Sebastian Dango

Sublobar resections in stage IA non-small cell lung cancer: segmentectomies result in significantly better cancer-related survival than wedge resections.

OBJECTIVE Sublobar resections spare pulmonary function and offer a method of increasing resection rates in patients with lung cancer and limited functional operability. Previous studies demonstrated an increased local recurrence rate following wedge resections compared to segmentectomies in stage IA non-small cell lung cancer (NSCLC). However, a prognostic impact of this observation has never been shown and is still under debate. Therefore, this study has been performed to analyse the cancer-related survival of sublobar resections in stage IA patients. METHODS Over a 17-year period 87 patients underwent sublobar complete resection (R0) of stage IA NSCLC via thoracotomy. Sublobar resection was reserved for patients with cardiopulmonary impairment. Wedge resections with selective lymphadenectomy were performed in 31 patients (36%) and segmentectomies with systematic lymphadenectomy in 56 patients (64%). Patient characteristics, functional parameters, tumour specifics and follow-up duration were analysed concerning their distribution between the two groups. Kaplan-Meier curves were compared and possible joint effects between prognostic parameters were analysed by multivariate Cox regression analysis. RESULTS The median follow-up duration was 45 months. There was no significant difference between the two groups in gender (p=0.11), age (p=0.08), American Society of Anesthesiology physical performance status (ASA)-score (p=0.32), forced expiratory volume in 1s FEV(1) (p=0.08), tumour size (p=0.30), histology (p=0.17), grading (p=0.12), complication rate (p=0.15) and follow-up duration (p=0.29). The mean number of dissected lymph nodes in segmentectomies (12+/-6) was higher than in wedge resections (6+/-3) (p=0.0001). The 5-year survival rate was 63%. There were significantly less locoregional recurrences (p=0.001), an equal distribution of distant metastases (p=0.53) and a better cancer-related survival (p=0.016) following segmentectomies compared to wedge resections. Cox regression analysis showed that the prognostic effect of the resection type was independent from gender, age, ASA-score, respiratory function, tumour size, tumour histology, grading and number of dissected lymph nodes (p=0.04, relative risk 1.16). CONCLUSIONS Studies investigating survival after sublobar resection of stage IA NSCLC should always distinguish between anatomical segmentectomies and wedge resections. If limited functional operability requires a sublobar resection of stage IA NSCLC, segmentectomy with systematic lymphadenectomy should be preferred.

Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is associated with increased angiogenic potential in non-small-cell lung cancer.

Recent studies have challenged the previously postulated concept of a tumor-suppressive effect of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). A possible angiogenic influence of CEACAM-1 in non-small-cell lung cancer (NSCLC) has not been investigated so far. Therefore, we examined microvessel density (MVD) and CEACAM-1 expression in primary NSCLC and analyzed their possible correlations under consideration of their prognostic effects. Specimens from 82 consecutive patients with completely resected NSCLC were stained immunohistochemically using the monoclonal anti-CEACAM-1 antibody 4D1/C2 and the monoclonal anti-CD31 antibody JC70A. The prognostic relevance of CEACAM-1 expression and MVD was evaluated by univariate Kaplan-Meier and multivariate Cox regression analysis. The median follow-up period was 75 months (range 10-156 months). A high MVD (i.e., > or =31microvessels/400x microscopic field) was observed more frequently in tumors with high CEACAM-1 expression (i.e., >/=66% stained tumor cells) than in tumors with low CEACAM-1 expression (61.8% vs. 33.3%, respectively; p=0.01). In univariate survival analyses, high CEACAM-1 expression and high MVD were associated with development of distant metastasis (p=0.011 and 0.022, respectively) and decreased cancer-related survival (p=0.046 and 0.006, respectively). Multivariate Cox regression analysis demonstrated that the prognostic impact of CEACAM-1 depended on the prognostic influence of MVD, while MVD itself represented an independent prognosticator for unfavorable cancer-related survival (p=0.021; relative risk 2.1; 95% confidence interval, 1.1-4.0). Here we show for the first time that high CEACAM-1 expression is associated with an increased angiogenic activity in NSCLC, and that the prognostic influence of CEACAM-1 might be derived from this association.

Detection of MAGE-A Transcripts in Bone Marrow Is an Independent Prognostic Factor in Operable Non–Small-Cell Lung Cancer

Purpose: MAGE-A gene expression in humans is mostly restricted to tumor cells, and the role of MAGE-A transcripts and peptides as diagnostic markers and therapeutic targets is currently under investigation. Thus far, the clinical relevance of MAGE-A transcripts as marker for disseminated tumor cells in bone marrow of patients with operable lung cancer without overt metastases is still unclear. Experimental Design: Preoperative bone marrow aspirates from 50 consecutive patients with operable non–small-cell lung cancer free of distant metastases (i.e., pT1-4 pN0-2 M0 R0) were admitted to the study. Each bone marrow sample was divided and examined using multimarker MAGE-A reverse transcription-PCR (RT-PCR) and immunocytochemical staining with the anti-pancytokeratin antibody A45-B/B3. Multimarker MAGE-A RT-PCR consisted of multiple subtype-specific nested RT-PCRs with primers for MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12. The median follow-up duration was 92 months (range, 18-110 months). Results: Twenty-six (52%) lung cancer patients harbored MAGE-A transcripts in their bone marrow, as opposed to none of the 30 healthy controls tested. In all 7 patients with immunocytochemically positive bone marrow, MAGE-A transcripts were also detected. All different MAGE-A subtypes (MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12) were observed. Sixty-five percent of patients with MAGE-A transcripts in bone marrow exhibited only one subtype. Univariate (P = 0.03, log-rank-test) and multivariate survival analysis showed that MAGE-A transcripts in bone marrow were associated with poor outcome in pN0 patients (P = 0.02; relative risk, 7.6). Conclusions: Detection of MAGE-A transcripts in bone marrow predicts an unfavorable outcome in patients with early-stage operable lung cancer. This finding indicates that MAGE-A transcripts are clinically relevant markers of micrometastatic spread in lung cancer and supports further investigation of MAGE-A as potential future therapeutic target.

Detection of disseminated tumour cells in mediastinoscopic lymph node biopsies and endobronchial ultrasonography-guided transbronchial needle aspiration in patients with suspected lung cancer

PURPOSE Ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes (EBUS-TBNA) is apparently more accurate for cancer diagnosis than standard transbronchial needle aspiration (TBNA), but it is less sensitive than mediastinoscopy. The detection of disseminated tumour cells in transbronchial needle aspiration and mediastinoscopic biopsies could improve staging and might be helpful concerning indications for neoadjuvant regimen. The goal of this study was to develop a quantitative method for the detection of disseminated tumour cells (DTCs) in lymph node samples from patients with suspected lung cancer. PATIENTS AND METHODS We compared in a prospective trail EBUS-TBNA (n=58 patients, 86 samples) and mediastinoscopy (n=22 patients, 37 samples) in two largely independent cohorts of lung cancer patients. Eleven patients, 14 samples were analysed using both methods. Patients without evidence of malignant disease were available as controls for EBUS-TBNA (n=20 patients, 28 samples) and mediastinoscopy (n=6 patients, 8 samples). Real-time quantitative mRNA analysis was performed for the cytokeratin 19 (CK19) and MAGE-A genes (MAGE-A 1-6, MAGE-A12) as markers, using a LightCycler 480 instrument. RESULTS CK19 mRNA expression in EBUS-TBNA samples was detected in 84/86 (98%) and in 28/28 control samples (100%). After mediastinoscopy 16/37 (43%) samples of lung cancer patients were CK19 mRNA positive while controls showed no CK19 mRNA expression (0/8). MAGE-A expression was detectable in 42/86 (49%) EBUS-TBNA samples and in 13/37 (35%) mediastinoscopy samples. MAGE-A expression was detected in EBUS-TBNA controls in 3/28 (11%) and 1/8 (12%) mediastinoscopy controls. High MAGE-A expression correlated with increased tumour stage. CONCLUSION Since CK19 expression was detected in all EBUS-TBNA samples from the control patients, but not in mediastinoscopy samples, we conclude that CK19 is not suitable as a marker for disseminated tumour cells in samples attained by EBUS-TBNA. One possible explanation is a contamination with epithelial cells from the bronchial tubes. MAGE-A genes are promising markers for disseminated tumour cells in lymph nodes in patients with suspected lung cancer which merit further investigation.

Impact of chest tube clearance on postoperative morbidity after thoracotomy: results of a prospective, randomised trial

OBJECTIVE In many centres of thoracic surgery, milking of chest tubes is performed to prevent them from blocking. The usefulness of chest tube clearance is discussed controversially. Therefore, we investigated the impact of postoperative chest tube milking on postoperative outcome in a prospective, randomised trial. METHODS Within a period of 11 months, 145 patients undergoing pulmonary resection through thoracotomy were included in the study. Two chest tubes each (silicone drainage, Redax, Mirandola, Italy) were placed in all patients (ventral tube 21Ch and dorsal tube 24Ch). Milking was applied to both chest tubes for 1 min every 2h within the first 48 h postoperatively and continuous suction of -20 cm H(2)O was maintained for 48 h. Duration of chest tube drainage, quantity and quality of effusion or air leakage, co-morbidity, length of hospital stay and 30-day postoperative morbidity and mortality were analysed. Furthermore, outcome was measured by assessment of chest radiographs at the time of discharge from hospital. RESULTS Randomisation resulted in milking of chest tubes of 73 patients and in observation of chest tubes without any manipulation in 72 patients. Twenty-one patients had to be excluded from further analysis due to violation from the study protocol (n=9), necessity of replacement of a chest tubes (n=9) and re-operation for bleeding (n=3). The 30-day mortality rate was 1.4% in each group and the 30-day morbidity was 49.3% in the milking group and 52.8% in the observation group. Milking of chest tubes was not associated with a lower postoperative mortality or morbidity (p=0.99 and p=0.67, respectively; chi-square test). We observed a significant increase of postoperative pleural effusion drainage in the milking group 48 h after surgery (p=0.004; unpaired t-test). No correlation was seen between milking of chest tubes and the duration of chest tube drainage, quality of effusion, air leakage or length of hospitalisation. CONCLUSIONS We showed for the first time that postoperative chest tube milking is associated with a significant increase of pleural fluid drainage. Postoperative morbidity and mortality was not improved and therefore chest tube milking cannot be recommended as a routine postoperative procedure.

The role of a pseudocapsula in thymic epithelial tumors: outcome and correlation with established prognostic parameters. Results of a 20-year single centre retrospective analysis

BackgroundTreatment of thymoma is often based on observation of only a few patients. Surgical resection is considered to be the most important step. Role of a pseudocapsula for surgery, its clinical significance and outcome compared with established prognostic parameters is discussed which has not been reported so far.Methods84 patients with thymoma underwent resection and analysis was carried out for clinical features, prognostic factors and long-term survival.ResultsFifteen patients were classified in WHO subgroup A, 21 in AB, 29 in B and 19 patients in C. Forty two patients were classified in Masaoka stage I, 19 stage II, 9 stage III and 14 stage IV. Encapsulated thymoma was seen in 40, incomplete or missing capsula in 44 patients. In 71 complete resections, local recurrence was 5%. 5-year survival was 88.1%. Thymomas with pseudocapsula showed a significant better survival (94.9% vs. 61.1%, respectively) (p = 0.001) and was correlated with the absence of nodal or distant metastasis (p = 0.04 and 0.001, respectively). Presence of pseudocapsula as well as the Masaoka and WHO classification, and R-status were of prognostic significance. R-status and Masaoka stage appeared to be of independent prognostic significance in multivariate analysis.ConclusionIntraoperative presence of an encapsulated tumor is a good technical marker for the surgeon to evaluate resectability and estimate prognosis. Although the presence of a capsula is of strong significance in the univariate analysis, it failed in the multivariate analysis due to its correlation with clinical Masaoka stage. Masaoka stage has a stronger relevance than WHO classification to determinate long-term outcome.

The future in diagnosis and staging of lung cancer : Molecular techniques

Lung cancers at the same stage of disease have markedly different rates of disease progression. In this review, we will address current molecular techniques which provide new opportunities according to diagnosis, prediction of survival or selection of therapy. New molecular techniques might be helpful in TNM staging and lead to additional individual prognostic information. A revised TNM system could include a TNM component and a molecular supplemental component allowing new markers to be evaluated without undermining the value of classic TNM staging. Furthermore, molecular techniques might be helpful in the early or differential diagnosis of lung cancer. Since many new targeted agents are effective only if their respective molecular markers are mutated or expressed at sufficient levels, DNA-based or RNA-based techniques have the potential to influence treatment selection in the future. Overall, we can expect that molecular markers will contribute to a more personalized lung cancer treatment.

Initial experience with a synthetic sealant PleuraSeal™ after pulmonary resections: a prospective study with retrospective case matched controls

The objective of this study was to evaluate postoperative outcome and efficacy of a hydrogel tissue sealant for prevention of alveolar leakage after open lung resections.20 consecutive patients were enrolled in the PleuraSeal™ sealant group (PSG) and case matched with 20 retrospective controls (CG) with standard treatment. Assessment of postoperative air leakage was performed until chest tube removal. Patients were followed until 30 days after discharge.At end of surgery, 100% in the PSG and 0% in the CG were air leak free (p < 0.001). Duration of postoperative chest tube suction was shorter in PSG (p < 0.001), and air leak chest tube was removed earlier (p = 0.03). Limitation for chest tube removal due to a pulmonary leak was 35% in CG and 5% in PSG (p = 0.04). Patients remaining air leak free thru discharge was 95% and 15% for PSG and CG (p < 0.001).The study demonstrated a superior efficacy of PleuraSeal™ sealant compared with standard surgical treatment for sustained sealing of postoperative air leakage and causes shorter air leak chest tube duration.

MAGE qPCR Improves the Sensitivity and Accuracy of EBUS-TBNA for the Detection of Lymphatic Cancer Spread

Introduction: Microscopic examination of histologic slides or cytologic specimens of mediastinal lymph node samples obtained by diagnostic mediastinoscopy or endobronchial ultrasound-guided fine-needle aspiration (EBUS-TBNA) is routinely used for the staging of lung cancer patients. Therefore, we explored whether the detection of tumor-associated mRNA in lymph node samples from patients with suspected lung cancer adds diagnostic accuracy to conventional histopathological staging. Methods: We examined 202 lymph nodes obtained by EBUS-TBNA or mediastinoscopy from 89 patients with lung cancer. Lymph node samples from patients with nonmalignant disease were available as controls (60 samples from 31 patients). Real-time quantitative mRNA analysis was performed for melanoma antigen-A genes (MAGE-A 1–6, MAGE-A 12) using a LightCycler 480 instrument. Results: MAGE transcript levels in control and cancer patients differed widely, and the 95% confidence interval served to define the threshold between negative and positive samples. MAGE 1 to 6 transcripts were detected in 35 of 122 (28.7%) lymph nodes obtained by EBUS-TBNA and 16 of 80 (20.0%) lymph nodes obtained by mediastinoscopy. MAGE 12 transcripts were detected in 10 of 122 (8.2%) lymph nodes obtained by EBUS-TBNA and 9 of 80 (11.3%) lymph nodes obtained by mediastinoscopy. Although the accuracy of histopathological diagnosis after EBUS-TBNA and mediastinoscopy was 69.6% and 84.1%, respectively, it increased to 81.2% and 86.4%, respectively, when combined with MAGE-quantitative polymerase chain reaction. Conclusions: The combination of EBUS-TBNA and MAGE-quantitative polymerase chain reaction increases the accuracy of tumor cell detection to the level seen with mediastinoscopy.

Endobronchial ultrasound‐guided transbronchial needle aspiration and its role in non‐small cell lung cancer: Diagnostic impact and limitations

A diagnostic work‐up to evaluate possible mediastinal lymph node involvement in patients with non‐small cell lung cancer (NSCLC) should be performed once suspected as a result of computed tomography. Cytological/histological verification is always compulsory. In recent years, diagnostic tools for mediastinal evaluation have made great technical progress with the introduction of endosonographic real‐time ultrasound techniques such as endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA). Mediastinal masses as well as lymph node enlargement can be clarified by endosonographic guided biopsies and play a key role in cytological examination of mediastinal lymph nodes. The proven high sensitivity of endosonographic guided biopsies and the high negative predictive value of 20% may challenge mediastinoscopy, which has a sensitivity of 80–95%. However, with a higher positive predictive value and being the best explored method in the literature, mediastinoscopy still has a better diagnostic yield for mediastinal staging. However, according to us EBUS‐TBNA should be considered for staging in patients with NSCLC primarily, but negative results must be followed by mediastinoscopic evaluation.