Mast cell phenotype, TNFα expression and degranulation status in non-small cell lung cancer.

Mast cell infiltration of tumour islets represents a survival advantage in non-small cell lung cancer (NSCLC). The phenotype and activation status of these mast cells is unknown. We investigated the mast cell phenotype in terms of protease content (tryptase-only [MCT], tryptase + chymase [MCTC]) and tumour necrosis factor-alpha (TNFα) expression, and extent of degranulation, in NSCLC tumour stroma and islets. Surgically resected tumours from 24 patients with extended survival (ES; mean survival 86.5 months) were compared with 25 patients with poor survival (PS; mean survival 8.0 months) by immunohistochemistry. Both MCT and MCTC in tumour islets were higher in ES (20.0 and 5.6 cells/mm2 respectively) compared to PS patients (0.0 cells/mm2) (p < 0.0001). Both phenotypes expressed TNFα in the islets and stroma. In ES 44% of MCT and 37% of MCTC expressed TNFα in the tumour islets. MCT in the ES stroma were more degranulated than in those with PS (median degranulation index = 2.24 versus 1.73 respectively) (p = 0.0022), and ES islet mast cells (2.24 compared to 1.71, p < 0.0001). Since both MCT and MCTC infiltrating tumour islets in ES NSCLC patients express TNFα, the cytotoxic activity of this cytokine may confer improved survival in these patients. Manipulating mast cell microlocalisation and functional responses in NSCLC may offer a novel approach to the treatment of this disease.

Video assisted thoracoscopic thyroidectomy for retrosternal goitre.

INTRODUCTION: Thyroidectomy for retrosternal goitre is usually carried out through a cervical incision. Around 4-12% of patients, however, require an extracervical approach, usually by sternotomy. Anatomically, the thyroid extends deep behind the great vessels in the pretracheal fascia. A sternotomy is therefore not only a substantial incision but this anterior approach is also not ideal for exposure. We report the use of video assisted thoracoscopic surgery (VATS) instead of a sternotomy or thoracotomy in conjunction with a transverse cervical incision for these patients. METHODS: A retrospective descriptive study was carried out of seven patients with retrosternal goitre who underwent a VATS thyroidectomy. RESULTS: Twenty-one patients with retrosternal goitre were referred to our institution for surgical excision with the anticipation of requiring an extracervical incision. Of these, seven (median age: 68 years, range: 58-73 years) underwent a VATS thyroidectomy. The median operating time was 218 minutes (range: 120-240 minutes). The median diameter of the retrosternal goitre was 70 mm (range: 40-145 mm). Only one patient required conversion to a manubriotomy to deliver the bulky thyroid and one patient suffered a transient right recurrent laryngeal nerve palsy. The median postoperative pain scores for days 0 and 1 were 1 (range: 0-5) and 0 (range: 0-3) respectively. The median length of stay was 5 days (range: 3-7 days). CONCLUSIONS: The use of VATS in thyroidectomy for retrosternal goitre offers a minimally invasive approach resulting in less morbidity while affording excellent exposure.

The need for thoracic surgery in adult patients receiving extracorporeal membrane oxygenation: a 16-year experience.

OBJECTIVES: Patients on extracorporeal membrane oxygenation (ECMO) are at risk from thoracic complications such as bleeding or pneumothorax, which may subsequently necessitate thoracic surgical intervention. We aimed to: 1) analyse the indication and nature of thoracic surgical intervention in these patients and 2) analyse the effect of a change in the ECMO circuit from roller pump to centrifugal pump on transfusion requirements pre and post thoracotomy. METHODS: We retrospectively reviewed a prospectively collected database of 569 adults put on ECMO between 1995 and 2011. Patients undergoing thoracotomy were identified and outcomes were statistically analysed. RESULTS: Forty thoracotomies were performed in 18 patients [61% male, median age 31 (14-56) years, one bilateral procedure]. The indications for ECMO included: pneumonia 14/18 (78%), trauma 2/18 (11%) and other 2/18 (11%). Median duration on ECMO was 13 (1-257) days and the time to initial thoracotomy was 10 (1-183) days. The indications for thoracotomy were: excessive bleeding post chest drain insertion (11/19, 58%), uncontrolled air leak (9/19, 47%) and pleural effusion (4/19, 21%). The primary operations were 12/19 (63%) evacuation of haemothorax, 3/19 (16%) lung repair, 2/19 (11%) diagnostic lung biopsy and 2/19 (11%) other. Ten patients needed a further 21 thoracotomies (3 lobectomies); average 2 (1-5) per patient. In total, 30/40 (75%) thoracotomies were performed for bleeding complication. The change from roller to centrifugal pump trended towards a reduction in mean transfusion requirements in these patients following thoracotomy (11.5 versus 4 units, p=0.14). The in-hospital mortality was 7/18 (39%) patients. There were no statistically significant predictors of poor outcome. CONCLUSIONS: The need for thoracotomy whilst on ECMO is 3.2% in this large series. Intervention may be complicated, thus, either ECMO specialists should have thoracic training or thoracic surgeons should be on-site. Potential mortality is high and, although not statistically significant, a difference in transfusion requirements was observed following the change of circuit.

Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival.

There is a marked survival advantage for patients with nonsmall cell lung cancer (NSCLC) expressing high numbers of macrophages in their tumour islets. The primary aim of the present study was to determine the immunological phenotype of NSCLC-associated macrophages. CD68(+) macrophages expressing markers of a cytotoxic M1 phenotype or a noncytotoxic M2 phenotype were identified in the islets and stroma of surgically resected tumours from 20 patients with extended survival (median 92.7 months) and 20 with poor survival (median 7.7 months), using immunohistochemistry. The islet density of both M1 and M2 macrophages was markedly increased in extended compared with poor survival patients. In the extended survival group, M1 islet density was significantly increased compared with M2 density, 70% of islet macrophages were positive for M1 markers versus 38% for M2, and the islet:stromal ratio of M1 macrophages was markedly increased compared with M2. The 5-yr survival for patients with above and below median expression of M1 macrophages in the islets was >75 and <5%, respectively. Macrophages infiltrating the tumour islets in nonsmall cell lung cancer were predominantly of the M1 phenotype in patients with extended survival. The survival advantage conferred by islet macrophage infiltration may be related to their cytotoxic antitumour activity.

Surgical treatment of combined hepatic and pulmonary colorectal cancer metastases.

AIMS: Surgical resection of combined hepatic and pulmonary metastases remains controversial in light of limited supportive evidence. This study aimed to audit our initial experience with this aggressive surgical strategy. METHODS: Between 1997 and 2006 we assessed 19 patients with colorectal cancer metastases for combined liver and lung metastasectomy, of whom 16 patients underwent surgery. We retrospectively reviewed perioperative and survival data. RESULTS: Synchronous liver metastases were present in three out of 16 patients at time of diagnosis of the primary tumour, and one out of 16 patients had synchronous lung and liver metastases with the primary tumour. Of those 12 patients who developed metachronous metastases five patients developed liver metastases first, one patient developed pulmonary metastases first, and six patients developed synchronous liver and lung metastases. Thirty nine operations were performed on 16 patients. The median hospital stay was 5.5 (2-10) days for the pulmonary and 7 (1-23) days for the hepatic resections. There were no in-hospital deaths. Chemotherapy was given to five patients prior to metastasectomy and nine received adjuvant chemotherapy following metastasectomy. Median survival from diagnosis of metastatic disease was 44 months (8-87 months). Estimated 1-year survival from diagnosis of metastatic disease was 94%, estimated 5-year survival was 20%. CONCLUSION: We believe an aggressive but selective surgical approach to combined hepatic and pulmonary colorectal metastases is justified by limited resource requirements and encouraging survival.

EGFR expression: associations with outcome and clinicopathological variables in malignant pleural mesothelioma.

Malignant mesothelioma (MM) is a fatal tumour of increasing incidence which is related to asbestos exposure. This work evaluated expression in MM of Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry in 168 tumour sections and its correlations with clinicopathological and biological factors. The microvessel density (MVD) was derived from CD34 immunostained sections. Hematoxylin and eosin stained sections were examined for intratumoural necrosis. COX-2 protein expression was evaluated with semi-quantitative Western blotting of homogenised tumour supernatants (n=45). EGFR expression was correlated with survival by Kaplan-Meier and log rank analysis. Univariate and multivariate Cox proportional hazards models were used to compare the effects of EGFR with clinicopathological and biological prognostic factors and prognostic scoring systems. EGFR expression was identified in 74 cases (44%) and correlated with epithelioid cell type (p<0.0001), good performance status (p<0.0001), the absence of chest pain (p<0.0001) and the presence of TN (p=0.004), but not MVD or COX-2. EGFR expression was a good prognostic factor in univariate analysis (p=0.01). Independent indicators of poor prognosis in multivariate analysis were non-epithelioid cell type (p=0.0001), weight loss, performance status and WBC>8.3x10(9)L(-1). EGFR status was not an independent prognostic factor. EGFR expression in MM correlates with epithelioid histology and TN. EGFR may be a target for selective therapies in MM.

Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life.

BACKGROUND: In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the meta-analysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens. METHODS: The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364). RESULTS: 65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less from chemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival. CONCLUSIONS: The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enable patients and their clinicians to make more informed treatment choices.

A prospective audit evaluating the role of video-assisted cervical mediastinoscopy (VAM) as a training tool.

OBJECTIVE: Cervical mediastinoscopy is an important diagnostic and staging technique. Limited operative field and visibility have traditionally made it a difficult procedure to learn and supervise. Video-assisted techniques can aid training in the procedure. We designed a prospective study to assess the usefulness of video-assisted mediastinoscopy (VAM) as a training tool. METHODS: 43 patients were operated upon by two trainees during their initial formation in general thoracic surgery (25 patients in 15 months, and 18 patients in 9 months, respectively). INDICATIONS: staging (n = 23), diagnosis of enlarged mediastinal nodes (n = 14) and diagnosis/staging (n = 6). End-points of the study: operative time, need of consultant assistance during procedures, and ability of the trainee to identify all nodal stations independently. RESULTS: There were no complications. The mean operative time was 29 (range 18-51) min. Valid histological samples were obtained in all cases. There were no false negative results in the 13 patients who underwent subsequent lung resection (sensitivity 100%). Operative time (R2 = 0.83 and 0.77), need for consultant assistance (R2 = 0.98 and 0.94), and failure to independently reach all nodal stations (R2 = 0.95 and 0.94) significantly decreased with experience in both trainees' cases (cubic curve fit; P < 0.001 throughout). DISCUSSION: VAM permits a rapid learning and adequate supervision of the technique without compromising safety, operative time or completeness of the procedure. The main advantages are: increased visual field, image magnification, adequate light source and the ability to use two instruments simultaneously. VAM should be the technique of choice in thoracic surgical teaching units.

Experience with video-assisted surgery for suspected mediastinal tumours.

AIM: To assess the therapeutic feasibility of video-assisted thoracoscopic surgery (VATS) in the excision of suspected mediastinal tumours. METHODS: The case notes of 24 consecutive patients referred to a single surgeon between 1997 and 2002 for excision of suspected mediastinal tumours were reviewed. The operative, post-operative and pathological characteristics of patients treated thoracoscopically and by open procedure were analysed. RESULTS: Thirteen of 24 patients underwent thoracoscopic excision. The mean age of the two groups was similar as was the mean operating time and duration of chest drainage. However, patients in the thoracoscopic group had less chest drainage, less pain and a shorter hospital stay. CONCLUSIONS: Video-assisted thoracoscopic excision of mediastinal tumours is a safe and technically feasible procedure and may offer significant post-operative advantages over open procedures.

The case for routine cervical mediastinoscopy prior to radical surgery for malignant pleural mesothelioma.

OBJECTIVES: To assess whether cervical mediastinoscopy is necessary before radical resection of malignant pleural mesothelioma (MPM). METHODS: Patients who underwent radical excision of MPM in a 48-month period were prospectively followed for evidence of disease recurrence and death. Histological evidence of extra pleural lymph node metastases was correlated with survival. Lymph node size at intraoperative lymphadenectomy was correlated with the presence of metastatic tumour. RESULTS: The 55 patients who underwent radical resection (51 extra pleural pneumonectomies and 4 radical pleurectomies) comprised 50 men and 5 women with a median age of 58 years, range 41-70. Histological examination revealed 50 epithelioid, four biphasic and one sarcomatoid histology. Postoperative IMIG T stage was stage I 4, II 11, III 30 and IV 10. Postoperatively the 17 patients with metastases to the extra pleural lymph nodes had significantly shorter survival (median 4.4 months, 95% CI 3.2-5.4) than those without (median survival 16.3 months, 95% CI 11.6-21.0) P=0.012 Kaplan-Meier analysis. Seventy-seven extra pleural lymph nodes without metastases were measured with a mean long axis diameter of 16.9 mm (range 4-55); 22 positive nodes had a mean long axis diameter of 15.2 mm (range 6-30). In 15 of the 17 patients with positive extra pleural nodes, the nodes could have been biopsied at cervical mediastinoscopy. CONCLUSIONS: This study confirms that extra pleural nodal metastases are related to poor survival. Pathological nodal involvement cannot be predicted from nodal dimensions. These data suggest that all patients being considered for radical resection of MPM should preferentially undergo preoperative cervical mediastinoscopy irrespective of radiological findings.

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

OBJECTIVES: To assess the impact of lung volume reduction surgery (LVRS) on postoperative pain. METHODS: Fifty-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. RESULTS: Significant 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. CONCLUSION: Postoperative 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.

En-bloc chest wall and lung resection for non-small cell lung cancer. Predictors of 60-day non-cancer related mortality.

OBJECTIVE: Predictors for early mortality after isolated pulmonary resection have been identified and clear guidelines regarding fitness for surgery have been produced. However, the additional risk of en-bloc chest wall resection has not been extensively studied. AIM: We analyzed our total experience of combined chest wall and lung resection for non-small-cell lung cancer (NSCLC) to identify additional risk factors for early non-tumour related mortality. PATIENTS AND METHODS: A retrospective review of 41 consecutive patients, with median age of 69 (range 37-84) years, operated by a single surgeon over a 4-year period. Univariate analysis was performed to assess the relationship of selected preoperative and operative variables on mortality within 2 months from surgery. RESULTS: Low preoperative body mass index, age over 75 years, and preoperative FEV(1) of less than 70% of predicted were associated with a significantly increased 60-day mortality. In those patients with any of these risk factors 60-day mortality was 47% (8 of 17). In those with none of the above there was no mortality (of 24 patients) (P=0.0004). DISCUSSION: En-bloc pulmonary and chest wall resection for NSCLC should be avoided in the elderly, those with limited respiratory reserve or significant weight loss. These factors render the patient highly susceptible to chest complications leading to increased mortality.

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.

Lung volume reduction surgery--a comparison of the long term outcome of unilateral vs. bilateral approaches.

OBJECTIVE: Bilateral lung volume reduction surgery (LVRS) is thought to be preferable to unilateral surgery due to greater initial benefit but the subsequent rate of decline may also be greater. We compared the long term physiological and health status outcome of LVRS performed on one or simultaneously on both lungs. METHODS: Prospective data were collected on a consecutive series of 65 patients undergoing LVRS who were all suitable for bilateral surgery. Twenty-six patients: age 59 (8) years underwent bilateral LVRS by video-assisted thoracoscopy (VAT) or sternotomy and 39 patients: age 60 (6) years underwent unilateral VAT. The perioperative effects of LVRS on spirometry were prospectively recorded at 3, 6, 12 and 24 months. RESULTS: The unilateral group had similar preoperative lung volumes to the bilateral patients: forced expiratory volume in 1s (FEV(1)) 26 vs. 30% predicted, RV 275 vs. 246% predicted and total lung capacity (TLC) 148 vs. 142% predicted. Unilateral LVRS was associated with significantly lower weight of lung resected: 80 (31) vs. 118 (46) g; hospital stay: 16 (10) days vs. 28 (22) days. Thirty-day mortality was 3% in the unilateral and 8% in the bilateral group (P=0.34). Postoperative ventilation occurred in 5% in the unilateral and in 42% in the bilateral group (P=0.0002). The decline of FEV(1) during the first postoperative year was significant in the bilateral group (-313 ml/y, P=0.04) but not significant in the unilateral group (-50 ml/y, P=0.18). SF 36 scores in all eight domains were similar in both groups preoperatively and at any postoperative interval. CONCLUSION: We have found no benefit from bilateral simultaneous LVRS and prefer unilateral LVRS because of the lower morbidity, resulting in earlier discharge, and slower decline in physiological benefit.

Can pneumonectomy for non-small cell lung cancer be avoided? An audit of parenchymal sparing lung surgery.

BACKGROUND: Lung cancer resection rates are suboptimal in the UK. Pneumonectomy has a higher perioperative mortality risk than lobectomy. To increase resection rates and improve outcomes we have implemented a policy of parenchymal sparing surgery for tumours involving a main stem bronchus. METHODS: In a prospective 4 year study of 119 consecutive patients operated upon by a single surgeon the perioperative course, pathology and survival were compared for 81 patients undergoing pneumonectomy and 38 patients in whom pneumonectomy was avoided by bronchoplastic+/-angioplastic procedures. RESULTS: The rate of pneumonectomy decreased significantly with increasing experience with parenchymal sparing surgery (R(2)=0.98, P<0.001) with 21 of the last 30 patients (70%) avoiding pneumonectomy. There were no significant inter-group differences in patient characteristics, perioperative course or outcome. One-year survival was 64% after pneumonectomy and 73% after sleeve lobectomy. However the perioperative loss of respiratory function was significantly lower in the patients in whom pneumonectomy was avoided (P=0.0003). CONCLUSIONS: Pneumonectomy can be avoided in a large proportion of patients with non-small cell lung cancer of a main stem bronchus without adversely affecting outcome but with preservation of lung function