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).

NOP10 predicts lung cancer prognosis and its associated small nucleolar RNAs drive proliferation and migration.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide underlining the urgent need for new biomarkers and therapeutic targets for this disease. Long noncoding RNAs are critical players in NSCLC but the role of small RNA species is not well understood. In the present study, we investigated the role of H/ACA box small nucleolar RNAs (snoRNAs) and snoRNA-bound ribonucleoproteins (snoRNPs) in the tumorigenesis of NSCLC. H/ACA box snoRNPs including the NOP10 core protein were highly expressed in NSCLC. High levels of either NOP10 mRNA or protein were associated with poor prognosis in NSCLC patients. Loss of NOP10 and subsequent reduction of H/ACA box snoRNAs and rRNA pseudouridylation inhibited lung cancer cell growth, colony formation, migration, and invasion. A focused CRISPR/Cas9 snoRNA knockout screen revealed that genomic deletion of SNORA65, SNORA7A, and SNORA7B reduced proliferation of lung cancer cells. In line, high levels of SNORA65, SNORA7A, and SNORA7B were observed in primary lung cancer specimens with associated changes in rRNA pseudouridylation. Knockdown of either SNORA65 or SNORA7A/B inhibited growth and colony formation of NSCLC cell lines. Our data indicate that specific H/ACA box snoRNAs and snoRNA-associated proteins such as NOP10 have an oncogenic role in NSCLC providing new potential biomarkers and therapeutic targets for the disease.

[Management of Lung Abscess - Diagnostics and Treatment]. / Management des pulmonalen Abszesses: Diagnostik und Behandlung.

Lung abscess is a localized infectious pus-filled cavity of the lung tissue by viral, bacterial, mycotic or parasitic pathogens. Currently, there are different classifications, which are based primarily on the genesis and duration of symptoms. Important steps for diagnosis are in addition to clinical examination, laboratory and chest X-ray especially bronchoscopy with microbiological examinations and computed tomography. Treatment of lung abscesses continues to be a domain of conservative antibiotic therapy. The vast majority of cases can be cured with this. Interventional procedures such as transthoracic or endobronchial abscess drainage with subsequent irrigation can effectively support the healing process. Thoracic surgery is particularly important in cases of failure of conservative and interventional therapy as well as secondary abscesses on the basis of a lung carcinoma. Mostly anatomical resections are required. Alternatively, VAC therapy (vacuum-assisted closure therapy) may be considered in seriously ill, old, immunosuppressed, and multimorbid patients with complicated abscesses (e.g. perforation in the pleural cavity and sero-pneumothorax).

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 (Th), CD8+ cytotoxic (Tc) and FOXP3+ regulatory T (Treg) 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 Th cells, Treg cells and Tc 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 <1 was associated with high grade NSCLC tumors (P=0.020). High CD8+ T cell infiltration was an independent prognostic factor for OS (P=0.040) and progression-free survival (PFS) (P=0.012) in the entire study collective. The OS benefit of high CD8+ infiltration was especially prominent in PD-L1 negative NSCLC (P=0.001) but not in PD-L1 positive tissue (P=0.335). Moreover, positive FOXP3+ expression in tumor infiltrating lymphocytes was associated with increased OS (P=0.007) and PFS (P=0.014) in SCC but not in ADC and LCC (all P>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+ Tc cells correlated with improved prognostic outcome in stage I-III NSCLC. Th cells and Treg cells have implications on outcome with respect to tumor histology and biology.

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. KEY POINTS: Expression of CD34 on cancer associated fibroblasts (CAFs) is an independent prognostic factor in stage I-III NSCLC. SMA+ cancer associated fibroblasts are associated with higher tumor stages in NSCLC and might contribute to tumor progression in NSCLC.

Prostate specific membrane antigen (PSMA) expression in non-small cell lung cancer.

OBJECTIVES: PSMA (prostate-specific membrane antigen) is overexpressed in prostate cancer cells and is reported to be a promising target for antibody-based radioligand therapy in patients with metastasized prostate cancer. Since PSMA expression is not restricted to prostate cancer, the underlying study investigates PSMA expression in non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Immunohistochemistry was used to identify PSMA expression in n = 275 samples of NSCLC tissue specimens. By means of CD34 co-expression, the level of PSMA expression in tumor associated neovasculature was investigated. The impact of PSMA expression on clinicopathologic parameters and prognosis was evaluated. RESULTS: PSMA tumor cell expression in NSCLC is as low as 6% and was predominantly found in squamous cell carcinoma (p = 0.002). Neovascular PSMA expression was found in 49% of NSCLC. High neovascular PSMA expression was associated with higher tumor grading (G3/G4) (p < 0.001). Neither for PSMA tumor cell expression, nor for PSMA neovascular cell expression prognostic effects were found for the investigated NSCLC cases. CONCLUSION: Here, we report on the expression of PSMA in NSCLC tissue samples. Against the background of a potential treatment with radiolabeled PSMA ligands, our data might serve for the future identification of patients who could benefit from this therapeutic option.

Correction: Potential therapeutic impact of CD13 expression in non-small cell lung cancer.

[This corrects the article DOI: 10.1371/journal.pone.0177146.].

Potential therapeutic impact of CD13 expression in non-small cell lung cancer.

BACKGROUND: Aminopeptidase N (CD13) is a zinc-binding protease that has functional effects on both cancerogenesis and tumor angiogenesis. Since CD13 is an antigen suitable for molecular targeted therapies (e.g. tTF-NGR induced tumor vascular infarction), we evaluated its impact in NSCLC patients, and tested the effects of the CD13-targeted fusion protein tTF-NGR (truncated tissue factor (tTF) containing the NGR motif: asparagine-glycine-arginine) in vivo in nude mice. METHODS: Expression of both CD13 and CD31 was studied in 270 NSCLC patients by immunohistochemistry. Clinical correlations and prognostic effects of the expression profiles were analyzed using univariate and multivariate analyses. In addition, a microarray-based analysis on the basis of the KM plotter database was performed. The in vivo effects of the CD13-targeted fusion protein tTF-NGR on tumor growth were tested in CD1 nude mice carrying A549 lung carcinoma xenotransplants. RESULTS: CD13 expression in tumor endothelial and vessel associated stromal cells was found in 15% of the investigated samples, while expression in tumor cells was observed in 7%. Although no significant prognostic impact was observed in the full NSCLC study cohort, both univariate and multivariate models identified vascular CD13 protein expression to correlate with poor overall survival in stage III and pN2+ NSCLC patients. Microarray-based mRNA analysis for either adenocarcinomas or squamous cell carcinomas did not reveal any significant effect. However, the analysis of CD13 mRNA expression for all lung cancer histologies demonstrated a positive prognostic effect. In vivo, systemic application of CD13-targeted tissue factor tTF-NGR significantly reduced CD13+ A549 tumor growth in nude mice. CONCLUSIONS: Our results contribute a data basis for prioritizing clinical testing of tTF-NGR and other antitumor molecules targeted by NGR-peptides in NSCLC. Because CD13 expression in NSCLC tissues was found only in a specific subset of NSCLC patients, rigorous pre-therapeutic testing will help to select patients for these studies.

Epigenetic dysregulation of KCa 3.1 channels induces poor prognosis in lung cancer.

Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the KCa 3.1 channel gene (KCNN4) promoter to be hypomethylated in an aggressive non-small-cell lung carcinoma (NSCLC) cell line and in patient samples. Accordingly, KCa 3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased KCa 3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro-metastatic NSCLC cells depended on KCa 3.1 activity. Mechanistically, elevated KCa 3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca(2+) influx. KCa 3.1 blockade strongly reduced the growth of xenografted NSCLC cells in mice as measured by positron emission tomography-computed tomography. Thus, loss of DNA methylation of the KCNN4 promoter and increased KCa 3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients.

Is sleeve lobectomy comparable in terms of short- and long-term results with pneumonectomy after induction therapy? A multicenter analysis.

BACKGROUND: Sleeve lobectomy (SL) is considered a valid therapeutic option in untreated, centrally located non-small cell lung cancer (NSCLC) even in patients "fit" for pneumonectomy (PN). Nevertheless, SL feasibility and long-term results after induction therapy (IT) have been only rarely investigated. We herein report the results of a multicenter retrospective study on NSCLC patients who underwent PN or SL after IT for locally advanced NSCLC. METHODS: From January 1992 to January 2012, 119 consecutive patients (94 males, 25 females) underwent in three tertiary referral centers either SL (bronchial, arterial, or both) or PN for locally advanced NSCLC after IT (chemotherapy alone or combined chemoradiotherapy). The indication for SL was based on technical feasibility. Clinical and pathologic variables were retrospectively reviewed, and treatment results were assessed and compared in both groups. Survival was calculated by Kaplan-Meier method and compared by the log-rank test as well the Cox regression model. RESULTS: Sleeve lobectomy was performed in 51 patients and PN, in 68 patients. Thirty-day mortality and morbidity rates were 3.9% and 9.8% for SL and 2.9% and 22.1% for PN, respectively. Five-year survival rates were 53.8% after SL and 43.1% after PN, respectively (p = 0.28). Overall recurrence rate was 42.8% after SL and 47.0% after PN (p = 0.34); relapse was locoregional in 22.4% of SL cases and 12.1% after PN, respectively (p = 0.011). The Cox analysis suggested pN status and right side as independent risk factors for death in the SL group (hazard ratio, 1.96; 95% confidence interval, 1.12 to 3.44; p = 0.018; and hazard ratio, 2.96; 95% confidence interval, 1.13 to 8.66; p = 0.047, respectively). As well, pN status and right side were a strong predictor of relapse (hazard ratio, 2.33; 95% confidence interval, 1.17 to 4.64; p = 0.016; and hazard ratio, 2.96; 95% confidence interval, 1.13 to 8.66; p = 0.046, respectively) in SL patients. CONCLUSIONS: For locally advanced NSCLC, SL represents a safe and effective surgical option when compared with PN even after IT, with substantially comparable early and long-term results. Nevertheless, further investigations on a large cohort of patients are needed.

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.

Management of pleural empyema with single-port video-assisted thoracoscopy.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of an original technique of single-port video-assisted thoracoscopy (S-VATS) for the minimally invasive treatment of pleural empyema in fibrinopurulent stage. METHODS: Single-port video-assisted thoracoscopy was performed under general anesthesia and single-lung ventilation using a 2-cm incision after ultrasound localization of the projected midpoint of the pleural effusion. Through the single access, a video scope and standard thoracoscopy instruments were simultaneously introduced to perform debridement and lavage of the pleural cavity. Postoperatively, patients underwent continuous or intermittent pleural irrigation through the chest tube until microbiological confirmation of sterility of the pleural fluid. RESULTS: Between November 2004 and December 2009, a total of 61 patients underwent S-VATS for pleural empyema in stage I (7%) or II (93%). Median age was 63.5 years (range, 22-94 years). Male-to-female ratio was 4.2. Surgery was performed 3 to 60 days after the onset of symptoms. Macroscopically complete debridement of the pleural cavity was achieved in most (98%) cases. Median operation time was 53 minutes (range, 29-90 minutes). No intraoperative complications occurred. In-hospital mortality and morbidity rates were 3% and 16%, respectively. Deaths were caused by diffuse metastatic colon cancer in one case and severe apoplectic insult in the other. Chest tube was removed after a median time of 12 days (range, 4-64 days). Four (6.5%) patients experienced a relapse of empyema; this was caused by complicated residual pleural space (two cases), persistent pleuropulmonary fistula (one case), or both (one case). CONCLUSIONS: It seems that S-VATS is a safe and effective procedure for the treatment of pleural empyema in fibrinopurulent stage.

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. PATIENTS AND METHOD: On exploratory analysis, patients were grouped according to location and time of diagnosis of nodal metastasis: group I, pN2-disease in the aortopulmonary region (N=14); group II, pN2-disease at other level (N=30); group III, cN2-disease with response to induction treatment (ypN0; N=21); group IV, cN2-disease without response to induction treatment (ypN1-2; N=27); group V, pN1-disease (N=66). RESULTS: From 1999 to 2005, 158 patients (median age: 64 years) with node-positive NSCLC were treated at our institution either by neoadjuvant chemo-radiotherapy plus surgery or by surgery plus adjuvant therapy (chemotherapy, radiotherapy, or both). Operative mortality and major morbidity rates were 2% and 15%. Five-year survival rates were 19% for group I, 12% for group II, 66% for group III, 15% for group IV, and 29% for group V (P<.05). On multivariate analysis, time of N+-diagnosis, extent of nodal involvement and therapy approach were significantly linked to prognosis. CONCLUSION: The survival of patients with node-positive NSCLC does not depend on anatomical location of nodal disease, but strongly correlates to extent of nodal metastases and treatment modality. Combined therapy approaches including chemotherapy and surgery may improve long-term survival.