Prognostic factors of resected node-positive lung cancer: location, extent of nodal metastases, and multimodal treatment

Objective: To investigate the prognostic significance of location and extent of lymph node metastasis in resected non-small cell lung cancer (NSCLC), and to weigh up the influence of treatment modalities on survival

Mutations of the EPHB6 Receptor Tyrosine Kinase Induce a Pro-Metastatic Phenotype in Non-Small Cell Lung Cancer

Alterations of Eph receptor tyrosine kinases are frequent events in human cancers. Genetic variations of EPHB6 have been described but the functional outcome of these alterations is unknown. The current study was conducted to screen for the occurrence and to identify functional consequences of EPHB6 mutations in non-small cell lung cancer. Here, we sequenced the entire coding region of EPHB6 in 80 non-small cell lung cancer patients and 3 tumor cell lines. Three potentially relevant mutations were identified in primary patient samples of NSCLC patients (3.8%). Two point mutations led to instable proteins. An in frame deletion mutation (del915-917) showed enhanced migration and accelerated wound healing in vitro. Furthermore, the del915-917 mutation increased the metastatic capability of NSCLC cells in an in vivo mouse model. Our results suggest that EPHB6 mutations promote metastasis in a subset of patients with non-small cell lung cancer

The Long Noncoding MALAT-1 RNA Indicates a Poor Prognosis in Non-small Cell Lung Cancer and Induces Migration and Tumor Growth

Introduction:The functions of large noncoding RNAs (ncRNAs) have remained elusive in many cases. Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1 (MALAT-1) is an ncRNA that is highly expressed in several tumor types.Methods:Overexpression and RNA interference (RNAi) approaches were used for the analysis of the biological functions of MALAT-1 RNA. Tumor growth was studied in nude mice. For prognostic analysis, MALAT-1 RNA was detected on paraffin-embedded non-small cell lung cancer (NSCLC) tissue probes (n = 352) using in situ hybridization.Results:MALAT-1 was highly expressed in several human NSCLC cell lines. MALAT-1 expression was regulated by an endogenous negative feedback loop. In A549 NSCLCs, RNAi-mediated suppression of MALAT-1 RNA suppressed migration and clonogenic growth. Forced expression of MALAT-1 in NIH 3T3 cells significantly increased migration. Upon injection into nude mice, NSCLC xenografts with decreased MALAT-1 expression were impaired in tumor formation and growth. In situ hybridization on paraffin-embedded lung cancer tissue probes revealed that high MALAT-1 RNA expression in squamous cell carcinoma of the lung was associated with a poor prognosis. On genetic level, MALAT-1 displays the strongest association with genes involved in cancer like cellular growth, movement, proliferation, signaling, and immune regulation.Conclusions:These data indicate that MALAT-1 expression levels are associated with patient survival and identify tumor-promoting functions of MALAT-1

Tumor infiltrating T cells influence prognosis in stage I-III non-small cell lung cancer

Background: T cell infiltration in non-small cell lung cancer (NSCLC) is essential for the immunological response to malignant tissue, especially in the era of immune-checkpoint inhibition. To investigate the prognostic impact of CD4(+) T helper cells (T-h), CD8(+) cytotoxic (T-c) and FOXP3(+) regulatory T (T-reg) cells in NSCLC, we performed this analysis. Methods: By counterstaining of CD4, CD8 and FOXP3 we used immunohistochemistry on tissue microarrays (TMA) to evaluate peritumoral T-h cells, T(reg )cells and T-c cells in n=294 NSCLC patients with pTNM stage I-III disease. Results: Strong CD4(+) infiltration was associated with higher tumor stages and lymphonodal spread. However, strong CD4(+) infiltration yielded improved overall survival (OS) (P=0.014) in adenocarcinoma (ADC) and large cell carcinoma (LCC) but not in squamous cell carcinoma (SCC). A CD4/CD8 ratio 0.05). Here, prognostic effects were prominent in PD-L1 positive SCC (P=0.023) but not in PD-L1 negative SCC (P=0.236). Conclusions: High proportion of CD8(+) T-c cells correlated with improved prognostic outcome in stage I-III NSCLC. T-h cells and T-reg cells have implications on outcome with respect to tumor histology and biology

Postoperative outcome after palliative treatment of malignant pleural effusion

Background The objective of this nationwide, registry-based study was to compare the two most frequently used procedures for the palliative treatment of a malignant pleural effusion (MPE) and to evaluate differentiated indications for these two procedures. Methods This was a retrospective observational study based on data of the “PLEURATUMOR” registry of the German Society for Thoracic Surgery. Patients who were documented in the period from January 2015 to November 2021 and had video-assisted thoracic surgery (VATS) talc pleurodesis or implantation of an indwelling pleural catheter (IPC) were included. Results A total of 543 patients were evaluated. The majority suffered from secondary pleural carcinomatosis (n = 402; 74%). VATS talc pleurodesis (n = 361; 66.5%) was performed about twice as often as IPC implantation (n = 182; 33.5%). The duration of surgery was significantly shorter in IPC-patients with 30 min compared to VATS talc pleurodesis (38 min; p = 0.000). Postoperative complication rate was 11.8% overall and slightly higher after VATS talc pleurodesis (n = 49; 13.6%) than after IPC implantation (n = 15; 8.2%). After VATS talc pleurodesis patients were hospitalized significantly longer compared to the IPC group (6 vs. 3.5 days; p = 0.000). There was no significant difference in postoperative wound infections between the groups (p = 0.10). The 30-day mortality was 7.9% (n = 41). Conclusion The implantation of an IPC can significantly shorten the duration of surgery and the hospital stay. For this reason, the procedure should be matched with the patient's expectations preoperatively and the use of an IPC should be considered not only in the case of a trapped lung

High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma

Via immunohistochemistry (IHC) on tissue micro arrays (TMA) clinical and prognostic impact of p53 co-playing 5′-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein expression was evaluated in 252 NSCLC patients. Confirmatory, gene expression database. mRNA levels of NT5DC2 were studied in 1925 NSCLC patients. High protein expression of NT5DC2 resulted in reduced median overall survival (OS) of patients with stage I-III adenocarcinoma (ADC) (Log Rank p = 0.026, HR 2.04 (1.08–3.87)), but not in squamous cell carcinoma (SCC) (p = 0.514, HR 0.87 (0.57–1.33)). Findings on OS were reproduced via gene expression analysis in ADC (p < 0.001, HR 1.64 (1.30–2.08)) and SCC (p = 0.217, HR 0.86 (0.68–1.09)). Yet, NT5DC2 mRNA levels were higher in SCC compared to ADC (p < 0.001) and in pN2 tumors compared to pN0/1 tumors (p = 0.001). Likewise, NT5DC2 protein expression associated with high-grade SCC. Moreover, NT5DC2 expression was positively correlated with p53 protein (p = 0.018) and TP53 gene expression (p < 0.001) and its survival effect was p53 dependent. While p53 expression was negatively associated with the presence of CD34+ cancer associated fibroblasts (CAFs), NT5DC2 expression insignificantly tended to higher levels of SMA+ CAFs (p = 0.065)

High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma

Simple Summary Lung cancer is the leading cause of cancer related deaths and non-small cell lung cancer (NSCLC) is its most relevant subtype. Here, we present data on p53 co-playing 5 '-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein- and gene-expression and its clinical implication and prognostic value. NT5DC2 overexpression was associated with advanced lymphonodal spread and reduced survival in patients with adenocarcinoma of the lung. Moreover, dysregulated p53 in combination with overexpressed NT5DC2 might promote malignancy by interaction with cancer associated fibroblasts. Via immunohistochemistry (IHC) on tissue micro arrays (TMA) clinical and prognostic impact of p53 co-playing 5 '-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein expression was evaluated in 252 NSCLC patients. Confirmatory, gene expression database. mRNA levels of NT5DC2 were studied in 1925 NSCLC patients. High protein expression of NT5DC2 resulted in reduced median overall survival (OS) of patients with stage I-III adenocarcinoma (ADC) (Log Rank p = 0.026, HR 2.04 (1.08-3.87)), but not in squamous cell carcinoma (SCC) (p = 0.514, HR 0.87 (0.57-1.33)). Findings on OS were reproduced via gene expression analysis in ADC (p < 0.001, HR 1.64 (1.30-2.08)) and SCC (p = 0.217, HR 0.86 (0.68-1.09)). Yet, NT5DC2 mRNA levels were higher in SCC compared to ADC (p < 0.001) and in pN2 tumors compared to pN0/1 tumors (p = 0.001). Likewise, NT5DC2 protein expression associated with high-grade SCC. Moreover, NT5DC2 expression was positively correlated with p53 protein (p = 0.018) and TP53 gene expression (p < 0.001) and its survival effect was p53 dependent. While p53 expression was negatively associated with the presence of CD34+ cancer associated fibroblasts (CAFs), NT5DC2 expression insignificantly tended to higher levels of SMA+ CAFs (p = 0.065)

Prognostic impact of CD34 and SMA in cancer-associated fibroblasts in stage I-III NSCLC

Background Epithelial-to-mesenchymal transition (EMT) is a crucial step in lung cancer pathogenesis. Among others, cancer-associated fibroblasts (CAFs) are reported to regulate this process. Objectives To investigate the prognostic and clinical impact, we analyzed CD34+ and SMA+ CAFs in non-small cell lung cancer (NSCLC). Methods Retrospectively, immunohistochemistry was performed to study stromal protein expression of both CD34 and SMA in 304 NSCLC patients with pTNM stage I-III disease. All tissue samples were embedded on tissue microarrays (TMAs). Results Our analysis revealed an association for CD34+ CAFs with G1/2 tumors and adenocarcinoma histology. Moreover CD34+ CAFs were identified as an independent prognostic factor (both for progression free survival [PFS] and overall survival [OS] in stage I-III NSCLC). Besides, SMA+ expression correlated with higher pTNM-tumor stages and lymphatic spread (pN stage). In turn, SMA-negativity was associated with improved PFS, but no prognostic impact was found on OS. Of interest, neither CD34+ CAFs nor SMA+ CAFs were associated with the primary tumor size, localization and depth of infiltration (pT stage). Conclusions CD34 was identified as an independent prognostic marker in pTNM stage I-III NSCLC. Moreover, loss of CD34+ CAFs might influence the dedifferentiation of the NSCLC tumor from its cell origin. Finally, SMA+ CAFs are more prevalent in NSCLC tumors of higher stages and lymphonodal positive NSCLC