D.A. Waller

Tracking genomic cancer evolution for precision medicine: the lung TRACERx study.

TRACERx, a prospective study of patients with primary non-small cell lung cancer, aims to map the genomic landscape of lung cancer by tracking clonal heterogeneity and tumour evolution from diagnosis to relapse.

Angiogenesis is an independent prognostic factor in malignant mesothelioma.

Angiogenesis is essential for tumour growth beyond 1 to 2 mm in diameter. The clinical relevance of angiogenesis, as assessed by microvessel density (MVD), is unclear in malignant mesothelioma (MM). Immunohistochemistry was performed on 104 archival, paraffin-embedded, surgically resected MM samples with an anti-CD34 monoclonal antibody, using the Streptavidin–biotin complex immunoperoxidase technique. 93 cases were suitable for microvessel quantification. MVD was obtained from 3 intratumoural hotspots, using a Chalkley eyepiece graticule at × 250 power. MVD was correlated with survival by Kaplan–Meier and log-rank analysis. A stepwise, multivariate Cox model was used to compare MVD with known prognostic factors and the EORTC and CALGB prognostic scoring systems. Overall median survival from the date of diagnosis was 5.0 months. Increasing MVD was a poor prognostic factor in univariate analysis (P = 0.02). Independent indicators of poor prognosis in multivariate analysis were non-epithelial cell type (P = 0.002), performance status > 0 (P = 0.003) and increasing MVD (P = 0.01). In multivariate Cox analysis, MVD contributed independently to the EORTC (P = 0.006), but not to the CALGB (P = 0.1), prognostic groups. Angiogenesis, as assessed by MVD, is a poor prognostic factor in MM, independent of other clinicopathological variables and the EORTC prognostic scoring system. Further work is required to assess the prognostic importance of angiogenic regulatory factors in this disease.

Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura.

Matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and -9), play a significant role in tumour invasion and angiogenesis. The expression and activities of MMPs have not been characterised in malignant mesothelioma (MM) tumour samples. In a prospective study, gelatinase activity was evaluated in homogenised supernatants of snap frozen MM (n=35), inflamed pleura (IP, n=12) and uninflammed pleura (UP, n=14) tissue specimens by semiquantitative gelatin zymography. Matrix metalloproteinases were correlated with clinicopathological factors and with survival using Kaplan–Meier and Cox proportional hazard models. In MM, pro- and active MMP-2 levels were significantly greater than for MMP-9 (P=0.006, P<0.001). Active MMP-2 was significantly greater in MM than in UP (P=0.04). MMP-2 activity was equivalent between IP and MM, but both pro- and active MMP-9 activities were greater in IP (P=0.02, P=0.009). While there were trends towards poor survival with increasing total and pro-MMP-2 activity (P=0.08) in univariate analysis, they were both independent poor prognostic factors in multivariate analysis in conjunction with weight loss (pro-MMP-2 P=0.03, total MMP-2 P=0.04). Total and pro-MMP-2 also contributed to the Cancer and Leukemia Group B prognostic groups. MMP-9 activities were not prognostic. Matrix metalloproteinases, and in particular MMP-2, the most abundant gelatinase, may play an important role in MM tumour growth and metastasis. Agents that reduce MMP synthesis and/or activity may have a role to play in the management of MM.

Towards a biological staging model for operable non-small cell lung cancer

Non-small cell lung cancer is the most common cause of cancer-related death in North America and Europe. Despite improvements in the diagnosis and treatment of the disease the prognosis remains poor, the overall 5-year survival being 4-14%. An increased understanding of the molecular biology of the disease may identify novel targets for drug development. We evaluated epidermal growth factor receptor (EGFR), HER-2/neu, matrix metalloproteinase (MMP)-2, MMP-9, p53 and bcl-2 expression and microvessel density (MVD) in patients who underwent surgery with curative intent in our department between 1991 and 1996. Co-expression of EGFR/MMP-9, MVD and bcl-2 were found to be independent prognostic variables, which allowed prediction of patient outcome independent of surgical stage. Other prognostic factors identified in our series were gender, surgical stage, platelet count, extent of necrosis, the hypoxia marker carbonic anhydrase-9 and beta-catenin. In collaboration with groups in Oxford and Greece, we were also able to establish the angiogenic growth factors vascular endothelial growth factor and platelet-derived endothelial growth factor as prognostic variables. The inter-relationships between these factors are currently being examined in an expanded patient series. Through this work we hope to be able to construct an integrated biological prognostic model which can be tested in prospective studies. This work has identified several potential targets for novel therapeutic agents currently in development.

The effects of an intentional transition from extrapleural pneumonectomy to extended pleurectomy/decortication.

OBJECTIVESnFor many years, extrapleural pneumonectomy (EPP) was the operation of choice for the radical management of pleural mesothelioma in the UK. However, doubts surrounding the efficacy of EPP, and the change in demographics of the affected population, have prompted a transition in our practice towards extended pleurectomy/decortication (EPD). The aim of this study was to determine the effects an intentional transition from EPP to EPD has had on patient outcome.nnnMETHODSnData from 362 patients undergoing radical surgery (229 EPD, 133 EPP) during 1999-2014 were included. Demographics and outcome were compared between the two groups; EPP versus EPD.nnnRESULTSnThe median age of patients undergoing EPD was significantly higher than those undergoing EPP [57 years (range 14-70 years) vs 65 years (range 42-81 years), P < 0.001]. There was a significantly higher proportion of patients with performance status ≥1 in the EPD group (46.3 vs 35.4%, P = 0.047). There was no difference in the median length of hospital stay between the two groups [14 days (range 1-133 days) vs 13 days (range 0-93 days), P = 0.409]. There was also no difference between the groups in terms of in-hospital mortality (EPP 5.3% and EPD 6.6%, P = 0.389), 30-day mortality [EPP 8 (6.0%) and EPD 8 (3.5%), P = 0.294] or 90-day mortality [EPP 18 (13.5%) and EPD 21 (9.2%), P = 0.220]. There was a significantly higher early reoperation rate in the EPP group (15.0 vs 6.2%, P = 0.008) but a significantly higher late reoperation rate in the EPD group (0.8 vs 5.3%, P = 0.037). There was no significant difference in overall survival or disease-free interval between the two groups (P = 0.899 and P = 0.399, respectively). However, overall survival was significantly greater in patients over the age of 65 undergoing EPD (12.5 vs 4.7 months, P = 0.001).nnnCONCLUSIONnThe transition from EPP to EPD in our standard practice has enabled us to operate on more elderly, frail patients with no significant increase in use of hospital resources, and without detriment to overall survival.

Postoperative pain detracts from early health status improvement seen after video-assisted thoracoscopic lung volume reduction surgery.

OBJECTIVESnTo assess the impact of lung volume reduction surgery (LVRS) on postoperative pain.nnnMETHODSnFifty-two patients, 34 male/18 female, median age 59 (46-70) years, underwent unilateral video-assisted thoracoscopic (VAT) LVRS. FEV(1), TLC, RV and RV/TLC ratio were assessed preoperatively and at 3, 6, 12 and 24 months post surgery. At the same time interval health status was assessed by Euroquol and SF 36 questionnaires.nnnRESULTSnSignificant improvements in health status, as assessed by SF 36, persisted from 3 months to 1 year. However, in the pain domain there was a worsening of the mean score from 74 preoperatively to 64 at 3 months, 68 at 6 months, 73 at 12 months and 65 at 24 months. The improvements in Euroquol score were not statistically significant. However, they became significant for at least 2 years postoperatively, when those patients who had a worsening pain score postoperatively were excluded. While the percentage of patients with a worsening of pain scores measured with SF 36 remained between 40 and 45% even 2 years after LVRS, when using Euroquol this percentage did decrease from 30% at 3 months to 14% at 2 years. There was no significant correlation between the change of scores and length of operation, hospital stay or air leak. It was also not statistically significant whether these patients had an extra procedure (redo thoracotomy or insertion of extra drain postoperatively). There were some significant correlations between changes in hyperinflation and changes in pain scores but this was not consistent for Euroquol and SF 36.nnnCONCLUSIONnPostoperative pain detracts from global improvement in health status after LVRS even after unilateral VATS. There may be an influence of alterations in chest mechanics after surgery on the development of pain.

The management of the diaphragm during radical surgery for malignant pleural mesothelioma

OBJECTIVESnMacroscopic complete resection with lung preservation is the objective of radical management of pleural mesothelioma (MPM). Total removal of visceral and parietal pleura (pleurectomy/decortication) almost invariably proceeds to an extended pleurectomy/decortication (EPD) to ensure macroscopic complete resection. We suspected this may not always be necessary.nnnMETHODSnWe reviewed 314 patients, 86.0% male, median age 62 years (range 14-81 years) undergoing radical surgery for MPM from 1999 to 2014, by either EPD or extrapleural pneumonectomy. The extent of diaphragmatic muscle involvement was recorded from postoperative pathology. Patients were divided into three groups: no involvement, non-transmural, transmural diaphragmatic invasion.nnnRESULTSnA total of 213 (68%) patients underwent EPD, 237 (75.5%) had epithelioid disease and 57.6% were node positive. There was no difference between the three groups in terms of age, cell type, laterality, neoadjuvant chemotherapy and operation. There was a higher degree of diaphragm involvement in females (P = 0.01) and in patients with positive lymph nodes (P = 0.01). No evidence of diaphragmatic involvement was found following pathological assessment of the resection specimen in 119 patients (37.9%). The incidence of abdominal disease progression was 23.9%. There was no correlation with degree of diaphragmatic invasion (ρ = 0.01 P = 0.88). Overall survival of those with abdominal progression was similar to those with progression elsewhere: 14.5 vs 13.0 months (P = 0.79), and with those with no progression (16.7 months, P = 0.189). There was no difference in survival when stratified by diaphragmatic involvement (P = 0.44).nnnCONCLUSIONSnIn our cohort, there was no evidence of diaphragmatic invasion in over 30% of patients, and we have also failed to find evidence that peritoneal disease progression affects overall survival following radical management. It may therefore theoretically be unnecessary to resect the diaphragm in all cases, and a pleurectomy-decortication could suffice. However, there is an unknown risk of R2 resection which would prejudice survival, and as such we would advocate resecting the diaphragm in all cases to avoid an R2 resection.

Patient experience of lung volume reduction procedures for emphysema: a qualitative service improvement project

The aim of this service improvement project was to gain understanding of the patient experience of lung volume reduction surgery (LVRS) and endobronchial valve (EBV) placement, from referral through to post-discharge care. Focus group interviews were carried out in two tertiary centres in London and Leicester, UK. Sixteen patients who had undergone lung volume reduction surgery (LVRS), endobronchial valve (EBV) placement, or both, were recruited. Prior to participation in each focus group, participants completed a questionnaire to guide and focus discussion. Thematic analysis identified common themes to the participant experience of receiving lung volume reduction interventions. Themes included patient focus on declining health and the need to “fight” for a referral; consequences of having procedures and potential unexpected complications; and vulnerability post discharge and limited continuity of care. Participants were clear that the benefits of having had either LVRS or EBV procedures outweighed any difficulties experienced. Participants were keen to have further similar interventions if appropriate. These data confirm the need to develop more systematic lung volume reduction pathways, provide appropriate information, and ensure that post-discharge care is optimal. Patients feel they have to fight to get a lung volume reduction procedure; a more systematic approach is needed http://ow.ly/82Oy30cLORk

How does the timing of chemotherapy affect outcome following radical surgery for malignant pleural mesothelioma

OBJECTIVESnThere is little evidence regarding the use of chemotherapy as part of multimodality treatment of malignant pleural mesothelioma (MPM). We aimed to determine whether, in those patients fit for chemotherapy, a delay in this treatment affected survival.nnnMATERIALS AND METHODSnWe analysed postoperative variables of 229 patients undergoing either extrapleural pneumonectomy (EPP) (81 patients) or extended pleurectomy-decortication (EPD) (197 patients) for MPM at a single centre. There was no standard protocol for additional chemotherapy and varied with referral centre. Outcome was compared between 4 chemotherapy strategies: true adjuvant therapy, neo-adjuvant therapy, therapy reserved until evidence of disease progression in those otherwise fit in the post-operative setting, and those unfit for chemotherapy.nnnRESULTSnThere was no effect of the timing of chemotherapy on overall or progression free survival in patients fit enough for treatment (p=0.39 and p=0.33 respectively). However delaying chemotherapy until evidence of disease progression in patients with non-epithelioid disease had a detrimental effect on overall survival (OS), and on progression free survival (PFS) in lymph node positive patients (15.6 vs. 8.2 months p=0.001, and 14.9 vs. 6.0 months p=0.016). Further analysis of 169 patients receiving platinum/pemetrexed as first line treatment, showed similar results; there was no effect of the timing of chemotherapy on OS or PFS (p=0.80 and p=0.53 respectively) and an improved OS in patients with non-epithelioid disease, and improved PFS in those with lymph node metastases, if chemotherapy was given in the immediate adjuvant setting (p=0.001 and 0.038) when therapy was not delayed until disease progression.nnnCONCLUSIONnOur results suggest that the timing of additional chemotherapy may be important in those with a poorer prognosis on the basis of cell type and nodal stage. In these patients additional postoperative chemotherapy should not be delayed.

P63 Salvage lung volume reduction surgery after failure or complications of endobronchial treatment with one-way valves for severe emphysema

Introduction Endobronchial lung volume reduction with one-way valves (ELVR), in combination with staged unilateral VATS lung volume reduction surgery (LVRS), multiplicates the options of treatment for emphysema. No experience has yet been reported in literature of the use of LVRS after failure of ELVR. We aimed therefore to review our current series. Methods 7 consecutive patients (3 male, age 68, 59–76) had successfull Chartis assessment and ELVR, and subsequently underwent salvage LVRS following failure or complications of primary procedure. All patients were suitable candidates for either approach according to our criteria (average RV/TLC 67 range 56–77, FEV1 32% range 25–38, DLCO 32%, range 24–55), with 4 patients classifying as moderate to high risk for LVRS and the rest as moderate or low. They were offered both options and opted for ELVR on the assumption of reduced risks and shorter hospitalisation. Valves were not removed prior to LVRS, except in one case who was also the first chronological patient in our series. Results Delayed collateral ventilation with no lobar collapse and no functional improvement at any time was observed in 3 patients. The remainder had lobar collapse with initial improvement: of these, 1 developed ipsilateral pneumothorax with persisting air leak leading to LVRS, 2 developed contralateral upper lobe compensatory hyperinflation (1R, 1L) and 1 ipsilateral lower lobe compensatory hyperinflation. No significant morbidity or 30-day/in-hospital mortality. Median lenght of stay after LVRS was 11 days (4–34), slightly longer (19 days, 4–34) for patients who were operated for contralateral hyperinflation or whose EBV was removed prior to VATS (no valve in situ on the operated side). Duration of drainage was also longer in these patients compared to the whole group, 18 (6–30) vs. 8 (5–30) days. Average EQ-5D score was 49.7 (18.9–71) six months after LVRS, vs. 42 (18.9–81.4) preoperatively, with only one patient reporting further deterioration. Conclusion ELVR can be considered as a trial of LVR not precluding salvage LVRS. Removal of endobronchial valves prior to surgery seems unnecessary and may actually be protective against excessive postoperative air leak. Occurrence of compensatory hyperinflation may suggest that single-stage bilateral ELVR could also be considered. Abstract P63 Figure 1