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Isabelle Opitz
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SH01 - Highlight of the Previous Day (ID 98)
- Event: WCLC 2019
- Type: Highlight of the Previous Day Session
- Track:
- Presentations: 6
- Now Available
- Moderators:Isabelle Opitz, Ritsuko Komaki-Cox
- Coordinates: 9/09/2019, 11:00 - 12:30, San Francisco (2009)
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SH01.01 - Surgery (Now Available) (ID 3658)
11:00 - 12:30 | Presenting Author(s): Khaled Alkattan
- Abstract
- Presentation
Abstract
Section not applicable
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SH01.02 - Radiation (Now Available) (ID 3659)
11:00 - 12:30 | Presenting Author(s): Laurie Gaspar
- Abstract
- Presentation
Abstract not provided
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SH01.03 - Advanced Lung Cancer (Now Available) (ID 3660)
11:00 - 12:30 | Presenting Author(s): Digambar Behera
- Abstract
- Presentation
Abstract
Will submit as and when available.
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SH01.04 - Targeted Therapy (Now Available) (ID 3661)
11:00 - 12:30 | Presenting Author(s): Rosario Garcia Campelo
- Abstract
- Presentation
Abstract not provided
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SH01.05 - Mesothelioma (Now Available) (ID 3662)
11:00 - 12:30 | Presenting Author(s): Michele Carbone
- Abstract
- Presentation
Abstract not provided
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SH01.06 - Immunotherapy (Now Available) (ID 3855)
11:00 - 12:30 | Presenting Author(s): Margarita Majem
- Abstract
- Presentation
Abstract not provided
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Author of
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IBS06 - Multimodality Treatment - Realtime Data from National Registries (Ticketed Session) (ID 37)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 07:00 - 08:00, Dublin (1997)
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IBS06.01 - Realtime Data from Europe ETOP / ESTS Database (Now Available) (ID 3331)
07:00 - 08:00 | Presenting Author(s): Isabelle Opitz
- Abstract
- Presentation
Abstract
Title: Mesothelioma Realtime Data from Europe - ETOP Mesoscape / ESTS Database
Introduction:
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. Despite a still increase in incidence, it remains an orphan disease and studying limited numbers of MPM cases hampers the derivation of solid conclusions.
The combination of two databases including clinical as well as pathological information will allow researchers to improve the knowledge and facilitate decision-making in patients with MPM.
The European Thoracic Oncology Platform (ETOP) Mesoscape project and the European Society of Thoracic Surgeons’ (ESTS) database are designed to address clinical, pathological, and molecular characteristics of mesothelioma patients and their impact on outcome. The joined analysis of both databases is a unique approach to real-time data reflecting the reality of mesothelioma characteristics, treatment and prognosis in Europe.
Materials and Methods:
A decentralized biobank with fully annotated tissue samples is established for ETOP Mesoscape. Selection criteria for participating centers included sufficient number of cases, and documented ethical approval. Patient selection is based on availability of comprehensive clinical data with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue.
The ESTS database is a clinical database with pre-operative, intra-operative and post-operative data. A minimum set of data is captured, including demographic, histology, treatment, staging and follow up data.The characteristics between the two databases are compared using the Fisher’s exact test (for categorical variables) and Mann-Whitney test (for continuous variables), while Kaplan-Meier method (with log-rank test).
Results:
Up to 29 May 2019, the ETOP Mesoscape included information on 497 patients from 10 centers, diagnosed between 1999-2018. In the ESTS database, as of April 2019, 2269 patients are included, diagnosed between 1989-2019.
Patients in both databases are primarily men (84% in the ETOP, 71% in the ESTS), of 0/1 ECOG Performance status (46/46% and 59/29% in ETOP and ESTS respectively), with known previous exposure to asbestos (75% and 93%) and median ages 64 and 67 years old.
Significant differences are detected between the two data sources with respect to gender, exposure to asbestos and age (p-value <0.001).
The primary histology of patients is epithelioid (72% in ETOP and 70% in ESTS), followed by biphasic (22%; 17%) and sarcomatoid (6%; 9%) (not significantly different between the two databases).
Clinical staging is available for 77% of the patients in ETOP, but only for the 28% in the ESTS database. The stage distribution (I/II/III/IV) is 14/29/42/15% in the ETOP and 23/21/41/16% in the ESTS (significantly difference p<0.001).
Among the biomarkers common in both data sources, Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97% in both cases; WT1: 89% and 87% in the ETOP and ESTS database respectively).
For the ETOP cases 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive.
Palliative treatment has been administered in 41% of the ETOP cases. Among them, 84% received palliative chemotherapy (with the vast majority 92%, using multiple agents). Palliative surgery was undertaken in 32% (62 of 194 patients with available information) and palliative radiotherapy for 13% of the patients.
Complete resection has been performed in 59% of the ETOP Mesoscape patients. This was combined with induction chemotherapy (81%), while adjuvant chemotherapy and radiotherapy was administered in 4% and 37% respectively.
The surgical approach adopted for the ESTS patients was either video-assisted thoracoscopic surgery (VATS) (59%) or thoracotomy (41%) based on a subset of 887 patients with available information. Post-operation treatment information is available for 620 ESTS patients. Among them, 71% received chemotherapy, 54% underwent surgery and 15% radiotherapy.
Conclusion:
We present the combined results from the ETOP Mesoscape and the ESTS database, one of the largest databases. These two series allow us to report on mesothelioma epidemiology and treatment.
Up to now, the comparison of the baseline characteristics of the patients of the two data sources revealed some statistically significant differences with respect to gender, age, exposure to asbestos and clinical stage.
As tissue from all ETOP Mesoscape patients is preserved locally and is available for detailed molecular investigations, Mesoscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome, besides providing an overview of the molecular landscape.
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MA01 - Oligometastatic Disease (ID 114)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Oligometastatic NSCLC
- Presentations: 1
- Now Available
- Moderators:Anne Marie Clasina Dingemans, Matthias Guckenberger
- Coordinates: 9/08/2019, 10:30 - 12:00, Copenhagen (1980)
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MA01.06 - Prognostic Factors of Oligometastatic Non-Small Cell Lung Cancer Following Radical Therapy: A Multicenter-Analysis (Now Available) (ID 3063)
10:30 - 12:00 | Presenting Author(s): Isabelle Opitz
- Abstract
- Presentation
Background
Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from radical therapy. We aimed to identify factors related to better prognosis, in a multicenter analysis of patients who underwent surgery of primary tumours, in combination with radical treatment of metastatic sites, and chemo- or chemoradiation.
Method
We retrospectively reviewed the records of oligometastatic patients who all underwent anatomical resection of primary tumor, treated at 4 centers, (August 2001-November 2018). Oligometastasis was defined as ≤5 synchronous metastases in ≤2 organs. Radical metastatic treatment was surgery (n=48), radiotherapy (n=36) or a combination (n=41). Univariate analysis and multivariate Cox proportional hazards model were used for identification of prognostic factors on overall survival (OS) and progression-free survival (PFS). Survival was estimated by Kaplan-Meier analysis. P-value < 0.05 was considered significant.
Result
We treated 125 patients; 72 (58%) were male, aged 60±9.8 years, with 88 (70%) adenocarcinoma, and following pathological (pN) stage: pNx: 1 (1%), pN0: 57 (46%), pN1: 23 (18%), pN2: 44 (35%). Brain metastasis was most common (n=76; 61%) followed by adrenal (n=13; 11%) and bone (n=12; 10%). Systemic therapy was administered in 102 (82%). Median follow-up was 60 months (95%, CI: 41-86).
One-, 2-, 3-, and 5-years OS was 80%, 58%, 49% and 36% respectively. Several patient-related and treatment-related factors showed a correlation with OS at univariate analysis. Multivariate analysis showed that patients ≤60 years (HR 0.47, 95% CI:0.28-0.78, p=0.004), and/or pN0, compared to pN1,2 (HR 0.38, 95% CI: 0.22-0.66, p=0.001), had a significant survival benefit (Figure 1A). Bone metastasis were associated with worse prognosis (HR 2.122, 95% CI: 1.00-4.48, p=0.05).
Twenty-eight patients were ≤60 years with pN0, and had 1- and 5-year survival of 100 and 83%.
PFS at 1-, 2-, 3- and 5-years was 41%, 29%, 25% and 23% respectively. In the multivariate analysis, absence of mediastinal lymphnode involvement (HR: 0.483, 95% CI: 0.305-0.764, p=0.002) and surgical treatment of metastasis (HR: 0.553, 95% CI: 0.347-0.880, p=0.013) remained independently associated with better outcome (Figure 1B). The administration of treatments after first progression was strongly associated with better prognosis (HR: 0.252, 95% CI: 0.076-0.834, p=0.013).
Conclusion
Our experience demonstrates, in a multicenter setting, that radical treatment of selected oligometastatic NSCLC results in excellent 5-year survival. Nodal status correlates with both OS and PFS. Surgical metastasectomy appears to improve PFS, but multimodality treatment, especially in case of recurrence, remains mandatory.
These data might contribute to develop future combined strategies in the era of immunotherapy.
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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.03 - Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma (Now Available) (ID 2349)
15:45 - 17:15 | Author(s): Isabelle Opitz
- Abstract
- Presentation
Background
Loss of the tumor suppressor NF2 is frequent in malignant pleural mesothelioma (MPM). NF2 suppresses tumorigenesis in part by inhibiting Cullin4 ubiquitin ligase (CUL4) complex. Here we aimed to evaluate an importance of CUL4 in MPM.
Method
We evaluated the expression of CUL4A and CUL4B in tissue microarrays using immunohistochemistry. We tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation, in 13 cell lines and 3 primary cells in 2D and 3D culture. Four groups of SCID mice haboring intraperitoneal (ip.) pevonedistat sensitive (MSTO211H) or resistant (ACC-Meso1) cell lines were treated with pevonedistat (50 mg/kg; ip.) on a 5day on/5day off schedule for 3 cycles. Treatment efficacy was assessed by means of overall survival.
Result
CUL4B expression was associated with clinical outcomes (figure 1). Five MPM cell lines (38%) were highly sensitive to pevonedistat (IC50<500 nM). This remained true in 3D spheroid culture. The treatment induced S/G2 cell cycle arrest and accumulation of cells undergoing DNA re-replication (containing >4N DNA content) known to be mediated by p21 and CDT1 accumulation. Indeed the accumulation of p21 and CDT1 was more pronounced in pevonedistat sensitive cell lines after the treatment. Two of primary cells (67%) were sensitive to pevonedistat and also showed higher CDT1 accumulation following the treatment compared to the resistant cells. In vivo, pevonedistat treatment significantly prolonged survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth (phosphorylated histoneH3 positive) in pevonedistat sensitive tumor but increased apoptosis (cleaved–caspase3 positive) in pevonedistat resistant tumor.
Conclusion
High CUL4B expression may play a role in MPM progression. Inhibition of cullins by pevonedistat induced growth arrest and DNA re-replication strongly in a subset of MPM. The major mechanism seems to be mediated by p21 and CDT1 accumulation in vitro. Investigation of mechanisms in vivo is ongoing.
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P1.06 - Mesothelioma (ID 169)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.06-15 - Safety of Irradiation Combined with Intracavitary Cisplatin-Fibrin After Lung-Sparing Surgery in a Rat Model of Mesothelioma (ID 2372)
09:45 - 18:00 | Presenting Author(s): Isabelle Opitz
- Abstract
Background
To investigate feasibility and toxicity of new localized therapeutic treatment combinations for malignant pleural mesothelioma (MPM), we performed lung-sparing surgery followed by cisplatin-fibrin application and hemithoracic irradiation in an orthotopic immunocompetent rat model of MPM.
Method
Male F344 rats (n=9) were implanted sub-pleurally (parietal pleura) with 1 million rat mesothelioma cells (IL45-luciferase). Formed tumor nodules confirmed by IVIS bioluminescence imaging (BLI) were resected on day 9 after implantation. Following resection, animals were treated with local-intracavitary cisplatin-fibrin or placebo (NaCl-fibrin). Three days later, CT guided local irradiation of the former tumor region, resembling IMRT in human patients, was performed. Irradiation was given in a single high dose application using the image-guided stereotactic small animal irradiation X-RAD SmART (small animal radiotherapy) and image guided biological irradiator PXi (precision X-Ray) with precise localization.
Treatment schemes after tumor resection were as followed:
i) Intracavitary cisplatin-fibrin application (n=2)
ii) Irradiation with 10 Gy (n=2)
iii) Irradiation with 20 Gy (n=1)
iv) Intracavitary cisplatin-fibrin plus 10 Gy radiotherapy (n=2)
v) Intracavitary cisplatin-fibrin plus 20 Gy radiotherapy (n=2)
Wellbeing of the animals was monitored daily until the predefined termination criteria were reached. Particular attention was given to possible irradiation toxicity related pulmonary side effects and weight loss.
Result
We successfully treated 1-2 animals per group according to the methods above. The irradiation was performed after visualization of the tumor with BLI- and CT-imaging to ensure an individual treatment plan. None of the animals, whether with radiotherapy alone or in combination with cisplatin-fibrin application, showed any signs of pulmonary side effects. In addition, none had reduced pulmonary functions, measured by increased breathing or the appearance of blue or white colored ear/extremities/eyes assuming desaturation. Furthermore, neither significant body weight loss of ≥ 15%, deterioration of body conditioning score nor of the activity score were observed in the immediate post-interventional phase. In all animals, termination endpoint was reached because of tumor relapse.
Conclusion
In this pilot study, we have shown that irradiation alone and in combination with local intracavitary cisplatin-fibrin application in rats is safe and feasible up to a dosage of 20 Gy. The efficacy of the various treatment schemes and a possible radio-sensitizing effect by intracavitary cisplatin is currently being evaluated in the same animal model.
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P1.06-18 - MicroRNA Expression Is Linked to Response of Malignant Pleural Mesothelioma to Cisplatin-Pemetrexed Chemotherapy (ID 2367)
09:45 - 18:00 | Author(s): Isabelle Opitz
- Abstract
Background
Treatment of malignant pleural mesothelioma is difficult due to a high intrinsic drug resistance of these tumors. Currently, platinum-based chemotherapy represents the backbone of MPM treatment. However, only approximately 40% of patients respond to this therapy, and true predictors for response have yet to be identified. Towards this end, we here investigate the expression of microRNAs in responders and non-responders to chemotherapy.
Method
FFPE tumour samples were available from 32 MPM patients, who showed either partial response (PR, N=21) or progressive disease (PD, N=11) following 3-4 cycles of cisplatin-pemetrexed chemotherapy. RT-qPCR based microRNA profiling was performed on chemo-naïve tissue of 5 PD and 5 PR patients using TaqMan Low Density Arrays (TLDAs, Thermo Fisher), which cover the expression of 754 microRNAs. Candidate microRNAs with differential expression (P≤0.05 Mann-Whitney Test) were then measured in the remaining samples using microRNA-specific RT-qPCR. Expression of these microRNAs was also assessed in post-chemotherapy specimens (obtained during extrapleural pneumonectomy) and compared to that in chemo-naïve samples. In addition, for two candidates, preliminary in vitro experiments investigating the effect of microRNA overexpression (transfection with microRNA mimics) on cell growth were performed.
Result
TLDA-based profiling identified 35 microRNA with differential expression between patients with PD and PR following cisplatin-pemetrexed chemotherapy. The majority of these microRNAs showed higher expression in patients who showed no reponse to therapy. In an initial step, 8 candidates identified from the profiling (miR-145, miR-193a-3p, miR-30a-3p, miR-24, miR-380-5p, miR-494, miR-625-3p, miR-221-3p) were further evaluated in additional 16 PR and 6 PD samples. This confirmed a trend towards differential expression for miR-145 (p=0.08). Interestingly, when comparing expression pre- and post-chemotherapy, levels of miR-145 significantly decreased in patients with PD, while they remained stable in PR. Lack of validation of other microRNAs could be the result of the low number of cases with PD in this preliminary validation set, and additional samples will included. For miR-221-3p and miR-380-5p, preliminary analysis in vitro showed that overexpression in established MPM cell lines results in an increased sensitivity towards cisplatin.
Conclusion
Taken together, our data show that several microRNAs show trends towards differential expression between responders and non-responders to chemotherapy. Overall, higher expression appears to be linked to PD under cisplatin-pemetrexed, however further in-depth investigations are required. Furthermore, preliminary in vitro data suggest that altering expression of specific microRNAs has the potential to increase sensitivity of MPM to chemotherapy.
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P1.13 - Staging (ID 181)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Staging
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.13-02 - Should Aortic Lymph Nodes be Considered Hilar Lymph Nodes in Patients with Completely Resected NSCLC? A Multicenter Study (ID 380)
09:45 - 18:00 | Author(s): Isabelle Opitz
- Abstract
Background
It has been suggested that aortic lymph nodes (stations #5 and #6, aortic-LNs) may have a similar prognostic significance as hilar-LNs (stations #10 and #11). Therefore we compared survival of lung cancer patients with aortic-LNs metastasis to those with N1 disease at the hilar-LNs.
Method
Between 2008 and 2017, 865 patients with left upper lobe (LUL) lung cancer underwent complete resection in three centers. Overall survival was assessed retrospectively and compared in four groups according to pN status: N0 (n = 429, 49.6%), N1 (n = 259, 29.9%), N25,6+ (only metastasized to stations 5 and/or 6 with/without N1 disease, n = 126, 14.6%), and N27+ (only metastasized to station 7 with/without N1 disease, n = 51, 5.9%). pN1 was divided two subgroups according to location; N1peripheral (n = 124), N1hilar (n = 135).
Result
Five-year survival rate was significantly better for N25,6+ than N27+ patients (32.7% vs 22.1%) (p=0.05) (Figure 1). Skip metastasis for aortic-LNs (n = 39) was a factor of better prognosis as compared to non-skip metastasis (n = 87) (42.5% vs. 26.3%) (p=0.03) although five year survival rates were similar for N2single (5+ or 6+) (n=96) and N2multiple (both 5+ and 6+) (n=30) patients (32.8% vs 32.3%, p=0.8). There was no statistically significant difference between the N25,6+ and N1hilar (p = 0.4), although N1peripheral had a significantly better survival than N25,6+ (p < 0.0001) (Figure 2).
In multivariate analysis, age (p<0.0001), N2 versus N0/1 (p<0.0001), N1hilar versus N1peripheral (p=0.006), N25,6+ versus N1peripheral (p=0.0001), N27+ vs N25,6+ (p=0.05), and N2non-skip 5 and/or 6+ vs N2skip 5 and/or 6+ (p=0.01) were significant independent negative prognostic factors (Table 1).
Conclusion
The prognostic significance of aortic-LNs is similar to hilar-LNs even if LUL tumors with hilar-LNs metastasis is associated with statistically not significant prognosis than aortic-LNs metastasis. In order to generalize this result, it needs to be validated in a bigger database.
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P1.15 - Thymoma/Other Thoracic Malignancies (ID 184)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.15-04 - Multimodality Treatment of Chest Wall Tumors: Induction Therapy Reduces Recurrence Rates (Now Available) (ID 1937)
09:45 - 18:00 | Author(s): Isabelle Opitz
- Abstract
Background
Chest wall resections are associated with significant morbidity. The present analysis reports a the outcome of a large series of chest wall tumor resections.
Method
Patients with primary and secondary chest wall malignancies undergoing resection and reconstruction were retrieved from our institutional database. Clinical and pathological parameter were correlated with long-term outcome
Result
The study includes 169 patients, who underwent chest wall resection and reconstruction for primary or secondary chest wall tumors between 1999 and 2018. The median age was 60 (range 10-87) years. 48 (28%) were primary tumors, whereas 121 (72%) were secondary tumors. Primary malignancies were predominantly sarcomas 39 (23%). For secondary malignancies, the largest subgroups were non-small cell lung cancer 65 (38%), breast cancer 24 (14%), and mesothelioma 20 (12%). Resection margins were free in 103 (61%), R1 in 60 (36%), R2 in 4 (2%). Perioperative complications occurred in 67 patients (40%). The 30-days mortality was 4% (n=7). 46 patients (27%) received preoperative chemotherapy, 52 patients (31%) preoperative radiotherapy. The median follow-up time was 21 (range 0-218) months. The median OS was 44 months (95% confidence interval (CI): 33-55 months[SI1] ). At the time of last follow-up 71% (n=120) of the patients were recurrent. Local recurrence rate was significantly lower in patients receiving preoperative therapy (16%) compared to patients receiving postoperative therapy (42%) or pre- and postoperative therapy (44%) (p=0.01). In patients receiving a preoperative chemotherapy, a R0 resection was significantly more often achieved (77%) than in patients receiving no preoperative chemotherapy (56%) (p=0.02). Preoperative radiotherapy had no influence on R0 resection (p=0.2). Defect size and resection status had no influence on OS (p=0.4 and p=0.8, respectively).
Conclusion
Surgical therapy is the cornerstone for the treatment of primary and secondary chest wall malignancies and can be performed with reasonable morbidity. Induction chemo- and/or radiotherapy improves the probability of free resection margin and has positive influence in survival.
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WS02 - Mesothelioma Workshop (Ticketed Session) (ID 102)
- Event: WCLC 2019
- Type: Workshop
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2019, 08:00 - 11:30, Interlaken (1988)
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WS02.01 - Update on MPM (ID 3846)
08:00 - 11:30 | Presenting Author(s): Isabelle Opitz
- Abstract
Abstract not provided
