Mind the gap! Interdisciplinary approach to anterior chest wall reconstruction after total sternectomy.

BACKGROUND: There are various reconstructive methods after total sternectomy. Reproducibility is scarce due to overall small patient numbers. Therefore we present a standardized, interdisciplinary approach for thoracic and plastic surgery. METHODS: Four patients underwent interdisciplinary chest wall reconstruction with STRATOS® titanium bars and myocutaneous vastus lateralis muscle free flap in our center. RESULTS: All patients reported chest wall stability after reconstruction. They reported good quality of life, no dyspnea, prolonged pain or impairment in lung function from rigid reconstruction. FEV1/FVC was overall better after surgery. Secondary wound healing was not impaired and there was no implant defect in follow up. CONCLUSIONS: We recommend an interdisciplinary surgical approach in chest wall reconstruction after total sternectomy. The combination of rigid reconstruction with titanium bars and a myocutaneous vastus lateralis muscle free flap renders excellent results in patient satisfaction and is objectifiable via spirometry.

Impaired immune responses and prolonged viral replication in lung allograft recipients infected with SARS-CoV-2 in the early phase after transplantation.

PURPOSE: Lung transplant recipients are at increased risk of severe disease following infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) due to high-dose immunosuppressive drugs and the lung is the main organ affected by Coronavirus disease 2019 (COVID-19). Several studies have confirmed increased SARS-CoV-2-related mortality and morbidity in patients living with lung allografts; however, detailed immunological studies of patients with SARS-CoV-2 infection in the early phase following transplantation remain scarce. METHODS: We investigated patients who were infected with SARS-CoV-2 in the early phase (18-103 days) after receiving double-lung allografts (n = 4, LuTx) in comparison to immunocompetent patients who had not received solid organ transplants (n = 88, noTx). We analyzed SARS-CoV-2-specific antibody responses against the SARS-CoV-2 spike and nucleocapsid proteins using enzyme-linked immunosorbent assays (ELISA), chemiluminescence immunoassays (CLIA), and immunoblot assays. T cell responses were investigated using Elispot assays. RESULTS: One LuTx patient suffered from persistent infection with fatal outcome 122 days post-infection despite multiple interventions including remdesivir, convalescent plasma, and the monoclonal antibody bamlanivimab. Two patients experienced clinically mild disease with prolonged viral shedding (47 and 79 days), and one patient remained asymptomatic. Antibody and T cell responses were significantly reduced or undetectable in all LuTx patients compared to noTx patients. CONCLUSION: Patients in the early phase following lung allograft transplantation are vulnerable to infection with SARS-CoV-2 due to impaired immune responses. This patient population should be vaccinated before LuTx, protected from infection post-LuTx, and in case of infection treated generously with currently available interventions.

COVID-19 in Recent Lung Transplant Recipients: Clinical Outcomes and Management Strategies.

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 owing 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 and 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 6 SARS-CoV-2 infections were hospital-acquired and the patients were still in inpatient treatment after lung transplantation. All patients suffered from symptoms. One patient did not receive antiviral therapy. Remdesivir was prescribed in 4 patients and the remaining patient received remdesivir, bamlanivimab and convalescent plasma. CONCLUSIONS: COVID-19 does not appear to cause milder disease in lung transplant recipients compared with 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.

Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery.

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.

Impact of cyclooxygenase-2 and prostaglandin-E2 expression on clinical outcome after pulmonary metastasectomy.

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. METHODS: From 04/2009 to 11/2013 53 patients with complete PM for CRC were included in this single-center study. Tissue samples of resected pulmonary metastases and available corresponding primaries were collected and assessed by immunohistochemistry for COX-2 and PGE2 expression of the tumor tissue and the peritumoral stroma. Results were correlated with clinical outcome parameters. 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.

Tumor-infiltrating lymphocyte subsets and tertiary lymphoid structures in pulmonary metastases from colorectal cancer.

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.

Clinical impact of c-MET expression and mutational status in patients with colorectal cancer lung metastases.

OBJECTIVES: The c-MET tyrosine kinase is known to play a key role in tumour promotion in a variety of cancers. The prognostic significance of c-MET pathway alterations has previously been described in primary colorectal cancer (CRC). However, data on the expression and genetic mutational status of c-MET in CRC pulmonary metastases (PM) are lacking. We aimed to assess the clinical implications of alterations in the c-MET pathway in patients undergoing pulmonary metastasectomy. METHODS: From April 2009 to November 2013, all patients with complete CRC lung metastasectomy were included in this study and prospectively followed up. Tissue samples of 51 PM and 33 paired primary CRCs were stained immunohistochemically for c-MET and phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Genetic alterations of MET were detected using an exome panel on a next generation sequencing (NGS) platform. Serum hepatocyte growth factor (HGF) levels were measured in a patient subset (n = 10) before and after metastasectomy. RESULTS: c-MET expression was significantly higher at the invasive front of metastases compared with central tumour areas (P = 0.020) and was associated with nuclear pSTAT3 expression (P = 0.042). pSTAT3 but not c-MET overexpression in PM was associated with time to tumour recurrence after metastasectomy (P = 0.036). Expression levels of neither c-MET nor pSTAT3 had an impact on time to lung-specific recurrence. However, patients with c-MET or pSTAT3 overexpression in PM had a significantly worse overall survival after metastasectomy (P = 0.023 and 0.008, respectively). Mutations in the MET gene were identified in 20 patients of our cohort by NGS, which failed to be of prognostic relevance. Serum HGF did not significantly differ between patients with PM and healthy controls. CONCLUSIONS: 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.

Increased lymphangiogenesis in lung metastases from colorectal cancer is associated with early lymph node recurrence and decreased overall survival.

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.

Elevated inflammatory parameters and inflammation scores are associated with poor prognosis in patients undergoing pulmonary metastasectomy for colorectal cancer.

OBJECTIVES: Pulmonary metastasectomy (PM) has evolved to become a standard treatment for colorectal cancer lung metastases. However, biomarkers to estimate the prognosis after PM are currently missing. We therefore investigated the prognostic impact of inflammatory-related biomarkers and scores in patients undergoing curative PM for colorectal cancer. METHODS: We analysed prospectively collected datasets of 52 patients treated in our institution between April 2009 and June 2014. Fibrinogen (cut-off 325 mg/dl), C-reactive protein (CRP, cut-off 0.5 mg/dl), the modified Glasgow prognostic score (mGPS) and the neutrophil-to-lymphocyte ratio (NLR) at the time of PM were tested for their prognostic power, and correlated to time to recurrence (TTR), time to lung-specific recurrence (TTLR) and overall survival (OS). RESULTS: Median OS after PM of all patients (n = 52, 21 females, 31 males, mean age ± standard deviation: 62.65 ± 11.41 years) was 36 months [95% confidence interval (CI) 24.7-47.3 months, number of events: n = 20/38.5%]. In univariable survival analyses, high fibrinogen [hazard ratio (HR) 5.51, 95% CI 1.21-25.17], elevated CRP (HR 2.81, 95% CI 1.08-7.28), mGPS >0 (HR 2.81, 95% CI 1.08-7.28) and an NLR of 4 or higher (HR 3.05, 95% CI 1.02-9.13) was associated with poor OS. Median TTR was 15 months for all patients (number of events: n = 35/67.3%). Fibrinogen (HR 3.79, 95% CI 1.32-10.94) and NLR (HR 2.99, 95% CI 1.20-7.46) but not CRP (P = 0.102) and mGPS (P = 0.102) were found to indicate TTR. With regard to TTLR (number of events: n = 26/50%), only NLR predicted early lung recurrence (HR 3.02, 95% CI 1.06-8.564). After multivariable analyses, fibrinogen was the only significant OS predictor. However, all investigated inflammatory biomarkers and scores were prognostic for TTR in multivariable analyses. Finally, we divided the study population into an inflammatory phenotype (one or more inflammatory marker/score-elevated) and a non-inflammatory phenotype group. The inflammatory phenotype was prognostic in uni- and multivariable analyses for all three outcome parameters (OS, TTR and TTLR). CONCLUSIONS: 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.