Prognostic value of nonangiogenic and angiogenic growth patterns in non-small-cell lung cancer

An essential prerequisite of nonangiogenic growth appears to be the ability of the tumour to preserve the parenchymal structures of the host tissue. This morphological feature is visible on a routine tissue section. Based on this feature, we classified haematoxylin and eosin-stained tissue sections from 279 patients with non-small-cell lung cancer into three growth patterns: destructive (angiogenic; n=196), papillary (intermediate; n=38) and alveolar (nonangiogenic; n=45). A Cox multiple regression model was used to test the prognostic value of growth patterns together with other relevant clinicopathological factors. For overall survival, growth pattern (P=0.007), N-status (P=0.001), age (P=0.020) and type of operation (P=0.056) were independent prognostic factors. For disease-free survival, only growth pattern (P=0.007) and N-status (P<0.001) had an independent prognostic value. Alveolar (hazard ratio=1.825, 95% confidence interval=1.117-2.980, P=0.016) and papillary (hazard ratio=1.977, 95% confidence interval=1.169-3.345, P=0.011) growth patterns were independent predictors of poor prognosis. The proposed classification has an independent prognostic value for overall survival as well as for disease-free survival, providing a possible explanation for survival differences of patients in the same disease stage

Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia

Although angiogenesis is a prerequisite for the growth of most human solid tumours, alternative mechanisms of vascularisation can be adopted. We have previously described a non-angiogenic growth pattern in liver metastases of colorectal adenocarcinomas (CRC) in which tumour cells replace hepatocytes at the tumour-liver interface, preserving the liver architecture and co-opting the sinusoidal blood vessels. The aim of this study was to determine whether this replacement pattern occurs during liver metastasis of breast adenocarcinomas (BC) and whether the lack of an angiogenic switch in such metastases is due to the absence of hypoxia and subsequent vascular fibrinogen leakage. The growth pattern of 45 BC liver metastases and 28 CRC liver metastases (73 consecutive patients) was assessed on haematoxylin- and eosin-stained tissue sections. The majority of the BC liver metastases had a replacement growth pattern (96%), in contrast to only 32% of the CRC metastases (P<0.0001). The median carbonic anhydrase 9 (CA9) expression (M75 antibody), as a marker of hypoxia, (intensity x % of stained tumour cells) was 0 in the BC metastases and 53 in the CRC metastases (P<0.0001). There was CA9 expression at the tumour-liver interface in only 16% of the BC liver metastases vs 54% of the CRC metastases (P=0.002). There was fibrin (T2G1 antibody) at the tumour-liver interface in only 21% of the BC metastases vs 56% of the CRC metastases (P=0.04). The median macrophage count (Chalkley morphometry; KP-1 anti-CD68 antibody) at the interface was 4.3 and 7.5, respectively (P<0.0001). Carbonic anhydrase 9 score and macrophage count were positively correlated (r=0.42; P=0.002) in all metastases. Glandular differentiation was less in the BC liver metastases: 80% had less than 10% gland formation vs only 7% of the CRC metastases (P<0.0001). The liver is a densely vascularised organ and can host metastases that exploit this environment by replacing the hepatocytes and co-opting the vasculature. Our findings confirm that a non-angiogenic pattern of liver metastasis indeed occurs in BC, that this pattern of replacement growth is even more prevalent than in CRC, and that the process induces neither hypoxia nor vascular leakage

Anti-angiogenic therapy for cancer: Current progress, unresolved questions and future directions

Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies. © 2014 The Author(s)

Effect of minimally invasive mitral valve surgery compared to sternotomy on short- and long-term outcomes:a retrospective multicentre interventional cohort study based on Netherlands Heart Registration

OBJECTIVES: Minimally invasive mitral valve surgery (MIMVS) has been performed increasingly for the past 2 decades; however, large comparative studies on short- and long-term outcomes have been lacking. This study aims to compare short- and long-term outcomes of patients undergoing MIMVS versus median sternotomy (MST) based on real-world data, extracted from the Netherlands Heart Registration. METHODS: Patients undergoing mitral valve surgery, with or without tricuspid valve, atrial septal closure and/or rhythm surgery between 2013 and 2018 were included. Primary outcomes were short-term morbidity and mortality and long-term survival. Propensity score matching analyses were performed. RESULTS: In total, 2501 patients were included, 1776 were operated through MST and 725 using an MIMVS approach. After propensity matching, no significant differences in baseline characteristics persisted. There were no between-group differences in 30-day mortality (1.1% vs 0.7%, P = 0.58), 1-year mortality (2.6% vs 2.1%, P = 0.60) or perioperative stroke rate (1.1% vs 0.6%, P = 0.25) between MST and MIMVS, respectively. An increased rate of postoperative arrhythmia was observed in the MST group (31.3% vs 22.4%, P < 0.001). A higher repair rate was found in the MST group (80.9% vs 76.3%, P = 0.04). No difference in 5-year survival was found between the matched groups (95.0% vs 94.3%, P = 0.49). Freedom from mitral reintervention was 97.9% for MST and 96.8% in the MIMVS group (P = 0.01), without a difference in reintervention-free survival (P = 0.30). CONCLUSIONS: The MIMVS approach is as safe as the sternotomy approach for the surgical treatment of mitral valve disease. However, it comes at a cost of a reduced repair rate and more reinterventions in the long term, in the real-world

Different growth patterns of non-small cell lung cancer represent distinct biologic subtypes.

BACKGROUND: We have recently shown the prognostic value of growth pattern classification in non-small cell lung cancer. The aim of this study is to validate the hypothesis that these growth patterns have a distinct angiogenic and proliferative profile. METHODS: Hematoxylin-eosin stained tissue sections of 239 patients with non-small cell lung cancer were classified into growth patterns. One representative tissue section per patient was double immunostained with CD34 and Ki-67 antibodies. Endothelial cell proliferation fraction, tumor cell proliferation fraction, microvessel density, and Chalkley count were assessed at the invading front and the center of the selected tumor section. RESULTS: According to the growth pattern classification, 161 patients (67.4%) had a destructive, 33 (13.8%) a papillary, and 45 (18.8%) an alveolar growth pattern. There were significant differences in endothelial cell proliferation fraction (p &lt; 0.001), tumor cell proliferation fraction (p &lt; 0.001), microvessel density (p &lt; 0.001), and Chalkley count (p &lt; 0.001) between the growth patterns. Multiple Cox regression analysis showed that a low endothelial cell proliferation fraction was consistently an independent prognostic factor for overall poor (hazard ratio = 0.93; confidence interval: 0.88 to 0.97, p = 0.002) and disease-free survival (hazard ratio = 0.94; confidence interval: 0.89 to 0.98, p = 0.007). CONCLUSIONS: Growth patterns have a distinct angiogenic and proliferative profile. In non-small cell lung cancer, a low degree of angiogenesis (a low endothelial cell proliferation fraction) is associated with poor prognosis

Real life cardio-thoracic surgery training in Europe: facing the facts

The objective of this study was to determine the current status of training in cardio-thoracic surgery in Europe and the residents' perception of the effects of the full implementation of the European Working Time Directive (EWTD) on training. We conducted a web-based survey of trainees registered with the European Association of Cardio-Thoracic Surgery and 79 respondents form the basis for this analysis. A majority of trainees (69.6%) are aware of the implications of the EWTD and 58.7% believe it will have an impact on their training. Most residents (98.7%) work well over the time limitations stated in the Directive and 96.2% are of the opinion that a 48-hour week would be insufficient to meet their learning needs. A large proportion (60.5%) of European trainees are dissatisfied with their training and report low-levels of regular assessment of their progress (37.8%) and of training facilities (27.4%). Only 23.3% of European trainers appear to attend training courses. Striking differences exist among European countries with regards to standards of training. These findings are alarming. Training in cardio-thoracic surgery across the European Union requires urgent attention to unify and improve the standards of training and compensate the potential negative impact of the EWTD