwaenepoel, E. Santermans, N. Hens, P. Pauwels, J.P. Van Meerbeeck, E. Smits
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a role in protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints might help to identify new immunotherapeutic targets and their predictive and/or prognostic value.
Methods:
Immunohistochemistry (IHC) was performed on tissue samples of untreated (n=40) and chemotherapy-pretreated (n=14) MPM patients. Different subsets if immune cells were identified based on staining for CD4, CD8, FoxP3, CD68, CD45RO and granzyme B. The expression of the immune checkpoints TIM-3, LAG-3, PD-1 and its ligand PD-L1 was also investigated. The relationship between the immunological parameters and survival, as well as response to chemotherapy was analyzed using the R statistical software.
Results:
All patients had CD8+ tumor infiltrating lymphocytes (TILs), CD68+ histiocytes and macrophages and CD45RO+ T cells in their stroma, with CD8+ TILs being the predominant cell type of the immune infiltrate. Stromal CD4+ TILs were found in 75% of the untreated and 71% of the pretreated samples. A subset of those cells was also FoxP3+ and these CD4+FoxP3+ cells were positively correlated with stromal CD4 expression (p<0.001). Less than half of the samples showed positivity for granzyme B. Both, untreated and pretreated patients had PD-1+ TILs, while only 10% of the untreated patients also had PD-1+ tumor cells. PD-L1 positivity on lymphocytes and/or tumor cells was observed for more than half of the patients, with significant differences according to the histological subtype (p<0.001). Patients with a sarcomatoid histology showed the most PD-1 expression. TIM-3 was expressed in tumor cells, stromal lymphocytes and plasma cells, less often in pretreated samples compared to untreated samples. All samples were negative for LAG-3. After multivariate analysis stromal CD45RO expression was found to be an independent negative predictive factor for response to chemotherapy (p=0.017) and expression of CD4 and TIM-3 in lymphoid aggregates were good prognostic factors (p=0.008; p=0.001).
Conclusion:
Our data reveal the diversity of immune cells present in MPM and point to TIM-3 as a new target in mesothelioma. Administering chemotherapy before or together with PD-1/PD-L1/TIM-3 blocking agents may not be the best combination sequence and further research on the predictive value of CD45RO in the stroma might guide patient selection for chemotherapy.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA02.08 - Discussant for OA02.05, OA02.06, OA02.07 (ID 6964)
11:00 - 12:30 | Author(s): M. Grusch
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
Author of
-
+
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
-
+
OA02.03 - Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study (ID 5988)
11:00 - 12:30 | Author(s): M. Jakopovic
- 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. .
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.02-049 - EGFR, KRAS and ALK Gene Alterations in Lung Cancer Patients in Croatia (ID 5943)
14:30 - 15:45 | Author(s): M. Jakopovic
- Abstract
Background:
Rates in targetable gene changes varies between different populations of lung cancer patients. Targetable gene changes include changes in EGFR and ALK gene, as well as KRAS gene. Primary aim of this study was to determine mutation status in purely Caucasian Croatian population.
Methods:
Rates in targetable gene changes varies between different populations of lung cancer patients. Targetable gene changes include changes in EGFR and ALK gene, as well as KRAS gene. Primary aim of this study was to determine mutation status in purely Caucasian Croatian population.
Results:
During 6 months period 324 newely diagnosed primary lung adenocarcinoma were tested. Out of 324 tested patients, 194 were males (60%) and 130 females (40%) mean age 64 years (range 35 to 88 years). Vast majority of patients were in stages 3 and 4 (more than 80%). Among males, 87% of patients were ever smokers, and among females 61% of patients were ever smokers. Significantly higher rates of evers smokers were recorded among males. EGFR mutations were present in 15.7% of patients (51 patients). There was a difference in EGFR mutation rates between males and females (5.6 vs 30.8%, p<0.0001). KRAS mutations (codones 12/12 and 61) were present in 35.8% (116) patients, and ALK translocation detected by IHC in 3.7% (12) patients.
Conclusion:
Molecular testing in primary lung adenocarcinoma patients was done in purely Caucasian Croatian population. EGFR mutation and ALK translocation rates were similar to previously published data. However, KRAS mutation rates were higher than previously published. This can be associated with high smoking rates in Croatian population.
-
+
P1.04 - Poster Session with Presenters Present (ID 456)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Pulmonology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.04-025 - The Impact of Emergency Presentation on Survival of Lung Cancer Patients (ID 5964)
14:30 - 15:45 | Author(s): M. Jakopovic
- Abstract
Background:
A significant proportion of lung cancer patients are diagnosed through emergency department (ED), which is usually associated with poorer prognosis. We investigated the assocation between diagnosis of lung cancer after presentation through emergency department due to symptoms associated to lung cancer.
Methods:
Medical charts of patients with lung cancer patients newly diagnosed in Department for Respiratory Diseases Jordanovac, University Centre Zagreb in years 2012 and 2103 were reviewed. Overall survival was calculated and was compared between groups.
Results:
The medical charts of 951 males and 407 females, mean age 64 years (males 64.5, females 62) were reviewed. 292 out od 1359 patients (21,5%) were diagnosed with lung cancer after initial presentation through ED. The most common reasons for ED admissions were hemopytsis (in 31% of patients), pneumonia (16%), brain metastasis (15%), dyspnea (10%) and superior vena cava syndrome in 8% of patients. There were no differences in histology subptypes between two different routes of presentation (most common histology subtype was adenocarcinoma followed by squamous histology). Significantly higher proportion of patients diagnosed after initial diagnosis through ED were at presentation in stage IV (61 vs 44%, p<0.0001), poorer performance status (ECOG 3-4 vs ECOG 0-1, p<0.0001), significantly less patients underwent surgical resection (14 vs 5%, p<0.0001) and radiotherapy (56 vs 73%, p<0.0001). Median overall survival (mOS) was significantly lower in patients diagnosed through ED (6.0 vs 10.0 months, p<0.0001). In patients with non-small cell lung cancer (NSCLC) results were similar (mOS 6.0 vs 10.0 months, p<0.0001). In patients with small cell lung cancer (SCLC) mOS was also significantly worse (7.0 vs 9.0 months, p<0.0001) in patients diagnosed through ED.
Conclusion:
Higher stage, reduced access to surgical resection and radiotherapy, and significantly lower overall survival regardless of histology subtypes among lung cancer patients who presents through emergency department, stress out the importance of earlier diagnosis of lung cancer patients so that initial presentation through emergancy department can be reduced.
-
+
P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.07-013 - Treatment Related Side Effects of Oral Topotecan in Small Cell Lung Cancer (ID 5000)
14:30 - 15:45 | Author(s): M. Jakopovic
- Abstract
Background:
Lung cancer is the most common tumor in men and the second most common tumor in woman according to the latest data available from the Croatian National Cancer Registry. Approximately 20% of all lung cancers are categorized as small cell lung cancer (SCLC). Topotecan is recommended as second-line chemotherapy in treatment of SCLC. Topotecan can be administrated orally with the same effectiveness as parenteral.
Methods:
The aim of this study was to determine toxicity of oral topotecan in second line of chemotherapy and to establish the frequency of drug related admissions.
Results:
A total of 177 courses of therapy were administered to the 64 patients, 17 woman and 47 men, with SCLC patients ranging from 42 to 77 years with the mean age of 59.3. All the patients were treated in University Hospital Centre Zagreb from January 2012 to October 2015. Included patients had ECOG performance status of 0 or 1. Topotecan was administrated every 21 day, at the dose of 2.3 mg/m[2]/day, during 5 days. Average number of courses received was 2.8. Of all included patients 17 of them (26.5%) were admitted to hospital because of adverse events related to topotecan administration. The majority of patient hospitalizations (11 patients, 16.9%) was due to febrile neutropenia. Other reasons for hospitalization were severe diarrhea in 4 patients (6.2%), pneumonia in 1 patient (1.5%) and severe electrolyte imbalance in 1 patient (1.5%). Of 17 admissions to hospital 10 (58.9%) of them were after application of first chemotherapy cycle, 3 (17.6%) after second cycle and 4 (23.5%) after third cycle. Quantitative hematologic toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. Anemia grade 3 or 4 occurred in 13 patients (20.3%). Grade 3 or 4 thrombocytpenia occurred in 7 patients (10.9%). Grade 3 or 4 neutropenia occurred in 16 patients (25%). Of other, non-hematologic adverse effects the most serious was grade 3 or 4 diarrhea that occurred in 5 patients (7.8%).
Conclusion:
although admission of oral topotecan is well tolerated it is related with high rate of hospitalizations due to myelotoxicity and gastrointestinal toxicity during therapy.
-
+
P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.02-051 - Prognostic Value of the Pretreatment Peripheral Blood Markers in Patients with Non-Small Cell Lung Cancer (ID 6120)
14:30 - 15:45 | Author(s): M. Jakopovic
- Abstract
Background:
Lung cancer is the leading cause of cancer-related mortality worldwide. Regarding histological types, non-small cell lung cancer (NSCLC) represents 80% of all cases. In majority of all cases, NSCLC patients have locally advanced or metastatic disease at the time of diagnosis. Currently there is no predictive markers with clinical utility to guide treatment decisions in NSCLC patients undergoing therapy. We have compared mOS (median overall survival) before treatment (chemotherapy, radiotherapy or surgery) in patients with NSCLC regardless of the disease stage.
Methods:
Total of 1359 medical records of patients diagnosed with lung cancer Clinical hospital center Zagreb, Department of respiratory diseases Jordanovac during the year 2012 and 2013 were retrospectively collected and reviewed. Of that number, 1179 were NSCLC patients (all subtypes). We have analyzed normal and elevated biochemical markers: CRP (cut off value was 5.0 mg/L), leucocytes (cut of value was 10x10[9]/L), platelets (cut of value was 424x10[9]/L) and fibrinogen (cut off value was 4.1 g/L) in patients before treatment and calculated mOS (median overall survival). Since not all of 1179 patients performed pretreatment laboratory tests in our Department, we were unable to review laboratory findings of all diagnosed patients. mOS was measured and analyzed using the Kaplan-Meier and log-rank test.
Results:
We have found out that in case of elevated CRP and leukocytes values prior to treatment patients had lower mOS regardless of therapeutic modality. Additionally, elevated levels of fibrinogen and platelets do not affect mOS. From 1179 NSCLC patients, CRP was initially measured in 770. In 116 patients CRP was normal (<5mg/L) and in 654 elevated (>5mg/L). In patients with normal CRP mOS was 16 months, and in those with elevated CRP 10 months (p< 0.001). Leucocytes were initially measured in 842 patients. 444 patients had normal leucocyte values (<10 x10[9]/L) and 398 had elevated leucocytes (>10 x10[9]/L). Patients with normal leucocytes values had mOS of 13 months and those with elevated 10 months (p< 0.001).
Conclusion:
The prognostic impact of peripheral blood markers (CRP and leucocytes) supports the growing evidence of inflammation and cancer relationship. Elevated CRP and leucocytes before treatment are independent predictive factors for poorer mOS in NSCLC patients. The underlying mechanism by which these elevated markers affects the prognosis of lung cancer remains elusive.
-
+
P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.03b-009 - Brain Metastasis and Epidermal Growth Factor Receptor Mutations in Croatian Caucasians with Lung Adenocarcinoma (ID 5182)
14:30 - 15:45 | Author(s): M. Jakopovic
- Abstract
Background:
The brain is a common site of metastasis in non-small cell lung cancer (NSCLC). The aim of this study was two-fold: 1) to determine the incidence of brain metastasis (BM) in Caucasian lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations and 2) to evaluate the frequencies and potential relationship of the different EGFR mutations with BM.
Methods:
A retrospective cohort study was conducted at a Croatian tertiary hospital (Clinic for Respiratory Diseases “Jordanovac”) using data collected from medical records. Caucasian patients with primary NSCLC who were tested for EGFR mutation status between January 2014 and October 2015 were included.
Results:
Of 1040 NSCLC samples tested, 122 (11.7%) patients with lung adenocarcinoma harboured EGFR mutations; six EGFR positive (+) patients (four with BM) had repeat EGFR testing. The majority of EGFR mutants were females (n= 90, 77.6%), non-smokers (including never-smokers and former-smokers; n= 95, 92.2%), diagnosed with advanced disease (stage IIIB/IV) at first presentation (n= 75, 68.8%), and median age at initial diagnosis of primary lung cancer was 65 years (35 - 90). Twenty-three (19.8%) of 116 EGFR+ patients were diagnosed with BM; for six EGFR+ patients, data about BM was missing. Most were 64 years of age or younger (n= 15, 65.2%) at diagnosis of BM (median age: 62 years, 48 - 72). Synchronous BM disease at initial diagnosis of lung cancer was found in 43.5% of EGFR+ patients with BM (n= 10). There were more EGFR+ women with BM (n= 20, 87%) than men. Single exon 19 deletion and exon 21 L858R mutations were the most common subtypes in both EGFR+ patients without BM (n= 44, 47.3% and n= 27, 27.8%, respectively) and with BM (n= 13, 56.5% and n= 5, 21.7%, respectively). One BM patient (4.3%) had a double mutation (exon 19 and 21), while six non-BM patients (6.2%) had simultaneous pairings, most commonly between exon 19 and 20 (n=3, 3.1%). Although exon 18 mutations were seen in six patients without BM (6.2%), none were found in BM+EGFR+ patients. Exon 20 T790M mutation occurred in 17.4% of BM patients (n= 4) versus 15.3% of non-BM patients (n= 15). Rare EGFR double mutations (exon 18 and 20) were found in two non-BM patients (2.2%).
Conclusion:
Larger long-term prospective studies to explore and confirm these results in BM+EGFR+ patients are warranted. In the era of precision oncology, molecular testing of EGFR mutations may further clarify the pathogenesis of lung cancer-associated BM.
-
+
P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.02b-114 - Second Line Treatment of EGFR Positive Lung Adenocarcinoma - Our Experience (ID 6064)
14:30 - 15:45 | Author(s): M. Jakopovic
- Abstract
Background:
EGFR testing and specific targeted therapy of lung adenocarcinoma is a standard worldwide. In Croatia, tirosin-kinase inhibitors (TKI)are allowed as a second-line therapy for EGFR positive (+) patients. We analysed the median overall survival (mOS) differences between TKI- and.conventional chemotherapy-treated patients as a second-line therapy.
Methods:
Medical records of patients diagnosed with lung adenocarcinoma and tested for specific mutations in Clinical hospital center Zagreb, Department for respiratory diseases Jordanovac, during the year 2013 and 2014, were retrospectively collected and reviewed. Median overall survival (mOS) was measured and analyzed using routine statistic tests.
Results:
A total of 334 patients were tested for EGFR mutations, 47 of whom came positive and 287 negative. There was signifficant difference between the two subgroups regarding some demographic categories: the majority (78,7%) of the EGFR + patients were female, as opposed to the EGFR - group. Also, the EGFR+ patients were older on average ath time of diagnosis.(66,04 vs 63,04 years). After recieving first line platinum based chemotherapy a total of 20 positive EGFR patients recieved second-line therapy. 15 were treated with TKI and 5 recieved pemetrexed. In the EGFR negative group, 100 patients received second-line therapy, 85 of whom recieved pemetrexed and the other 15 were treated with platinum- or gemcitabine- based chemotherapy. If analysing mOS of all the patients, there was statistically significant difference between the TKI-treated patients (mOS not met) compared to the other ones (mOS=20 months) (chi-square= 6,07; p=0,014). Also, if analysing only the EGFR positive patients, the mOS difference reached statistical significance, comparing the TKI-treated patients (mOS =24,3months) with those treated with pemetrexed. (mOS=15,7 months) (chi-square= 7,99; p=0,005)
Conclusion:
Our results showed the significance of molecular testing and specific TKI treatment of patients with EGFR positive lung adenocarcinoma, as they had a significatly better overall survival compared to patients treated with pemetrexed. The results are conclusive with the general experience and treatment recommendations, and should be implemented in every day praxis, i.e. enabling molecular testing and specific treatment for all EGFR+ patients, at least as a second-line therapy option, should be an imperative.
-
+
P3.05 - Poster Session with Presenters Present (ID 475)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.05-018 - Assessment of Skeletal Muscle Mass as a Predicitive Factor for Chemotherapy Toxicity and TTP in Advanced NSCLC Patients with Cancer Cachexia (ID 3889)
14:30 - 15:45 | Author(s): M. Jakopovic
- Abstract
Background:
Cancer cachexia and sarcopenia are frequently observed in cancer patients and associated with poor survival. We evaluated prevalence of cachexia and sarcopenia in NSCLC patients, relation to chemotherapy toxicity and time to tumor progression (TTP).
Methods:
In a prospective study we included 100 Caucasian patients with advanced NSCLC referred consecutively to our Department before starting 1st line platinum-doublet chemotherapy. Anthropometric and body composition measurements - total muscle cross sectional area, lumbar skeletal muscle index (LSMI) were done. Skeletal muscle cross-sectional area was measured at the third lumbar vertebra by CT scan, sarcopenia was defined using a previously published cut-off point, and TTP was specified.
Results:
Among 100 recruited patients 67 were male, median age 64 years, BMI 24.5±4.5, weight 68±15 kg, weight loss in previous 6 months 7±6 kg (9.4±7.7%), 55 patients had CT images that met the criteria for analysis. Median total muscle cross-sectional area at L3 was 142.97±35.64 cm[2 ]and median skeletal muscle index was 52.03 cm[2]/m[2]. Male patients had statistically significant higher lumbar skeletal muscle area and LSMI than female (53.31 vs. 40.95 cm[2]/m[2], P<0.001). A very high proportion of men met the criteria for sarcopenia compared to women; 60.5% and 17%, respectively. There were 34.6% sarcopenic patients among male who met the criteria as overweigh. Good correlation was observed between BMI and LSMI (r=0.614). The prevalence of cachexia and sarcopenia in study cohort was 69% and 47%, respectively. There was no statistically significant difference between the groups in frequency of chemotherapy toxicity, between TTP in cachectic (187 days) and non-cachectic patients (167 days) (HR (95% CI) = 0.83 (0.48-1.43); P = 0.470) nor between sarcopenic (218 days) and non-sarcopenic patients (209 days).
Conclusion:
Cachexia and sarcopenia were not found to be predictors of chemotoxicity nor TTP. CT scan is a reliable method for obtaining and calculating muscle area, easily measurable, reproducible and usable without expensive software technology in everyday practice.
