Lung cancer is the leading cause of cancer-related death and is usually diagnosed at an advanced stage, where lymph node/distant metastases are present. Only in about one-third of patients with non-small cell lung cancer (NSCLC) the disease is diagnosed as localized, for which a complete resection is the treatment of choice and a cure is possible. Hence, in most cases systemic therapy is required, either as part of a multimodal treatment or as sole therapeutic option. Despite advances in individualized approaches and modern chemotherapeutic regimens, the course of the disease remains unfavorable (1-3).It is widely acknowledged that the tumor microenvironment plays a critical role in tumor growth and spread, and in recent years, multiple therapeutic approaches have been developed based on this knowledge (4). In contrast to agents focusing on molecular targets such as the epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK), whose activity is confined to tumors with specific genetic alterations, immunotherapy is effective in various histological subtypes (5-8).Tumor microenvironment consists of tumor cells, the leukocyte infiltrate and the tumor associated immunologic microenvironment. One of the key players, the tumor associated macrophages (TAMs) can make up a large fraction of the tumor mass (9). Depending on the tumor microenvironment, macrophages can be polarized into different functional states, of which the two extremes are known as the M1 and M2 phenotypes. M1 macrophages have been shown to carry out pro-inflammatory, cytotoxic and thus mostly anti-neoplastic effects, whilst the M2 phenotype is responsible for tissue remodeling and repair and is believed to be involved in the subversion of adaptive immunity and thus the immunological interactions that promote tumor growth and progression. TAMs in the tumor microenvironment are mostly found to have the M2 phenotype (10). TAMs secrete a specific pattern of cytokines and chemokines and are one of the main producers of CC-chemokine ligand 18 (CCL18) in this context (11,12). CCL18 is responsible for the recruitment of naive T-cells and dendritic cells, and is capable of inducing regulatory T-cells. In the tumor microenvironment, it has been demonstrated to promote tumor spread and is believed to be one of the factors involved in the immune escape of tumor cells (13)(14)(15)(16)(17). 4667

Objective: The surgical resection of pulmonary metastases is associated with a survival benefit in selected patients. The use of laser devices for pulmonary metastasectomy (PM) is believed to facilitate the complete resection of metastases while preserving a maximum of healthy parenchyma. This is a prospective study to evaluate surgical outcome including the changes of lung function after laser–assisted surgery (LAS).Methods: A total of 77 operations in 61 patients in which PM was carried out in a curative intent were analyzed. A 1.320 nm diode-pumped Nd: YAG-Laser was used for resection of the metastases. Surgical and clinical data were collected using a standardized form and postoperative lung function changes 3 and 6 months after surgery were assessed using whole body plethysmography and diffusion capacity for carbon monoxide (DLCO). Size and distance of metastases to the pleural surface were measured radiologically.Results: A median of two metastases were resected per operation (range 1–13). The median duration of postoperative air leak was 1 day (range 0–11). LAS associated postoperative minor and major complications were observed in 4 (5%) cases and 1 (1%) case, respectively; there were no mortalities. The analysis of perioperative lung function showed that mean VC 3 months after surgery was reduced by 11 %, FEV1 by 11% and median DLCO by 11% (all p < 0.0001). There was almost no recovery of lung function between 3 and 6 months in the whole cohort. Patients with two or less metastases showed a recovery of lung function after 3 months regarding DLCO (p = 0.003). Decline of DLCO in the whole cohort correlated with the number of resected metastases at 3 months (r = 0.45, p = 0.006) and at 6 months (r = 0.42, p = 0.02) as well as depth of metastases in the parenchyma at 6 months (r = 0.48, p = 0.001).Conclusions: LAS is a safe and effective method for PM even for higher numbers of metastases, with short duration of postoperative air leak and little morbidity. Number and depth, but not size of metastases affect lung function changes after resection.

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