QUÉ ES HARDENING

At the moment, screening for lung cancer in patients with elevated risk profiles is a hot topic in imaging. A relative reduction in mortality from lung cancer in high-risk patients with low-dose CT screening of 20% was described recently[3]. A problem of screening is the high rate of false positive results requiring analysis or follow up. Furthermore, small nodules (often of subcentimeter size) are frequently encountered in daily practice as coincidental findings on CT scans made for all kinds of

indications.

All these small abnormalities require advanced analysis. Improvement of imaging technique to qualify them reliably is a major effort for equipment manufacturers. New PET tracer may be more specific than FDG. Also technological improvements in PET will bring a better resolution. The question is, whether all these novelties will improve diagnostic pathways.

Algorithms integrating combinations of non-invasive diagnostics such as biomarkers have to be validated in the future to differentiate early stage malignant disease from benign findings.

A promising innovation to combine with state of the art CT imaging in the analysis of small abnormalities is exhaled breath analysis[4]. Though not yet sensitive enough, it is expected that in the future, breath analysis might play an important role in decision making for very small lesions. Other biomarkers such as circulating tumor cells and circulating DNA in serum seem promising.

Interventional pulmonology

The incredible diagnostic shift that endoscopic and endobronchial ultrasound has made in pulmonology is hard to repeat because we are able now to diagnose formerly inaccessible anatomic areas.

Other non-surgical interventional modalities for the diagnosis of thoracic masses are not evident. Minor steps are made in improving the quality and user comfort of needles for EUS, EBUS and percutaneous applications.

Reports on EUS guided therapy in gastroenterology (particularly in pancreatic disease) with a flexible bipolary probe, combining radiofrequency ablation with cryothermal cooling are promising also for thoracic approaches[5]. In the future it is foreseen that EUS and EBUS will be applied for therapeutic purposes as well in pulmonology.

For pulmonologists, percutaneous US has gained ground for the analysis of pleural effusions but still with restraints. Only a small step further is the use of US to obtain more accurately samples for pathology, a field that was previously reserved for interventional radiologists. Similar to other disciplines, like cardiology, urology and gynaecology, percutaneous US should become an integral part of the pulmonology practice as well.

Although it is reasonable that EUS and EBUS are performed by dedicated pulmonologists in specialized centers due to high equipment costs and limited numbers of patients, for percutaneous US the situation is different.

Percutaneous US is cheap, applicable on a daily base and easy to learn. Training in percutaneous US skills, now limited to a few centers, should be offered to every pulmonologist during their education. More diagnostics in one hand has great advantages for the patient because it increases diagnostic speed and efficiency. Even though diagnostic surgery is not quite classifiable as interventional

pulmonology, it should be mentioned in this context. In recent years, important

developments in diagnostic surgery have been established. Minimal invasive surgery evolved and lowered the threshold to consult the surgeon for mediastinal and upper abdominal exploration. Initially, video-assisted thoracoscopic surgery (VATS) for diagnosing lung lesions and otherwise inaccessible hilar or mediastinal lesions was established. Gradually, robotic control is introduced in VATS, enabling even more precise handling of instruments and enabling access to more difficult sites in the thorax.

Pathology and molecular biology

The developments in this field are of the most exciting kind.

New predictive markers for lung cancer are detected and validated with high speed. Immunohistochemistry, fluorescent in situ hybridization and DNA sequencing are all tests that are performed on patient material. However, more tests have to be

performed on samples requiring more tumor cells. To counteract this development, next-generation sequencing (NGS) on DNA and RNA from paraffine embedded specimen provide one kind of test that needs only limited amounts of DNA and RNA. This approach is valuable when mutations, focal amplifications, copy number

aberrations and certain fusion proteins are predictive for the efficacy of targeted therapeutics. The success of this approach depends partly on the willingness of pulmonologists to obtain larger tumor samples to detect low-frequency mutations. Whole genome sequencing equipment is commercially available that is able to unravel all abnormalities in cancer genes in small amounts of tumor[6]. The clinical meaning of most abnormalities however, is not yet understood.

Nevertheless it is expected that knowledge of oncologic pathways will increase quickly with NGS, resulting in the discovery of more molecular targets and resistance mechanisms. New agents or combinations of agents and more insight in benefits and harms of certain treatments will improve personalized therapy.

The pulmonologist is constantly moving in a field with changing demands of the pathologist, depending on technical developments, at one side and changing understanding of clinical relevancy at the other side.

REFERENCES

[1] Jakobsen JN, Sorensen JB. Intratumor heterogeneity and chemotherapy-induced changes in EGFR status in non-small cell lung cancer. Cancer Chemother

Pharmacol 2012;69:289-99.

[2] Stigt JA. Endoscopic and percutaneous ultrasound guided aspirations in different directions. 2013. Available at: http://www.youtube.com/watch?v=zAqmYmqFYEs [3] National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409.

[4] Mazzone PJ, Wang XF, Xu Y, et al. Exhaled breath analysis with a colorimetric sensor array for the identification and characterization of lung cancer. J Thorac Oncol 2012;7:137-42.

[5] Arcidiacono PG, Carrara S, Reni M, et al. Feasibility and safety of EUS-guided cryothermal ablation in patients with locally advanced pancreatic cancer. Gastrointest Endosc 2012;76:1142-51.

[6] Daniels M, Goh F, Wright CM, et al. Whole genome sequencing for lung cancer. J Thorac Dis 2012;4:155-63.

Chapter 12