The presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) reflects an active inflammatory tumor microenvironment. High density of TILs as well as presence of TLS is associated with improved survival in various solid cancer types. We aimed to describe the density and distribution of TILs and TLS in pulmonary metastases (PMs) from primary colorectal cancer (CRC) and its correlation with clinicopathological variables. Fifty-seven CRC pulmonary metastasectomy specimen (PM) and 31 matched primary CRC specimen were included. Cluster of differentiation (CD)3+, CD8+, CD45RO+ and FoxP3+ TILs were evaluated by immunohistochemistry and density was scored semiquantitatively. TLS were evaluated based on morphological criteria. Survival time was defined from pulmonary metastasectomy to death or last follow up. A marked infiltration with CD3+, CD8+, CD45RO+ and FoxP3+ TILs was evident in CRC PM and matched primary CRC. Further assessment of the immune infiltrate in PM showed that a high density of FOXP3+ TILs at the invasive margin [HR 2.40 (1.11–6.96); P = 0.031] and low density of CD8+ cells in TLS [HR 0.30 (0.14–0.79); P = 0.016] were associated with a worse prognosis in univariate analysis. Moreover, a low CD8/FoxP3-ratio of TILs at the invasive margin (P = 0.042) and in TLS (P = 0.027) conferred an impaired prognosis after pulmonary metastasectomy. Our findings suggest that CRC PM harbor an immune active microenvironment. The balance of CD8+ and FoxP3+ T-cells at the tumor border and in TLS provides prognostic information in patients with CRC PM.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-016-9813-y) contains supplementary material, which is available to authorized users.

Inflammatory markers provided promising prognostic information in this cohort of curative PM patients after colorectal cancer. Further validation is needed to verify the prognostic role of these markers and establish them in clinical routine.

Background: Pulmonary metastasectomy is one of the cornerstones in the treatment of oligometastatic colorectal cancer (CRC). However, the selection of patients who benefit from a surgical resection is difficult. Mutational profiling has become an essential part of diagnosis and treatment of malignant disease.Despite this, comprehensive data on the mutational profile of CRC and its clinical impact in the context of pulmonary metastasectomy is sparse. We therefore aimed to provide a complete mutational status of CRC pulmonary metastases (PM) and corresponding primary tumors by targeted next-generation sequencing (tNGS), and correlate sequencing data with clinical outcome variables.Methods: Case-matched, formalin-fixed paraffin embedded surgical specimens of lung metastases (n=47) and matched primary CRC (n=24) were sequenced using the TruSeq Amplicon Cancer Panel (Illumina platform). Penalized Cox regression models were applied to identify mutations with prognostic impact.Results: Mutations were found most frequently in APC, TP53 and KRAS, in both PM and matched primary tumors. Concordance between primary tumors and PM was 83.5%. Adaptive elastic-net regularized Cox regression models identified mutations being prognostic for time to pulmonary recurrence (EGFR, GNAQ, KIT, MET, and PTPN11) and for overall survival (OS) (PDGFRA, SMARCB1, and TP53).Conclusions: Our findings suggest that CRC PM harbor a variety of conserved and de novo mutations. We could identify a mutational profile predicting clinical outcome after pulmonary metastasectomy. Moreover, our data provide a rationale for future targeted therapies of patients with CRC lung metastases.

Pulmonary metastasectomy (PM) is an accepted treatment modality in colorectal cancer (CRC) patients with pulmonary tumor spread. Positive intrathoracic lymph nodes at the time of PM are associated with a poor prognosis and 5-year survival rates of <20 %. Increased lymphangiogenesis in pulmonary metastases might represent an initial step for a subsequent lymphangiogenic spreading. We aimed to evaluate the presence of lymphangiogenesis in clinically lymph node negative patients undergoing PM and its impact on outcome parameters. 71 patients who underwent PM for CRC metastases were included in this dual-center study. Tissue specimens of pulmonary metastases and available corresponding primary tumors were assessed by immunohistochemistry for lymphatic microvessel density (LMVD) and lymphovascular invasion (LVI). Results were correlated with clinical outcome parameters. LMVD was 13.9 ± 8.1 and 13.3 ± 8.5 microvessels/field (mean ± SD) in metastases and corresponding primary CRC; LVI was evident in 46.5 and 58.6 % of metastases and corresponding primary CRC, respectively. Samples with high LMVD had a higher likelihood of LVI. LVI was associated with early tumor recurrence in intrathoracic lymph nodes and a decreased overall survival (p < 0.001 and p = 0.029). Herein, we present first evidence in a well-defined patient collective that increased lymphangiogenesis is already present in a subtype of pulmonary metastases of patients staged as N0 at the time of PM. This lymphangiogenic phenotype has a strong impact on patients' prognosis. Our findings may have impact on the post-surgical therapeutic management of CRC patients with pulmonary spreading.

To the best of our knowledge, this is the first structured evaluation of the c-MET axis in the context of pulmonary metastasectomy for CRC. Our results suggest that overexpression of c-MET/pSTAT3 is associated with an impaired prognosis following complete resection. Moreover, this work suggests that the value of c-MET tyrosine kinase inhibitors in the treatment of patients with CRC lung metastases should be assessed in clinical trials.

Background Covid-19 causes a wide range of symptoms, with particularly high risk of severe respiratory failure and death in patients with predisposing risk factors such as advanced age or obesity. Recipients of solid organ transplants, and in particular lung transplantation, are more susceptible to viral infection due to immune suppressive medication. As little is known about the SARS-CoV-2 infection in these patients, this study was undertaken to describe outcomes and potential management strategies in early COVID-19 infection early after lung transplantation. Methods We describe the incidence and outcome of COVID-19 in a cohort of recent lung transplant recipients in Munich. Six of 186 patients who underwent lung transplantation in the period between March 2019 until March 2021 developed COVID-19 within the first year after transplantation. We documented the clinical course and laboratory changes for all patients showing differences in the severity of the infection with COVID-19 and their outcomes. Results Three of six SARS-CoV-2 infections were hospital-acquired and the patients were still in inpatient treatment following lung transplantation. All patients suffered from symptoms. One patient did not received antiviral therapy. Remdesivir was prescribed in four patients and the remaining patient received remdesivir, bamlanivimab and convalescent plasma. Conclusion COVID-19 does not appear to cause milder disease in lung transplant recipients compared to the general population. Immunosuppression is potentially responsible for the delayed formation of antibodies and their premature loss. Several comorbidities and a general poor preoperative condition showed an extended hospital stay.

Background: Pulmonary metastasectomy (PM) is a standard procedure in the treatment of stage IV colorectal cancer (CRC). In most centers the indication for PM is solely based on clinical factors without taking the tumor biology into account. This results in diverse outcomes ranging from long-term remission to early recurrence. Inflammation is considered a hallmark of cancer development and progression. On the other hand the accessibility of CRC cells to the immune system reflects the grade of tumor aggressiveness.We sought to investigate the impact of cyclooxygenase-2 (COX-2) and prostaglandin-E2 (PGE2) expression in pulmonary metastases on different outcome parameters following PM. Results: COX-2 and PGE2 were detected in nearly every pulmonary CRC metastasis. Staining intensities of pulmonary metastases correlated only weakly with intensities found in primary tumors. When dividing metastases in high expressing and low expressing tumors, a trend towards longer recurrence free survival and improved survival was found in tumors with strong COX-2 and PGE2 staining. Conclusions:In conclusion, this pilot study shows that COX-2 and PGE2 are uniformly overexpressed in pulmonary metastases from CRC. High expression of COX-2 and PGE2 seems to reflect a beneficial tumor biology with late tumor recurrence and prolonged overall survival after PM.