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D. Waller
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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 2
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.04 - BRCA1/OCT1/MAD2L1 Axis Regulates a Bifurcating Apoptotic Pathway Induced by Vinorelbine in Mesothelioma (ID 2675)
18:30 - 20:00 | Author(s): D. Waller
- Abstract
Background:
There is currently no licenced second line therapy for mesothelioma patients upon relapse after pemetrexed cisplatin. The vinca alkaloid spindle poison, vinorelbine, exhibits useful activity in mesothelioma, warranting evaluation in a new UK randomised clinical trial, VIM. However the molecular determinants of efficacy are unclear. We have reported that BRCA1 is an essential regulator of vinorelbine-induced apoptosis, and loss of detectable BRCA1 occurs in 39% of mesotheliomas. However the mechanisms governing BRCA1 dependent lethality has been lacking. We have utilized a functional genetic approach to uncover critical genes required for vinorelbine efficacy.
Methods:
Apoptosis was analysed by PARP cleavage and caspase 3/7 activity assay. Focused RNAi targeting Caspase 8, BAX and BAK was conducted to delineate critical death activators. Mouse embryonic fibroblasts (MEFs) wild type (WT) or double knockout (DKO) for BAX/BAK cells were also used. MAD2L1 expression was studied by western blot and qRT-PCR. Tumour explants were derived from 10 MPM patients.
Results:
Mitochondrial and caspase-8 dependent apoptosis pathways were shown by triple knockdown of BAX, BAK and Caspase 8 to be required to rescue completely from vinorelbine-induced apoptosis. Loss of BRCA1 recapitulated this apoptosis block and was associated with loss of Oct1 dependent MAD2L1 associated transcriptional upregulation. RNAi mediated silencing of MAD2L12 phenocopied BRCA1 loss. In cells selected for resistance to vinorelbine, MAD2L1 failed to upregulate, secondly to constitutive downregulation of BRCA1. Using mesothelioma explants derived at extrapleural decortication, exhibited either marked resistance or sensitivity to vinorelbine induced apoptosis; correlation with regulation of BRCA1/Oct1/MAD2L is ongoing and will be presented.
Conclusion:
BRCA1 functions through an Oct1/MAD2L1-dependent activation of both mitochondria dependent and independent pathways to induce apoptosis. This implicates a requirement for a functional spindle assembly checkpoint, with implications for expanding the biomarker repertoire governing vinorelbine efficacy in mesothelioma
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MINI38.09 - The Prognostic Significance of Nodal Metastatic Burden in Survival following Radical Surgery for Malignant Pleural Mesothelioma (ID 2776)
18:30 - 20:00 | Author(s): D. Waller
- Abstract
- Presentation
Background:
The staging of malignant pleural mesothelioma (MPM) remains undetermined. But it is still important for informing prognosis and selection for high risk surgery. The specific lymphatic drainage of the pleura implies that nodal staging based on that used in lung cancer may not be accurate for MPM. We have evaluated an alternative nodal staging strategy.
Methods:
We retrospectively analysed the pathology and outcome of 282 patients who survived for over 30 days following radical surgery for MPM: 190 extended pleurectomy decortication(EPD), 92 extrapleural pneumonectomy(EPP). All patients underwent intraoperative systematic nodal dissection. Nodal stations were assigned to all nodes, and patients were staged according to the current UICC system. The status and number of nodes in each station were recorded. Survival was calculated for the standard nodal stages (N0, N1, N2). We derived nodal groups Na, Nb, Nc based on the percentage of sampled nodes containing tumour, irrespective of nodal station: Na = N0, Nb ≤ median %, Nc > median %.
Results:
The type of surgery did not influence median survival; EPD 12.3 vs. EPP 14.5 months, p=0.46. The median survival of the standard nodal stages were: N0(113 patients), 16.5 months; N1(13 patients), 13.0 months; N2(156 patients), 11.8 months. There was no significance difference in survival between N1 and N2, p=0.65 but there was between N0 and N1/N2, p=0.04. The median percentage of nodal metastases was 43%. There were significant differences in median survival between Na, Nb and Nc, p=0.03. There were significantly more positive N2 nodes in group Nc (98%), than in group Nb (86%) p=0.001.
Figure 1Nodal stage No of patients Median survival (months) N0 113 16.5 N1 13 13.0 N2 156 11.8 Na - no metastases 113 16.5 Nb - 86 13.5 Nc - > 43% metastases 83 9.9
Conclusion:
There appears to be greater accuracy in a nodal staging system based on the nodal burden of metastases rather than an anatomically based system. There may be less accuracy in nodal staging in lung sparing radical surgery for MPM due to less extensive nodal sampling.
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ORAL 26 - Clinical Trials 2 (ID 127)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A. Scherpereel, C. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 702+704+706
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ORAL26.02 - What Are the Risks and Benefits of Extended Pleurectomy Decortication for Mesothelioma? A Review of the Largest Institutional Series in the UK (ID 2925)
10:45 - 12:15 | Author(s): D. Waller
- Abstract
- Presentation
Background:
Uncertainty surrounds the long term benefits of extended pleurectomy decortication(EPD). In the absence of randomized controlled evidence enabling informed consent for such a major procedure with little prospect of cure is challenging. We have reviewed the largest series of EPD procedures in the UK to provide existing selected evidence for decision making and future research surrounding radical surgery for mesothelioma.
Methods:
We retrospectively analysed the case notes and pathological reports of 266 patients who underwent EPD over the last 15 years to determine length of hospital stay, complication rates and survival.
Results:
Overall survival was: 48.0% at 1 year, 10.3% at 3 years and 2.7% at 5 years. In the most favourable subgroup, those with epithelioid pN0 pathology, the 1, 3 and 5 year survivals were 64.9%, 17.5%, and 5.2% respectively. Overall median survival was 12.2 months, ranging from 23.1 months in those with epithelioid pN0 disease to 6.2 months in those with non-epithelioid, node positive tumours. Post-operative mortality was 3.8% at 30-days and 9% at 90 days. Median length of hospital length of stay was 13 (5-70) days. Re-operation was required in 20 patients (11.9%). A significant increase in postoperative hospital stay was associated with: postoperative atrial fibrillation(14 vs. 20 days p=0.037); persistent air leak(19 vs. 13 days p<0.001); postoperative empyema(40 vs.14 days p<0.001) and subsequent removal of the prosthetic neodiaphragm(21 vs. 14 days p=0.013). Postoperative 30-day mortality was significantly higher in those patients who developed pneumonia(15.8% vs. 3.2% p=0.048). Postoperative 90-day mortality was significantly increased in those who developed a pleural empyema(71.4 v. 8.6% p=0.001), similarly overall survival was reduced in this group(3.1 vs. 12.7 months p=0.072). Duration of intercostal drainage was significantly associated with the development of an empyema(p<0.001) and with the incidence of prosthetic dehiscence of the neodiaphragm(p=0.042). Revisional surgery to remove an infected prosthesis had no detrimental effect on 30 or 90-day mortality, or on overall survival Adjuvant chemotherapy significantly increased overall survival (18.1 vs. 8.2 months p<0.001), but 22.7% patients with neodiaphragm dehiscence, and 28% of those with empyema, did not receive this due to these complications.Complication Rate (%) Persistent air leak 31.0 Atrial Fibrillation 16.7 Pneumonia 8.7 Diaphragmatic patch dehiscence 8.7 Mechanical 22.9 % Infection 77.1 % Empyema 4.8 Wound infection 4.4 Thromboembolic 6.3 Chylothorax 3.6
Conclusion:
Extended pleurectomy decortication(EPD) can be performed in high volume centres with acceptable risk. In all but a selected subgroup it remains a palliative procedure. Thus, reducing postoperative air leak, which increases pleural sepsis and perioperative risk and decreases adjuvant chemotherapy, is paramount. The true role of EPD can only be answered by a prospective randomized comparison with non-surgical treatment.
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