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

The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.

BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas.

AIMS: Discriminating small-cell lung carcinoma (SCLC) from large-cell neuroendocrine carcinoma (LCNEC) rests on morphological criteria, and reproducibility has been shown to be poor. We aimed to identify immunohistochemical markers to assist this diagnosis. METHODS AND RESULTS: Gene expression profiling on laser captured frozen tumour samples from eight SCLC and eight LCNEC tumours identified a total of 888 differentially expressed genes (DEGs), 23 of which were validated by qRT-PCR. Antibodies to four selected gene products were then evaluated as immunohistochemical markers on a cohort of 173 formalin-fixed paraffin-embedded (FFPE) SCLC/LCNEC tumour samples, including 26 indeterminate tumours without a consensus diagnosis. Three markers, CDX2, VIL1 and BAI3, gave significantly different results in the two tumour types (P < 0.0001): CDX2 and VIL1 in combination (either marker positive) showed sensitivity and specificity of 81% for LCNEC while BAI3 showed 89% sensitivity and 75% specificity for SCLC. Of the 26 indeterminate tumours 15 (58%) showed an immunophenotype suggesting either SCLC or LCNEC, eight (31%) showed staining of both tumour types, and three (11%) were negative for all markers. CONCLUSION: A panel of three markers, BAI3, CDX2 and VIL1, is a useful adjunct in the diagnosis of these tumour types.

The new case for cervical mediastinoscopy in selection for radical surgery for malignant pleural mesothelioma.

OBJECTIVES: Selection criteria for radical surgery in malignant pleural mesothelioma (MPM) and related clinical trials remain controversial. The relative importance of nodal metastases and the need for pre-operative nodal staging are undetermined. METHODS: From a prospective database, we identified 212 patients with non-sarcomatoid MPM (160 epithelioid and 52 biphasic). A total of 127 patients underwent extrapleural pneumonectoctomy (EPP) and 85 lung-sparing total pleurectomy (LSTP) with lymphadenectomy. We investigated the effect of nodal burden and distribution in survival by testing for differences between N0, N1 and N2 disease and constructing a theoretical model dividing the patients into four groups according to diseased nodes identified in the surgical specimen: Group 0, no nodal disease; Group CM, nodes accessible by cervical mediastinoscopy (CM): Stations 2, 3a, 4 and 7; Group EBUS/EUS, nodes accessible by endobronchial (EBUS) or endoscopic (EUS) ultrasound: Stations 2, 3a, 4 and 7-11. Group EM, extramediastinal nodes not accessible by CM or EBUS/EUS: Stations 5, 6, internal mammary, pericardial and diaphragmatic lymph nodes. RESULTS: There was no difference in overall median survival between EPP and LSTP [15.6, SE 1.8, 95% confidence interval (CI) 12-19 months versus 13.4, SE 2.3, 95% CI 9-18 months, P=0.41]. Patients with N0 disease (n=94) had the best prognosis: median survival was 19.6 months (SE 3, 95% CI 13.2-26) versus 12 months for the 19 patients with N1 (SE 1.5, 95% CI 9-15) and 13.6 months for 99 patients with N2 (SE 1.7, 95% CI 10-17), P=0.015. Subgroup analysis of patients with nodal metastases revealed no significant survival difference between group CM and group EBUS/EUS: achieving maximum theoretical diagnostic yield CM could detect 63 (54%) of patients with nodal disease and the median survival of this group was 13.6 months (SE 2, 95% CI 9.6-17.6). EBUS/EUS could detect an additional 30 cases (26%) with survival of 11.3 months (SE 1, 95% CI 9-13.6). The survival in group EM (25 cases, 21%, median survival 18.7 months, SE 6, 95% CI 7-30) was significantly better than groups CM or EBUS/EUS, P=0.002. CONCLUSIONS: There is a strong case for routine CM as a method of prognostic staging in all patients undergoing radical surgery for MPM. The addition of EUS staging and the detection of nodal metastases inaccessible to mediastinoscopy had no prognostic benefit.

Long-term survival after lung-sparing total pleurectomy for locally advanced (International Mesothelioma Interest Group Stage T3-T4) non-sarcomatoid malignant pleural mesothelioma.

OBJECTIVES: There is a body of opinion that advocates extrapleural pneumonectomy (EPP) as the only radical treatment option for locally advanced (T3/T4) malignant pleural mesothelioma (MPM). We tested the hypothesis that lung-sparing total pleurectomy (LSTP) can be as effective as EPP in locally advanced MPM with reduced risk. METHODS: We analysed prospective data on 165 patients (128 with epithelioid and 37 with biphasic MPM) with pT3 (n = 108) and pT4 (n = 57) tumours. Ninety-eight (59.4%) of the patients underwent EPP and 67 (40.6%) LSTP. We compared intergroup differences in: length of stay (LOS), post-operative complications, survival, pattern of disease progression and disease-free interval (DFI). RESULTS: There were significantly more complications after EPP: 67 (68%) vs. 29 (43%) in LSTP, P = 0.002. Thirty-day mortality was 7% for EPP and 3% for LSTP (P = 0.31). LOS was similar (mean 19 days for EPP, 15 days for LSTP, P = 0.19). We noted only minor differences in the initial site of disease progression. In 33 (41%) of EPP patients, disease progressed locally compared with 22 (44%) after LSTP. Seventeen patients post-EPP (21%) had distal progression compared with only three (6%) post-LSTP and synchronous distal and local recurrence was similar: 15 (19%) post-EPP vs. 12% for LSTP (P = 0.11). There was no significant intergroup difference in median survival: EPP 14.7 months (SE 1.3, 95% CI 12.2-17.2) vs. LSTP 13.4 months (SE 1.9, 95% CI 9.7-17.1), P = 0.91, nor in DFI: EPP 10.7 months (SE 0.8, 95% CI 9-12) vs. LSTP 16 months (SE 1, 95% CI 9-22). In chemonaive patients (n = 124), adjuvant chemotherapy was received by significantly more patients after LSTP (32/53 LSTP vs. 26/71 EPP patients, P = 0.011). Estimated 1-5 years survival for EPP was 58, 30, 11, 9 and 6% and for LSTP 52, 28, 20, 13 and 4%. CONCLUSIONS: In disagreement with standard opinion, we advocate LSTP as the procedure of choice in locally advanced MPM: it offers at least equally as good oncological results as EPP in this group of patients with reduced early complications. Despite a tendency for increased local recurrence in the LSTP group, overall survival is not compromised.

Surgical assessment of malignant pleural mesothelioma: have we reached a critical stage?

OBJECTIVE: The International Mesothelioma Interest Group (IMIG) classification is the most widely used staging system but is based on post-resectional parameters. We aimed to test the association between clinical and pathological staging and to identify possible discrepancies. METHODS: We identified 164 consecutive patients (144 males and 20 females, with mean age 58 years) who underwent radical surgery (114 extrapleural pneumonectomy; 50 radical pleurectomy/decortication) for malignant pleural mesothelioma (MPM). The patients were clinically staged with CT + or - MRI (CT, computed tomography; MRI, magnetic resonance imaging). RESULTS: Clinical T (cT) stage proved to be the same as pathological T (pT) stage in 44%; understaged in 46% and overstaged in 10%. Clinical N (cN) stage proved to be the same as pathological N (pN) stage in 56%; understaged in 31% and overstaged in 13%. Disease-free interval (DFI) was associated with cT stage (median DFI 29 months, SE 13, 95% CI 3-54 months for cT1; median 5, SE 3, 95% CI 3-6 months for cT4, p=0.02) but not clinical N stage (median DFI 12 months, SE 1, 95% CI 9-15 months for cN0; median DFI 11 months, SE 0.3, 95% CI 10-12 months for cN2, p=0.5) and was associated with both pT (median DFI 31 months, SE 17, 95% CI 0-64 months for pT1; median DFI 8 months, SE1, 95% CI 6-11 months for pT4, p=0.03) and pN stage (median DFI 14 months, SE 3, 95% CI 9-20 months for pN0; median DFI 10 months, SE 1, 95% CI 8-13 months for pN2, p=0.02). Overall survival was associated with cT stage (median survival 25 months, SE 3, 95% CI 20-30 months for cT1; median survival 11 months, SE 3, 95% CI 10-11 months for cT4, p=0.01) but not cN stage (median survival 15 months, SE 2, 95% CI 11-19 months for cN0; median survival 15 months, SE 2, 95% CI 12-19 months for cN2, p=0.49) and pN stage (median survival 22 months, SE 3, 95% CI 19-27 months for pN0; median survival 14 months, SE 1, 95% CI 12-17 months for pN2, p=0.01) but not pT stage (median survival 27 months, SE 4, 95% CI 19-35 months for pT1; median survival 12 months, SE 2, 95% CI 9-15 months for pT4, p=0.06). Pathological IMIG stage was associated with DFI and overall survival; however, preoperative IMIG stage was less useful. CONCLUSIONS: There are deficiencies in the current staging system for MPM and discrepancies between clinical and pathological systems. Future improvements are needed in clinical descriptors of nodal status and pathological descriptors of T stage. Subsequent IMIG stage grouping also needs revision.

Synchronous ileal carcinoid and primary colonic neoplasms: a case report.

Primary colonic tumours with synchronous ileal carcinoid tumours are rare in occurrence and are mainly found incidentally on autopsies or pathological examination of resected surgical specimens. This article describes a case of adenomatous colonic polyps, adenocarcinoma of sigmoid colon and concurrent malignant carcinoid tumour of ileocaecal junction, detected on colonoscopic examination. The radiological staging investigations revealed no distant spread of disease. The patient was effectively treated with subtotal colectomy, resection of terminal ileum, excision of locoregional lymph nodes and the bowel continuity was restored with stapled ileo-rectal anastomosis. This article is as an example of concomitant presence of two types of malignant tumours, effectively managed surgically.

The pattern of lymph node involvement influences outcome after extrapleural pneumonectomy for malignant mesothelioma.

OBJECTIVE: We sought to examine the distribution and prognostic implications of nodal metastasis in patients undergoing extrapleural pneumonectomy for malignant mesothelioma in a specialist center. METHODS: We have examined the lymphadenectomy specimens from 92 consecutive cases of malignant mesothelioma undergoing extrapleural pneumonectomy from September 1999 through February 2005 inclusive. Nodal stations (Naruke) were assigned to all nodes, and patients were staged according to the current International Union Against Cancer system. The status and number of nodes in each station were recorded, and results were correlated with the results of preoperative mediastinoscopic findings (n = 30) and survival. RESULTS: The nodal distribution was 48 N0, 9 N1, and 35 N2. Single and multistation nodal involvement was present in 20 and 24 cases, respectively. Among the patients undergoing mediastinoscopy, N2 disease after extrapleural pneumonectomy occurred in 10 (33%). Skip N2 metastasis was present in 10 (42%) cases. Positive N2 nodes inaccessible by mediastinoscopy were present in 17 (49%) cases. N2 metastasis was associated with reduced survival (P = .02), but there was no difference between N1 and N2 cases (P = .4). The number of positive nodes correlated with survival (P = .001), although the number of involved stations and their anatomic location did not. There was no difference in survival between skip N2 cases and either other N2 or N1 cases. CONCLUSIONS: The classical anatomic location is not as important as the scatter of nodal involvement. Every effort should be made to obtain biopsy specimens from as many stations as possible before undertaking extrapleural pneumonectomy for malignant mesothelioma.

Tumor necrosis correlates with angiogenesis and is a predictor of poor prognosis in malignant mesothelioma.

OBJECTIVES: Malignant mesothelioma (MM) is a fatal tumor of increasing incidence related to asbestos exposure. Microscopic tumor necrosis (TN) is a poor prognostic factor in solid tumors, but it has not been characterized in MM. We wished to evaluate the incidence of TN in MM and its correlations with clinicopathologic factors, angiogenesis, and survival. METHODS: TN was graded in 171 routine formalin-fixed, paraffin-embedded hematoxylin-eosin-stained tumor sections by two independent observers. Angiogenesis was assessed by the microvessel count (MVC) of CD34 immunostained sections. TN was correlated with survival by Kaplan-Meier and log-rank analysis, and stepwise, multivariate Cox models were used to compare TN with angiogenesis and established prognostic factors and prognostic scoring systems. RESULTS: TN was identified in 39 cases (22.8%) and correlated with low hemoglobin (p = 0.01), thrombocytosis (p = 0.04), and high MVC (p = 0.02). TN was a poor prognostic factor in univariate analysis (p = 0.008). Patients with TN had a median survival of 5.3 months vs 8.3 months in negative cases. Independent indicators of poor prognosis in multivariate analysis were nonepithelioid cell type (p = 0.0001), performance status > 0 (p = 0.007), and increasing MVC (p = 0.004) but not TN. TN contributed independently to the European Organisation for Research and Treatment of Cancer (EORTC) [p = 0.03] and to the Cancer and Leukemia Group B (CALGB) [p = 0.03] prognostic groups in respective multivariate Cox analyses. CONCLUSIONS: TN correlates with angiogenesis and is a poor prognostic factor in MM. TN contributes to the EORTC and CALGB prognostic scoring systems.