Severin Schmid

Altered purinergic signaling in the tumor associated immunologic microenvironment in metastasized non-small-cell lung cancer.

OBJECTIVES Purines are well-known as intracellular sources for energy but they also act as extracellular signaling molecules. In the recent years, there has been a growing interest in the therapeutic potential of purinergic signaling for cancer treatment. This is the first study to analyze lung purine levels and purinergic receptors in non-small-cell lung cancer (NSCLC) patients. MATERIALS AND METHODS In this prospective clinical trial we enrolled 26 patients with NSCLC and 21 patients with chronic obstructive pulmonary disease (COPD) without signs of malignancy. The purine concentrations were analyzed in bronchoalveolar lavage fluid (BALF) using fluorescent/luminescent assays. Expression of purinergic receptors and ectonucleotidases were analyzed using real time quantitative polymerase chain reaction (RT-qPCR). RESULTS Patients with NSCLC have significantly lower ATP and ADP concentrations in BALF than patients with COPD (p=0.006 and p=0.009). Expression of the ectonucleotidase CD39 is significantly higher in BAL cells from cancer patients compared to COPD (p=0.001) as well as in metastasized tumors compared to non-metastasized tumors (p=0.009). Receptor-analysis revealed a higher expression of P2X4 (p=0.03), P2X7 (p=0.001) and P2Y1 (p=0.003) in BAL cells of tumors with distant metastasis. CONCLUSION Our data suggests a role for CD39 in lung cancer tumor microenvironment, influencing tumor invasiveness and metastasization. Potentially the increased degradation of ATP and ADP leads to a subversion of their anti-neoplastic effects. Furthermore P2Y1, P2X4 and P2X7 receptors are upregulated in BAL cells in metastatic disease. Our findings might facilitate the identification of new therapeutic targets for cancer immunotherapy.

A threshold of systemic MAGE-A gene expression predicting survival in resected non-small cell lung cancer.

Purpose: Quantitative measurement of minimal residual disease predicting recurrence in individual cancer patients is available only in very few indications, such as acute lymphoblastic leukemia, but is still missing in most solid tumors, including non–small cell lung cancer (NSCLC). Experimental Design: MAGE-A expression levels in blood and bone marrow determined as calibrator-normalized relative ratios by quantitative multimarker real-time RT-PCR for transcript amplification of MAGE-A1, -A2, -A3/6, -A4, -A10, and -A12 in 94 patients with completely resected NSCLC were correlated with survival in a clinical study. Results: Patients with MAGE-A expression levels ≥0.2 in at least one sample of bone marrow or blood at tumor surgery had a significantly reduced overall (P = 0.007), cancer-free (P = 0.002), and distant metastasis–free survival (P < 0.001) versus patients below 0.2 in all samples without significant difference in locoregional recurrence–free survival. The corresponding HRs (≥0.2 vs. <0.2) for death, cancer-related death, and development of distant metastasis were 2.56 [95% confidence interval (CI), 1.42–4.63], 3.32 (95% CI, 1.66–6.61), and 4.03 (95% CI, 1.77–9.18), respectively. Five-year Kaplan–Meier estimates of distant metastasis–free survival were 43% (MAGE-A ≥ 0.2) versus 87% (MAGE-A < 0.2). Conclusions: MAGE-A expression in blood or bone marrow at tumor surgery is an independent predictor of survival in resected NSCLC. The reliable prediction of distant metastasis in individual patients with a statistically proven impact on overall survival may help to refine patient selection for adjuvant therapy urgently needed, especially in the clinical management of elderly patients. Clin Cancer Res; 23(5); 1213–9. ©2016 AACR.

Prognostic factors in solitary fibrous tumors of the pleura

BACKGROUND Solitary fibrous tumors of the pleura (SFTP) are rare neoplasms originating from submesothelial mesenchymal cells with fibroblastic differentiation. The clinical behavior of SFTPs is mostly benign; however, up to 20% of patients develop local recurrence and/or distant metastasis. Although different risk-stratification models have been described, definitive criteria to predict a malignant clinical course of SFTP are still lacking. METHODS In a retrospective analysis at a single-institution, 25 patients with histologically proven SFTP were identified. Clinicopathologic and survival data were collected and pathologic sections reviewed. Different markers and risk-stratification models were correlated with disease- and overall-free survival by Kaplan-Meier analysis. RESULTS Of 25 SFTP, 8 tumors (32%) were classified as malignant according to the World Health Organization criteria. Three patients (12%) developed recurrence. Cohort median follow-up was 28 mo, and median overall survival was 160 mo. Comparison of proliferation markers showed higher mitosis count per high-power field and MIB-1 labeling index (MIB) in malignant compared with nonmalignant SFTP. MIB was identified as a predictor for disease-free survival. Applying the previously reported classifications to categorize SFTP according to the probability to show malignant behavior, significant differences in disease-free survival were also present in our cohort. CONCLUSIONS In the present analysis of rare SFTP, previously proposed staging systems were applicable for prediction of disease-free survival. Independently of treatment, MIB was the only sole predictive marker. A prospective multi-institutional database could be helpful in establishing detailed predictive criteria in patients diagnosed with SFTP.

Significance of the resection margin in bronchopulmonary carcinoids

BACKGROUND Complete surgical resection is the treatment of choice in bronchopulmonary carcinoids. Previously published data showed no inferiority of sublobar versus lobar resection. Data on the length of resection margins are lacking; thus, we aimed to analyze resection margins in pulmonary carcinoids and correlated them with survival and recurrence. METHODS We retrospectively analyzed 85 patients who underwent surgery for atypical (AC) or typical (TC) pulmonary carcinoids. Patient charts were reviewed, and clinicopathologic and survival data were collected. Pathology reports were reviewed for length of resection margins. RESULTS The median follow-up period was 42.3 mo (range, 0.3-172.2). There was no statistically significant difference in disease-free survival (DFS) when comparing resection margins ≤2 mm to >2 mm (P = 0.93, hazard ratio = 1.7). When looking at AC alone, a worse DFS can be seen if the resection margin was smaller than 2 mm (P = 0.06, hazard ratio = 15.8). In AC, likelihood of recurrence was higher when the resection margin was ≤1 cm (odds ratio = 5.1, P = 0.28). In TC, this tendency was not present (odds ratio = 1.2, P = 1). CONCLUSIONS There is a trend toward a worse prognosis and higher likelihood of recurrence in smaller resection margins in AC in contrast to TC. Owing to low sample size, no definitive statements can be made based on this study; however, respective data on these rare tumors cannot be drawn from tumor databases. The resection margin is one of the critical issues for the treating surgeon, and any information on this topic is of highest importance to the field.

Prognostic value of lymph node ratio after induction therapy in stage IIIA/N2 non-small cell lung cancer: a monocentric clinical study

Background The optimal treatment modalities for patients with stage IIIA N2 non-small cell lung cancer (NSCLC) are still a matter of debate. To provide best outcome and to avoid unnecessary treatment patient selection for surgical therapy is crucial. In addition to mediastinal downstaging the lymph node ratio (LNR) has been suggested as a prognosticator in this patient group. Methods We retrospectively reviewed clinical and histopathologic data of 78 patients with stage IIIA N2 NSCLC, who underwent induction therapy with two cycles of platinum-based chemotherapy for intended surgery at our clinic between 2009 and 2016. To evaluate the prognostic value of the LNR the cut off was set at 0.33 as reported in prior literature. Results The median follow-up time was 30.1 months. In multivariate analysis mediastinal down staging was associated with a longer overall survival (OS): 52.2 (range, 5.9-89.7) months for ypN0 versus 24.6 (4.4-84.2) months for ypN1/2 (HR, 2.76; 95% CI, 1.07-7.1, P=0.0348). LNR ≤0.33 was linked to a better OS of 39.3 (range, 5.9-89.7) months compared to 14.7 (range, 4.4-66.2) months for a LNR >0.33 in univariate analysis (P=0.037). In multivariate analysis a statistical trend could be observed (HR, 2.82; 95% CI, 0.98-8.14, P=0.1). In patients with persistent lymph node involvement the LNR could also identify a subgroup of patients with a favorable prognosis (30.1 vs. 14.7 months, P=0.145). Conclusions Mediastinal downstaging remains the best prognosticator in stage IIIA N2 NSCLC after induction therapy. However, using the LNR in patients with persistent mediastinal lymph node metastasis a subgroup with a favorable prognosis could be identified. The LNR could aid in finding the best treatment modalities for these patients.

Pulmonary metastasectomy in sarcoma—experiences with laser- assisted resection

Background Previous data suggest a survival benefit in well selected patients with extrathoracic sarcoma after pulmonary metastasectomy. Different techniques have been described for pulmonary metastasectomy; however laser-assisted surgery (LAS) was suggested to provide the best outcome in patients with higher numbers of metastases. Methods Data were extracted from a prospectively maintained institutional database and a total of 83 patients who underwent pulmonary metastasectomy at our clinic in the last 11 years were identified. Results We analyzed a total of 106 operations of which LAS was performed in 46 and conventional resection in 60 cases. Significantly more metastases were resected in the LAS group compared to the conventional group [median, interquartile range (IQR): 6.5 (2.0-11.0) vs. 1.0 (1.0-3.5); P<0.0001]. Despite this difference the number of tumor recurrences was similar in both groups [64% tumor recurrences in the LAS group and 58% in the conventional group, odds ratio (OR) =1.3, P=0.6]. Furthermore, overall survival (OS) was comparable with a median survival of 77.6 and 29.0 months and 2- and 5-year survival rates of 71% and 63% as well as 53% and 36% in the respective cohorts [hazard ratio (HR) =0.74, P=0.43]. Conclusions Using LAS a significantly higher number of metastases were removed while producing similar long-term results as compared to patients treated by other techniques. Expectably, recurrence rates in metastasized sarcoma patients remain high with either surgical method. Future studies will have to evaluate possible advantages provided by LAS in a prospective manner.

CC-Chemokine Ligand 18 Is an Independent Prognostic Marker in Lymph Node-positive Non-small Cell Lung Cancer

Background/Aim: Tumor-associated macrophages (TAMs) are key players in the immune response in non-small cell lung cancer (NSCLC) and the main producers of CC-chemokine ligand 18 (CCL18). Our study aimed to analyze the clinical significance of CCL18 expression by TAMs in NSCLC. Material and Methods: Tissue multi-arrays from 243 non-selected patients with NSCLC were constructed. Immunohistochemical double staining for CD68 and CCL18 was performed and the number of CD68+, as well as CCL18+/CD68+ macrophages determined. Results: Comparison of early to advanced lung adenocarcinoma showed significantly more frequent CD68+ as well as CD68/CCL18 double-positive macrophages in advanced disease (p=0.03 and p=0.04). Multivariate analysis revealed a higher proportion of double-positive macrophages to be an independent prognosticator in lymph node-positive NSCLC (hazard ratio(HR)=0.6, 95% confidence interval(CI)=0.35-0.86, p=0.009). Conclusion: In advanced lung adenocarcinoma, infiltration of CCL18+ TAMs was increased and higher expression of CCL18 by TAMs was associated with a favorable prognosis in lymph-node positive NSCLC.

Typische und atypische Karzinoide der Lunge: chirurgische Behandlungsstrategie

Pulmonary typical (TC) and atypical carcinoids (AC) are lung tumors with neuroendocrine differentiation. Pulmonary carcinoids account for < 2 % of all lung cancers and the incidence is around 0,5/100 000. Depending on localization and extension they present incidentally or symptomatically with cough, hemoptysis and postobstructive pneumonia. Less than 1 % are associated with endocrine activity. TC and AC are differentiated by defined histopathologic criteria (mitotic rate, necrosis). Patients with TC have excellent long-term survival after non-anatomical lung resection. AC are associated with higher recurrence rates and anatomical lung resection should be preferred. Radical mediastinal lymph node dissection should be performed for both TC and AC. Complete surgical resection is the most significant prognostic factor for localized carcinoids. Surgical metastasectomy should also be considered in case of resectable metastatic disease.

Intrapulmonary Castleman’s Disease Pretending to Be a Lung Cancer—Work Up of an Intrapulmonary Tumour

A 24 year old male presented with a history of recurrent bronchopulmonal infections. Chest computed tomography was performed, revealing a right central mass. In the following bronchoscopy and ultrasound guided needle aspiration of the tumour no specific diagnosis could be obtained. Due to the central location of the tumour thoracotomy and middle lobe resection was performed. Histopathological analysis revealed an intrapulmonary, subpleural located Morbus Castleman of the hyaline-vascular type.Castlemans disease is a very rare disorder of the lymphatic tissue that is differentiated into two clinical subtypes. The localized type presents histologically almost always as the hyaline-vascular form. Findings have been reported in mediastinal lymph nodes, the abdomen and peripheral lymphnodes. Intrapulmonary development is very rare and only 9 cases have previously been described in literature.On the other hand the multicentric type accounts for approximately 10%-15% of cases and histologically usually presents as the plasma cell variant. It is accompanied by fatigue and general weakness and often requires systemic steroid or chemotherapy.The localized type develops less clinical symptoms and is curable by complete surgical resection.