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Objectives: The oncological equivalence of anatomical segmentectomy for early stage non-small cell lung cancer (NSCLC) is still controversial. Primary aim of this study was survival outcomes in combination with improved quality of life after segmentectomy compared with lobectomy in patients with pathological stage Ia NSCLC (up to 2 cm, 7th edition) Materials and Methods: We conducted a prospective, randomized, multicenter phase III trial to confirm the non-inferiority of segmentectomy to lobectomy in regard to prognosis (trial No. DRKS00004897). Patients were randomized to undergo either segmentectomy or lobectomy and followed up for 5-years survival and tumor recurrence. The 5-year hazard ratio comparing lobectomy with segmentectomy was required to remain above 0.5. Results: Between October 2013 and June 2016, 108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled; 54 were assigned to lobectomy and 54 (1 drop-out) to segmentectomy. In-hospital and 90 days mortality was 0% in both groups. Overall survival at 5 years was 86.52% in the lobectomy compared to 78.21% in the segmentectomy group (HR = 0.61, (95% CI 0.23–1.66), p-value of non-inferiority test, p-ni = 0.687). Disease free survival was 77.29% for the lobectomy and 77.96% for the segmentectomy patients (HR = 1.50, (95% CI 0.60–3.76), p-ni = 0.019). At a median follow-up of 5 years, no differences were noted in either the locoregional or distant recurrent disease in both groups (9.4% vs 7.4%, p-ni = 0.506). Conclusion: Overall survival, locoregional and distant recurrences was not significantly difference for patients undergoing either segmentectomy or lobectomy for stage Ia NSCLC. The targeted non-inferiority of segmentectomy to lobectomy could not be proven for primary endpoint overall survival, but was significant for the secondary endpoint of disease free survival.

Background: Pulmonary metastasectomy (PM) is an established treatment option for selected patients with stage IV solid tumors. The aim of this study was to investigate the feasibility of and survival rate in PM for elderly patients. Methods: We retrospectively analyzed all of the patients who underwent PM with curative intention at our institution. The patients were categorized into two groups: the elderly group (≥70 years old) and the non-elderly group (

Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non‐small‐cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted‐capture high‐throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early‐stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative‐intent tumor resection (median follow‐up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1–2 weeks postsurgery, and during follow‐up. Deep next‐generation sequencing using unique molecular identifiers was performed to identify and quantify tumor‐specific mutations in ctDNA. Twelve patients (57%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57% versus 19% ctDNA detection rate, and 12.47 versus 6.64 ng·mL−1, respectively). Four patients (19%) remained ctDNA‐positive at 1–2 weeks after surgery, with all of them (100%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA‐negative patients (33%) after surgery experienced relapse during follow‐up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression‐free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early‐stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse., ctDNA profiling in plasma revealed higher levels and detection rates of ctDNA during tumor resection as compared to pretreatment time points in patients with early‐stage or locally advanced NSCLC. Moreover, patients testing positive for ctDNA immediately after tumor resection had worse clinical outcomes than patients with undetectable ctDNA. Our research highlights the role of ctDNA assessment for guiding treatment in patients with respectable NSCLC.

Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133+ cancer stem cells and PD-L1+CD73+ myeloid cells were detectable in primary human SCLC tissues, suggesting that patients may benefit from the triple-immunotherapy. We conclude that the combination of AC133-specific CAR T cells, anti-PD-1-antibody and CD73-inhibitor specifically eliminates chemo-resistant tumor stem cells, overcomes SCLC-mediated T cell inhibition, and might induce long-term complete remission in an otherwise incurable disease.

The COVID-19 pandemic led to a major disturbance in the health care system. Many elective operations were postponed, including surgical oncology cases. Besides the need to contain hospital resources, this was also due to concerns about the safety to perform surgery during the pandemic and the impact of perioperative infections on postoperative outcomes. In this study we investigate the safety of surgery for thoracic malignancies during the COVID-19 pandemic.We retrospectively analysed the outcome of surgery for thoracic malignancies during the first, second and third waves of the COVID-19 pandemic (from 01.01. to 30.04.2020 and from 01.01. to 30.04.2021). As a control group we included the patients who received thoracic oncology surgeries during the same period in the last 2 years before the onset of the pandemic. The primary outcome was the rate of postoperative complications.236 operations were included in the pandemic group and 227 operations in the control group. There was no statistically significant difference in the rate of postoperative minor complications (16.1% vs. 18.5%, p = 0.5395) or major complications (12.2% vs. 10.13 %, p = 0.5563). The risk to develop postoperative pulmonary complications was not higher in the pandemic group (odds ratio 1.193, 95% CI 0.6515-2.203, p = 0.8232). There were 5 cases with COVID-19 infection after the operation in the pandemic group. There was no difference in the rate of postoperative mortalities (2 (0.85%) vs. 1 (0.44%), p 0.9999) There was no COVID-19 related mortality.Maintaining oncologic thoracic surgery during the COVID-19 pandemic is safe, feasible and not associated with increased risks of postoperative complications or mortalities.Die COVID-19-Pandemie hatte, neben der offensichtlichen Bedeutung als eigenständige Erkrankung, einen schwerwiegenden Einfluss auf alle Aspekte der medizinischen Versorgung. In der onkologischen Chirurgie mussten Operationen verschoben werden oder es kam zu verzögerten Diagnosen onkologischer Erkrankungen, was neben der Sorge um unzureichende Ressourcen auch in der Unsicherheit bezüglich der perioperativen Risiken begründet lag. In dieser Studie untersuchen wir die Sicherheit der Durchführung onkologischer thoraxchirurgischer Eingriffe während der COVID-19-Pandemie.Es wurden retrospektiv die Ergebnisse der thoraxchirurgischen Operationen bei onkologischen Patienten am Universitätsklinikum Freiburg während der 1., 2. und 3. Welle der COVID-19-Pandemie (vom 01.01. bis 30.04.2020 sowie vom 01.01. bis 30.04.2021) untersucht. Als Kontrollgruppe wurden die im gleichen Zeitraum vor der Pandemie (2018 und 2019) durchgeführten Operationen gewählt. Der primäre Endpunkt war das Auftreten postoperativer Komplikationen.236 Operationen in der Pandemiekohorte und 227 Operationen in der Kontrollkohorte wurden in die Studie eingeschlossen. Es gab keinen Unterschied in der Inzidenzrate von postoperativen Minor-Komplikationen (16,1% vs. 18,5%, p = 0,5395) oder Major-Komplikationen (12,2% vs. 10,13%, p = 0,5563) zwischen der Pandemiekohorte und der Kontrollkohorte. Es zeigte sich kein erhöhtes Risiko für postoperative pulmonale Komplikationen in der Pandemiekohorte (Odds Ratio = 1,193, 95%-KI= 0,6515–2,203, p = 0,8232). Eine COVID-19-Infektion nach der Operation trat bei 5 Patienten der Pandemiekohorte auf (2,29%). Die postoperative Motilität innerhalb von 30 Tagen waren vergleichbar zwischen der Pandemiekohorte und der Kontrollkohorte (2 (0,85%) vs. 1 (0,44%), p 0,9999). Es gab keine COVID-19-infektionsbedingte Mortalität.Die Durchführung von onkologischen thoraxchirurgischen Operationen während der COVID-19-Pandemie ist, unter Einhaltung der entsprechenden Sicherheitsmaßnahmen, sicher und weder mit einer erhöhten Komplikationsrate noch einer erhöhten Mortalität verbunden.

For early stage non-small cell lung cancer (NSCLC) retrospective data of functionally compromised patients undergoing segmentectomy showed equal outcomes for perioperative complications and quality of life (QoL) compared with lobectomy patients. However no prospectively randomized data comparing patients eligible for both procedures are available.We conducted a prospective, randomized, multicenter phase III trial and investigated perioperative complications and QoL in patients with NSCLC stage IA (7th edition) undergoing segmentectomy versus lobectomy. The EORTC Questionnaire Core-30 (QLQ C-30) supplemented by thirteen-item lung cancer-specific module (LC13) was assessed before surgery, at discharge, 6 weeks, 3, 6 and 12 months post-surgery.108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled, whereby 54 were assigned to lobectomy and 54 to segmentectomy. Due to nodal disease, tumor size and surgical reasons estimated during the operation, eight patients of the segmentectomy group received a lobectomy. In hospital and 90 days mortality was 0% in both groups. Perioperative complications were observed in 6 (11.3%) patients after segmentectomy and in 8 patients (14.8%) after lobectomy (p = 0.563), while the 90-day morbidity were 17% and 25.9% (9 and 14 patients), respectively (p = 0.452). Twelve months after surgery, there was a significant deterioration to the baselines of physical (p 0.001) and cognitive functioning (p = 0.025), dyspnea (p 0.001) and fatigue (p = 0.003) in the lobectomy group. Dyspnea showed a faster recovery in the segmentectomy compared to lobectomy group with statistical significance (p = 0.016 after 12 months).In patients with early-stage NSCLC, segmentectomy is associated with a statistically not significant lower perioperative morbidity and appears to provide a superior recovery in QoL compared with lobectomy patients.

Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133

Objectives Distant metastasis arising from thyroid cancer is rare but has been associated with significantly reduced long-term survival, especially when refractory to radioactive iodine ablation. We provide one of the largest studies worldwide reporting the outcome after salvage pulmonary metastasectomy for this entity, aiming to identify prognostic factors and to analyse surgical indication. Methods We retrospectively analysed the medical records of 43 patients who had undergone pulmonary metastasectomy for radioactive iodine-refractory thyroid cancer from 1985 to 2016. Results The median follow-up period was 77 (95% confidence interval 41-113) months. Twenty-three (53%) patients were alive at the time of analysis. The majority of tumours were follicular thyroid cancer by histology, with 23% identified as Hurthle cell subtype. Five- and 10-year disease-specific (DS) survival was 84% and 59%, respectively. Thirty-one (72%) patients underwent R0-resection with a 5- and 10-year DS survival of 100% and 77%, respectively. This was significantly reduced to 62% and 22% (P = 0.013) in case of incomplete resection, respectively. Ten years after R0-metastasectomy, 17 (55%) patients were recurrence-free. Systematic mediastinal lymphadenectomy was performed in 16 (37%) patients and was associated with improved long-term DS survival (10 years 88% vs 46%, P = 0.034). Moreover, a reduction of > 80% in serum thyroglobulin levels post-metastasectomy correlates with better long-term DS survival (10 years 81% vs 36%, P = 0.007). Conclusions Pulmonary metastasectomy is associated with good survival for selected patients with radioactive iodine-refractory metastases of differentiated thyroid cancer, especially if R0-resection can be achieved. Moreover, it is worth considering whether a significant reduction of tumour load, as indicated by thyroglobulin serum levels, seems possible.

Postoperative haemothorax following thoracic surgery is a rare complication, but associated with a high mortality. In the literature, this complication occurs in 0.6 to 4.6% of patients and with a mortality of 5.1 to 17.8%. In minor cases, chest tube placement, application of fresh frozen plasma (FFP) or transfusion can be sufficient to control the situation. In severe cases, re-thoracotomy is mandatory. The most frequent origin of bleeding is a bronchial or intercostal vessel (21 and 16%) or the area of pleural adhesions that were separated (10.5%). The pulmonal artery or vein were the origin of bleeding in 16% of cases while in most cases (37%) active bleeding could no longer be detected. A positive effect on postoperative outcome is observed after an early reoperation.Die postoperative Nachblutung nach thoraxchirurgischen Eingriffen ist eine seltene, aber mit einer hohen Mortalität verknüpfte Komplikation. In der Literatur wird die Häufigkeit mit 0,6 – 2% bzw. 3 – 4,6% angegeben bei einer Mortalität von 5,1 bis zu 17,8%. Bei leichten Blutungen kann der Abfluss über die Thoraxdrainagen, Substitution von Gerinnungsprodukten (Fresh frozen Plasma, Tranexamsäure) und die Transfusion von Erythrozytenkonzentraten (EK) ausreichend sein, um diese zu kontrollieren. Bei ausgeprägten Blutungen ist jedoch meist eine Rethorakotomie erforderlich. Die Ursache der Nachblutung liegt meist in einem Bronchial- oder Interkostalgefäß (21 und 16%) oder an der Thoraxwand bei ausgedehnter Pleurolyse (10,5%). Die Pulmonalarterie oder -vene war nur in 16% Ursache der Blutung und in den meisten Fällen (37%) konnte keine aktive Blutungsquelle mehr identifiziert werden. Einen günstigen Effekt auf das postoperative Outcome nach Nachblutung scheint die rasche Revisionsoperation zu haben.

Background The optimal perioperative analgesic strategy in video-assisted thoracic surgery (VATS) for anatomic lung resections remains an open issue. Regional analgesic concepts as thoracic paravertebral or epidural analgesia were used as systemic opioid application. We hypothesized that regional anesthesia would provide improved analgesia compared to systemic analgesia with parenteral opioids in VATS lobectomy and would be associated with a lower incidence of pulmonary complications. Methods The study was approved by the local ethics committee (AZ 99/15) and registered (germanctr.de; DRKS00007529, 10th June 2015). A retrospective analysis of anesthetic and surgical records between July 2014 und February 2016 in a single university hospital with 103 who underwent VATS lobectomy. Comparison of regional anesthesia (i.e. thoracic paravertebral blockade (group TPVB) or thoracic epidural anesthesia (group TEA)) with a systemic opioid application (i.e. patient controlled analgesia (group PCA)). The primary endpoint was the postoperative pain level measured by Visual Analog Scale (VAS) at rest and during coughing during 120 h. Secondary endpoints were postoperative pulmonary complications (i.e. atelectasis, pneumonia), hemodynamic variables and postoperative nausea and vomiting (PONV). Results Mean VAS values in rest or during coughing were measured below 3.5 in all groups showing effective analgesic therapy throughout the observation period. The VAS values at rest were comparable between all groups, VAS level during coughing in patients with PCA was higher but comparable except after 8–16 h postoperatively (PCA vs. TEA; p

Circulating tumor cells (CTC) have been studied extensively in various tumor types and are a well-established prognosticator in colorectal cancer (CRC). This is the first study to isolate CTC directly from the tumor outflow in secondary lung tumors. For this purpose in 24 patients with CRC who underwent pulmonary metastasectomy in curative intent blood was drawn intraoperatively from the pulmonary vein (tumor outflow). In 22 samples CTC-enumeration was performed using CellSieve-microfilters and immunohistochemical- and Giemsa-staining. Additionally 10 blood samples were analyzed using the CellSearch-System. We could isolate more CTC in pulmonary venous blood (total 41, range 0–15) than in samples taken from the periphery at the same time (total 6, range 0–5, p = 0.09). Tumor positive lymph nodes correlated with presence of CTC in pulmonary venous blood as in all cases CTC were present (p = 0.02). Our findings suggest a tumor cell release from pulmonary metastases in CRC and a correlation of CTC isolated from the tumor outflow with established negative prognostic markers in metastasized CRC. The presented data warrant further investigations regarding the significance of local tumor compartments when analyzing circulating markers and the possibility of tumor cell shedding from secondary lung tumors.

Background: The metastasis suppressor 1 (MTSS1) is a newly discovered protein putatively involved in tumour progression and metastasis. Material and Methods: Immunohistochemical expression of MTSS1 was analysed in 264 non-small-cell lung carcinomas (NSCLCs). Results: The metastasis suppressor 1 was significantly overexpressed in NSCLC compared with normal lung (P=0.01). Within NSCLC, MTSS1 expression was inversely correlated with pT-stage (P=0.019) and histological grading (P

An increased understanding of tumour biology as well as novel therapeutic options have led to a further differentiation of metastatic non-small cell lung cancer. Oligometastatic lung cancer has a relatively benign clinical course with few metastases, which are often confined to a single organ. To create the best outcomes, the ideal treatment must be used for each individual tumor biology, with consideration of the different treatment modalities. Surgery is of increasing significance in curative treatment concepts in metastatic lung cancers. In analogy to oligometastatic disease, the term "oligoprogression" has emerged in recent years. This describes a state in which metastatic lung cancers which express sensitizing mutations show progression of disease only at a limited number of anatomical sites whilst under therapy with tyrosine kinase inhibitors. Current studies have shown encouraging results for surgical therapy in combination with systemic therapy of both oligometastatic and oligoprogressive disease in well selected patients. It remains to be determined whether the observed survival benefits are based on the favourable tumour biology or the applied treatment modalities. Moreover, robust molecular markers have to be determined to identify patients who will benefit from aggressive surgical treatment, in order to avoid overtreatment.Das bessere Verständnis der Tumorbiologie sowie die neuen Therapien beim nicht kleinzelligen Lungenkarzinom haben zu einer weiteren Differenzierung der Therapie auch der metastasierten Erkrankung geführt. Der Begriff des oligometastatischen Lungenkarzinoms beschreibt vergleichsweise gutartige Verläufe mit nur wenigen, häufig auf ein Organsystem beschränkten Metastasen. Zum Erreichen eines optimalen Behandlungsergebnisses für jede charakteristische Ausprägung bzw. Tumorbiologie muss ein adäquater Therapieansatz unter Einbeziehung der verschiedenen Therapiemodalitäten gefunden werden. In diesem Rahmen gewinnt die Chirurgie auch in kurativen Konzepten zunehmend an Bedeutung. Analog zum oligometastatischen Lungenkarzinom wurde der Begriff der oligoprogressiven Erkrankung geprägt. Dieser resultierte insbesondere aus den Beobachtungen des Krankheitsverlaufs bei Lungenkarzinomen, die eine der gängigen Treibermutationen, wie die ALK-Fusion oder die EGFR-Mutation, aufweisen. In einigen Fällen findet sich hier eine auf wenige Herde begrenzte Progression der metastasierten Erkrankung bei sonst stabilem Befund. Bisherige Studien zeigen sowohl beim oligometastatischen als auch beim oligoprogressiven Lungenkarzinom bei entsprechend selektionierten Patienten ermutigende Ergebnisse, mit z. T. deutlichem Überlebensvorteil durch ein aggressives chirurgisches Vorgehen in Kombination mit der üblicherweise durchgeführten Systemtherapie. Zu klären bleibt jedoch, ob der beobachtete Überlebensvorteil lediglich aufgrund der günstigeren Tumorbiologie bei den ausgewählten Patienten oder aber aufgrund der gewählten Therapien zustande kommt. Zudem bedarf es in Zukunft exakterer Marker zur Identifikation geeigneter Patientenkollektive.

Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small-cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. In 2009, the International Association for the Study of Lung Cancer (IASLC) introduced a new lymph node map. Some changes in this map have an important impact on mediastinal staging. Moreover, more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of computed tomography (CT)-enlarged or positron emission tomography (PET)-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography [endobronchial ultrasonography (EBUS)/esophageal ultrasonography (EUS)] with fine-needle aspiration (FNA) is the first choice (when available), since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred to mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumours < 3 cm located in the outer third of the lung. In central tumours or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and FNA or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumours > 3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high standardized uptake value. For restaging, invasive techniques providing histological information are advisable. Both endoscopic techniques and surgical procedures are available, but their negative predictive value is lower compared with the results obtained in baseline staging. An integrated strategy using endoscopic staging techniques to prove mediastinal nodal disease and mediastinoscopy to assess nodal response after induction therapy needs further study.

Intrathoracic fistulae are among the potential sequelae of radiation therapy, empyema and abscess clearance and surgical tumour resections. Interdisciplinary plastic-reconstructive flap surgery is a helpful tool for the successful treatment of intrathoracic fistulae.From February 2006 to April 2016, 13 patients (3 females and 10 males) underwent flap surgery for bronchial (n = 5), tracheal (n = 2), oesophageal (n = 2), post-pneumonectomy bronchopleural fistula (n = 2), tracheo-oesophageal (n = 1), gastrobronchial (n = 1) and oesophagobronchial (n = 1) fistulae. Patient characteristics, identified pathogenic micro-organisms, treatment and decision criteria, long-term outcome and postoperative complications were evaluated by analysing patient charts and surgical reports.The mean age of the 13 patients who underwent reconstructive surgery was 55.5 years (range: 42-66 years). The median follow-up time was 31.4 months (range: 2-96 months). American Society of Anaesthesiologists classification was II for 1 patient, III for 8 patients and IV for 4 patients. In total, 18 flaps were performed (7 latissimus dorsi pedicled flaps, 7 pectoralis major pedicled flaps, 2 rectus abdominis myocutaneous flaps, 1 free temporo-parietal fascia flap and 1 intercostal muscle flap). A second flap was indicated in 5 cases (38.5%) due to fistula recurrence; of these, 1 patient developed a bronchial fistula after successful reconstruction of a gastrobronchial fistula. Eight of the 13 patients (61.5%) were evaluated postoperatively at regular intervals for at least 1 year and showed no signs of fistula recurrence.Our study showed that plastic-reconstructive flap surgery, although associated with significant morbidity and mortality, can be a life-saving tool for intrathoracic fistula reconstruction.DRKS00010447.

Summary Background Previous studies revealed that surgical lung biopsy in usual interstitial pneumonia (UIP) patients is accompanied with higher morbidity and mortality. The aim of this retrospective analysis was to assess morbidity and mortality of patients with suspected UIP undergoing surgical lung biopsy. Methods We conducted a retrospective study of 45 patients with suspected UIP pattern undergoing surgical biopsy for diffuse pulmonary infiltrates in our department. Data concerning medical history, histology, and survival status were extracted from the medical database of the University Medical Center Freiburg. Results UIP was diagnosed by experienced pneumo-pathologists according to the criteria of American Thoracic Society/European Respiratory Society (ATS/ERS) consensus classification. Due to adhesions the surgeon decided in two patients to perform wedge resection via open surgery. In 43 patients lung biopsy was performed via Video-assisted thoracoscopy (VATS). No intraoperative complications were observed. Postoperative complications consisted of bradyarrhythmia ( n = 1), gastrointestinal bleeding ( n = 1), bacterial pneumonia ( n = 1), candida pneumonia ( n = 1) and acute exacerbation ( n = 1). There was no 30-day mortality, but one patient was lost in follow-up and therefore censored. The intraoperative placed thoracic drain was removed at the first postoperative day in most cases (mean day of removal 1.9, ±2.6). The mean length of hospital stay was 8.1 days (±6.8). Conclusions We conclude that surgical biopsy can be safely performed in patients with suspected UIP.

Although thoracic epidural analgesia (TEA) is considered the gold standard for post-thoracotomy pain relief, thoracic paravertebral block (PVB) and intrathecal opioid (ITO) administration have also been shown to be efficacious. We hypothesized that the combination of PVB and ITO provides analgesia comparable with that of TEA.After local ethics committee approval, 84 consecutive patients undergoing open thoracic procedures were randomized to the TEA (ropivacaine 0.2%+sufentanil) or the PVB (ropivacaine 0.5%)+ITO (sufentanil+morphine) group. The primary endpoints were pain intensities at rest and during coughing/movement at 1, 2, 4, 8, 12, 24, 48, and 72 h after operation assessed by visual analogue scale (VAS) score. Data were analysed by multivariate analysis (anova; P0.05).Patient and surgical characteristics were comparable between the groups. The mean and maximal VAS scores were lower in the TEA (n=43) than in the PVB+ITO group (n=37) at several time points at rest (P0.026) and during coughing/movement (P0.021). However, in the PVB+ITO group, the mean VAS scores never exceeded 1.9 and 3.5 at rest and during coughing/movement, respectively; and the maximal differences between the groups (TEA vs PVB+ITO) in the maximal VAS scores were only 1.2 (3.4 vs 4.6) at rest, and 1.3 (4.4 vs 5.7) during coughing/movement.Although VAS scores were statistically lower in the TEA compared with the PVB+ITO group at some observation points, the differences were small and of questionable clinical relevance. Thus, combined PVB and ITO can be considered a satisfactory alternative to TEA for post-thoracotomy pain relief. ClinicalTrials.gov number. NCT00493909.

Background Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. Methods Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer PanelTM, MiSeq sequencing and data analyses (Illumina). Results By tNGS primary tumours were RAS wildtype in 5/14 and mutated in 9/14 (8/9 KRAS exon 2; 1/9 NRAS Exon 3) of cases. RAS mutation status was maintained in case-matched metastases throughout the disease course, albeit with altered allele frequencies. Case-matched analyses further identified a maximum of three sequence variants (mainly in APC, KRAS, NRAS, TP53) shared by all tumour specimens throughout the disease course per individual case. In addition, further case-matched de novo mutations were detected in synchronous and/or metachronous liver and/or lung metastases (e.g. in APC, ATM, FBXW7, FGFR3, GNAQ, KIT, PIK3CA, PTEN, SMAD4, SMO, STK11, TP53, VHL). Moreover, several de novo mutations were more frequent in synchronous (e.g. ATM, KIT, PIK3CA, SMAD4) or metachronous (e.g. FBXW7, SMO, STK11) lung metastases. Finally, some de novo mutations occurred only in metachronous lung metastases (CDKN2A, FGFR2, GNAS, JAK3, SRC). Conclusion Together, this study employs an adapted FFPE-based tNGS approach to confirm conservation of RAS mutation status in primary and metastatic tissue specimens of CRC patients. Moreover, it identifies genes preferentially mutated de novo in late disease stages of metachronous CRC lung metastases, several of which might be actionable by targeted therapies. Electronic supplementary material The online version of this article (doi:10.1186/s12943-016-0549-8) contains supplementary material, which is available to authorized users.

Background: The tumor microenvironment plays a critical role in tumor growth and spreading. Tumor-associated macrophages (TAM) make up a large proportion of the tumor mass and are one of the main producers of CC-chemokine ligand 18 (CCL18), which is believed to carry out important functions in the immunological interactions that promote tumor progression. Materials and Methods: Cytokines/chemokines were measured in bronchoalveolar lavage (BAL) from the tumor site and serum before and after resection in patients with proven non-small cell lung cancer (NSCLC). Results: CCL18 concentrations in BAL positively correlated with the radiologically determined tumor volume (r=0.72, p=0.0003) in NSCLC. In addition, tumors with lymph-node metastasis exhibited significantly higher CCL18 concentrations in BAL (p=0.049) than those without. Serum CCL18 concentrations did not differ significantly before and after tumor resection. Conclusion: The increased release of CCL18 with greater tumor size is most likely due to the accompanied growth of leukocyte infiltrate. With previous findings taken into account, this could be one factor contributing to tumor invasiveness and particularly lymphatic spread in patients with larger tumors.

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. 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.

Objectives The aim of this study was to assess the influence of video-assisted thoracic surgery (VATS) on our treatment decisions in FIGO III and IV ovarian cancer patients. Methods Patients with ovarian cancer and suspected supra-diaphragmatic involvement (pleural effusions, pleural carcinomatosis, lung metastasis, or enlarged supra-diaphragmatic lymph nodes) at chest computer tomography (CT) scan underwent VATS with or without laparoscopy (LSC) to decide for primary cytoreduction or neoadjuvant chemotherapy. Operation time, VATS complications (intrapleural hematoma, secondary hemorrhage with intervention, pneumonia and empyema) and shift in the therapeutic strategy due to VATS were evaluated. Results 17 patients were included into this study (1 patient with FIGO stage IIIb, 1 with IIIc and 15 with stage IV). The median operation time for VATS only was 46.5min (range: 20–50min, n=3). Perioperatively, no complications occurred. After surgical staging, the tumor was confined to the abdomen in four patients in whom primary cytoreduction was attempted. All other 13 patients underwent neoadjuvant chemotherapy. VATS altered the therapeutic management in 6/17 ovarian cancer patients (3 times upstaging, 3 times downstaging). Negative predictive values (NPV) for local and diffuse pleural carcinomatosis ranged between 0.5 and 0.71. Conclusion In this case series, VATS in addition to LSC showed negligible morbidity related to surgery and a short operation time. We were able to improve the accuracy of the FIGO staging and assessed operability more reliably in these patients than through imaging techniques alone.

Within the concert of immune reactions against tumour cells cytotoxic and regulatory T-cells are of utmost importance. Several studies revealed contradictory results on this issue. We therefore focused on functional expression patterns and localization of tumour-infiltrating T-lymphocytes in non-small cell lung cancer (NSCLC) and their impact on patient's survival. 232 curatively operated NSCLC patients were included. After histological reevaluation and construction of tissue-multi-arrays immunohistochemical doublestains for CD3/CD8 and CD4/CD25 were performed to evaluate the total number of T-cells and their subsets of cytotoxic and activated T-cells. Additionally, the localization of the lymphocytes was included in the analysis. Hereby, T-cells within the tumour stroma were regarded as stromal, those among cancer cells as intraepithelial. The number of lymphocytes differed significantly between the histological subtypes being most prominent in large cell carcinomas. Survival analysis showed that high numbers of stromal T-lymphocytes are of beneficial prognostic influence in NSCLC patients. This also proved to be an independent prognostic factor in adenocarcinomas. Thus, in a large and well characterized cohort of NSCLC this is the first study to determine the prognostic value of stromal T-lymphocytes, as these are an independent prognosticator in NSCLC especially in adenocarcinomas whereas intraepithelial T-cells are not.

Catumaxomab is a trifunctional monoclonal antibody consisting of a mouse immunoglobulin G2a part and a rat immunoglobulin G2b part with 2 different antigen binding sites binding the epithelial cell adhesion molecule antigen on tumor cells and CD3 on T lymphocytes. The intact Fc region provides a third functional binding site, binding and activating selectively Fcgamma receptor I, IIa, and III-positive accessory cells. These binding properties lead to specific tumor cell killing. As catumaxomab demonstrated efficacy in patients with malignant ascites, we performed this phase 1/2 trial in patients with malignant pleural effusion (MPE). We investigated a series of 3 escalating doses of 5 to 200 microg catumaxomab administered intrapleurally to patients with MPE containing epithelial cell adhesion molecule -positive cells. Primary objectives were determination of dose-limiting toxicity, safety, and tolerability. Secondary objectives were efficacy and pharmacodynamics. Twenty-four patients were treated with catumaxomab. Most frequent adverse events were pyrexia, elevated liver enzymes, nausea, and decreased lymphocytes. Dose-limiting toxicities were observed in 2 patients: One had pleural empyema and fatal sepsis and 1 had grade 3 erythema and hepatobiliary disorder. Five patients with breast cancer out of 7 evaluable patients had a response to treatment. Intrapleural administration of catumaxomab is feasible although the substantial number of drop-outs and deaths in short proximity to study treatment raise questions whether MPE is the right indication for catumaxomab or whether the patient population should be defined different. Safety profile was as expected reflecting catumaxomab's mode of action. Preliminary efficacy showed a suggestion of improvement in some patients.

Extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN, CD147) is a multifunctional protein that has been implicated in cancer invasion and metastasis by the induction of MMPs. To address its role in primary tumors of human non-small-cell lung cancer we assessed whether EMMPRIN expression is associated with the expression of MMP-2 and MMP-9 and with patient survival. Primary tumors of 150 patients (65 adenocarcinomas, 58 squamous cell carcinomas, and 27 of other subtypes) with completely resected lung cancers were stained by immunohistochemistry. We assessed intensity, extent, and cellular localization of EMMPRIN staining and determined MMP-2 and MMP-9 expression. 145 tumors expressed EMMPRIN (strong expression in 61 tumors), which was predominantly localized at the tumor cell membranes in 102 (68%) patients. We could not determine any correlation between EMMPRIN expression and MMP-2 or MMP-9 expression. The prognostic relevance of EMMPRIN was evaluated by Kaplan-Meier and multivariate Cox regression analysis in patients with adenocarcinoma (n=57) and squamous cell carcinoma of the lung (n=56). The median follow-up period was 36.0 months (range 4-156 months). Staining scores for EMMPRIN and MMP-2 and MMP-9 derived from staining intensities and percentages of positive cells did not predict outcome of patients. In contrast, univariate survival analysis demonstrated that membranous localization of EMMPRIN was associated with shortened survival in patients with adenocarcinoma (P=0.03; log-rank test), but not in squamous cell carcinoma. For the former patients, membranous EMMPRIN expression was also an independent predictor of patient survival (P=0.04; Cox regression analysis). The findings point to a role of EMMPRIN for the progression of adenocarcinoma of the lung that is unrelated to its function as inducer of MMPs.

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 Anaesthesiology physical performance status (ASA)-score (p = 0.32), forced expiratory volume in 1 s 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.

Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with non-small cell lung cancer (NSCLC) is of paramount importance. It will guide choices of treatment and determine prognosis and outcome. Over the last years, different techniques have become available. They vary in accuracy and procedure-related morbidity. The Council of the ESTS initiated a workshop on preoperative mediastinal lymph node staging. This resulted in guidelines for primary staging and restaging. For primary staging, mediastinoscopy remains the gold standard for the superior mediastinal lymph nodes. Invasive procedures can be omitted in patients with peripheral tumors and negative mediastinal positron emission tomography (PET) images. However, in case of central tumors, PET hilar N1 disease, low fluorodeoxyglucose uptake of the primary tumor and LNs > or = 16 mm on CT scan, invasive staging remains indicated. PET positive mediastinal findings should always be cyto-histologically confirmed. Transbronchial needle aspiration (TBNA), ultrasound-guided bronchoscopy with fine needle aspiration (EBUS-FNA) and endoscopic esophageal ultrasound-guided fine needle aspiration (EUS-FNA) are new techniques that provide cyto-histological diagnosis and are minimally invasive. Their specificity is high but the negative predictive value is low. Because of this, if they yield negative results, an invasive surgical technique is indicated. However, if fine needle aspiration is positive, this result may be valid as proof for N2 or N3 disease. For restaging, invasive techniques providing cyto-histological information are advisable despite the encouraging results supported with the use of PET/CT imaging. Both endoscopic techniques and surgical procedures are available. If they yield a positive result, non-surgical treatment is indicated in most patients.

Catumaxomab is a trifunctional monoclonal antibody with binding sites directed to human EpCAM and the human T cell antigen CD3 (anti-EpCAM x anti-CD3). Catumaxomab demonstrated efficacy when administered intraperitoneally in patients with EpCAM positive malignant ascites from ovarian cancer in terms of tumor cell killing and reduction of ascites generation. As EpCAM is also overexpressed in NSCLC, the present study was conducted in order to evaluate safety and tolerability of intravenous treatment with catumaxomab.UICC stage IB-IV NSCLC patients were eligible, if they had at least one prior therapy. Other inclusion criteria were: age 18-75 years, adequate bone marrow function and AST or gamma-GTor=2.5 ULN. Escalating doses of catumaxomab were administered over 8 h as a continuous intravenous infusion. Dose escalation started at 2 microg and was increased to 7.5 microg. In addition various doses of dexamethasone as premedication were investigated. All patients were pretreated with antihistamines.Dose limiting toxicity (DLT) was a grade 3 and 4 elevation of ALT, AST and gamma-GT, which was observed in dose level IV (10 mg dexamethasone premedication, 5 microg catumaxomab) and V (40 mg dexamethasone followed by 7.5 microg catumaxomab). Elevated liver enzymes decreased to grade 2 within 3-7 days and were at baseline level within 14 days after infusion. The maximum tolerated dose (MTD) was defined in dose level III (40 mg of dexamethasone followed by 5 microg of catumaxomab).Five micrograms of catumaxomab with a pre-medication of 40 mg dexamethasone and antihistamines can be recommended as first dose for i.v. therapy consisting of multiple catumaxomab infusions for patients with NSCLC.

Objective: Segmentectomy has recently been suggested as alternative to lobectomy for curative treatment of early-stage non-small cell lung cancer (NSCLC). This study was performed to investigate if localisation of the resected segment or width of resection margins influence local recurrence following complete segmentectomy of stage IA NSCLC. Methods: Between 1987 and 2002, 49 segmentectomies and 150 lobectomies were performed in patients with pT1pN0cM0-NSCLC in our institution. Indications for segmentectomy were a limited pulmonary function or severe comorbidity. The median follow-up duration was 54 months. Local recurrence was distinguished from secondary primary lung cancer and was defined as tumour within the same lung or in the ipsilateral mediastinum. Segment localisation, width of resection margins, tumour size, tumour type,grading andage wereanalysed concerningtheirinfluence onlocalrecurrence.Results:Localrecurrence occurred in16% of patients with segmentectomy and was significantly more frequent than in patients with lobectomy (5%; p = 0.005; log-rank test). Segmentectomy in the S1—3 region tended more frequently to local recurrence than segmentectomy in the remaining segments (p = 0.08; log-rank test): There was no recurrence following segmentectomy in the S7—10 region (n = 6) or of S4—5 (n = 5). Recurrence occurred in 7 (23%) out of 30 patients with segmentectomy in the S1—3 region and in 1 (12%) out of 8 patients with S6-segmentectomy. Also, resection margins 1 cm tended to be associated with local recurrence (p = 0.06; log-rank test). Conclusions: The frequency of local recurrence following segmentectomy might be influenced by segment localisation and width of resection margins. Segmentectomy within the S1—3 region should be avoided whenever possible. # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

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.Castleman's 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.

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.

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.

Many patients with early stage lung cancer (stage I and II) are curable by surgical resection. In patients with locally advanced disease surgery plays an important role in order to provide local tumor control. Therefore, the aim of all staging efforts in NSCLC must be to identify all patients, who might be potential candidates for a surgical approach. Current staging tools include imaging techniques like CT- and PET-scan, transthoracic, transbronchial or transeosophageal needle biopsies and finally surgical staging methods including mediastinoscopy and video-assisted thoracoscopic surgery (VATS). With respect to mediastinal lymph node staging, cervical mediastinoscopy is reported to have a sensitivity between 81 and 89%. This mainly due to the fact, that some lymph node levels (# 8, 9, 5, 6) are not accessible by the standard cervical approach. The morbidity and mortality of cervical mediastinoscopy is in experienced centers only minimal. In series with more than 1000 patients, the mortality was almost 0% and morbidity varied between 0.5 and 1%. Cervical mediastinoscopy can be performed also as an outpatient procedure. In addition to 'simple' lymph node staging, mediastinoscopy clarifies the local resectability of central tumors (T-factor). Currently, cervical mediastinoscopy is recommended by almost all scientific societies in patients with apparently resectable NSCLC who present with enlarged mediastinal lymph nodes of >1 cm in short axis diameter. Video-mediastinoscopy allows that the procedure gets even more standardized and preliminary data suggest that the sensitivity might be improved in comparison to conventional mediastinoscopy. Since VATS is widely accepted by the community of thoracic surgeons, it has become an important staging tool in many situations. VATS can be used to rule out or confirm a suspected contralateral lung metastasis. Furthermore, VATS is extremely useful to exclude malignant pleural effusions in otherwise operable patients. This examination can be done in the operating room immediately prior to formal thoracotomy. Additionally, VATS is effective to explore the local resectability in patients with suspected mediastinal infiltration or a lymphangiosis carcinomatosa within the mediastinum. VATS allows an accurate staging of more than 90% of the patients with suspected stage IIIB NSCLC. With respect to lymph node staging, VATS is complimentary to cervical mediastinoscopy because it helps to stage the lymph nodes in the A-P. window (#5, 6), as well as the lymph nodes paraesophageal (#8) and in the pulmonary ligament (#9). In conclusion, surgical staging methods provide a 100% specificity in combination with a high sensitivity and only a minimal morbidity. Currently, surgical staging is recommended by the majority of scientific societies for the staging of patients with apparently resectable NCSLC.

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.

The spectrum of primary neuroendocrine tumors of the lungs ranges from typical carcinoid tumors, which are relatively benign, to highly aggressive small-cell carcinoma. In this review, we summarize the treatment of bronchopulmonary carcinoid, a disease with an incidence of 0.5 per 100,000 persons per year in Western countries.We selectively searched the PubMed database for scientific evidence on the treatment of bronchopulmonary carcinoid, considering only articles published up to February 2015. We also performed a survival analysis of 84 patients with this disease who underwent interdisciplinary treatment at the University of Freiburg Medical Center.Carcinoid tumors account for less than 1% of all lung tumors. They manifest themselves clinically with cough (35%), hemoptysis (25%), and/or bronchial obstruction (40%), depending on their location, size, and pattern of growth. 30% of patients are asymptomatic, and less than 1% have hormone-associated symptoms. Typical and atypical carcinoid tumors are distinguished on a histological basis; the histologic differential diagnosis also includes large-cell neuroendocrine tumors and small-cell carcinoma of the lung. 80% of patients who undergo resection of typical carcinoid tumors survive at least 10 years. Atypical carcinoid tumors recur more commonly than typical ones. If the mediastinal lymph nodes are involved, adjuvant treatment should be considered.Because of their rarity, the treatment of bronchopulmonary carcinoid tumors presents an interdisciplinary challenge. Surgical resection, the treatment of choice for local carcinoid tumors, generally leads to long-term survival. The existing registers should be made more comprehensive so that the treatment of this disease can be better in the future.

OBJECTIVES: Bronchoplastic resections emerged as an alternative to pneumonectomy for patients with impaired pulmonary function and have gained popularity due to a marked decrease in morbidity and at least similar oncological outcome. Actual guidelines recommend sleeve resections whenever technically feasible, even in cases with adequate pulmonary reserve for pneumonectomy, in order to maximally preserve functional lung parenchyma. Various suture techniques were described; the existing evidence, however, is insufficient to recommend one of them as standard. The aim of this study was to compare two suture techniques for bronchus repair after sleeve resection. METHODS: Two groups of patients from two separate institutions were retrospectively analysed. In Group A (n= 20), the anastomosis was performed with a running suture at the membranous part and an interrupted suture for the rest of the circumference. In Group B (n= 40), a telescoping continuous suture was used. Intra- and postoperative findings directly related to the anastomosis were compared. The parameters were assessed as absolute numbers and percentages; the statistical significance was determined using Pearson’s χ 2 test for categorical variables and Student’s t-test for continuous data (P< 0.05 considered as significant). RESULTS: Other than tumour location and resection type (predominance of the right upper lobe for Group B), the groups were comparable regarding patient characteristics. The intraoperative anastomotic assessment revealed: patency 100% in both groups, initial air tightness (100 vs 82.5%; P= 0.047) and buttressing 85 vs 5%. No suture revision was necessary in both groups. The analysis of anastomosisrelated morbidity revealed no significant difference: atelectasis (1 in Group A and 2 in Group B; P=1), reversible anastomotic changes (0 vs 2; P=0.309), early stenosis (0 vs 0), bronchopleural fistula (1 vs 0; P=0.154), bronchovascular fistula (0 vs 0), late stenosis (1 vs 0; P=0.119) and reoperations (15 vs 5%; P=0.186). The operative mortality ratewas similar (2 vs 3; P=0.741) without intraoperative deaths. CONCLUSIONS: Sleeve resections are technically challenging, especially concerning the tension in the suture and size mismatch. In our series, there was no significant difference between the two groups regarding parameters directly related to the anastomosis. The interrupted suture without telescoping is the most cited technique, can be performed in several variations and can universally be used with good ability to compensate size mismatch. The telescoping continuous anastomosis is less time- and material-consuming and is especially valuable for large-calibre bronchi and relevant size mismatch.

Early metastasis is a well-known feature of poor prognosis in potentially resectable non-small cell lung cancer (NSCLC). However, a significant number of lymph node-negative patients die early of metastatic disease. Therefore, it has to be assumed that in some patients an early tumor cell dissemination has occurred which is clearly underestimated by current staging procedures. Recently, it has been shown, that an early dissemination of individual carcinoma cells to regional lymph nodes or bone marrow can be detected by using sensitive immunocytochemical techniques with monoclonal antibodies against epithelium-specific proteins. The incidence of immunohistochemically positive patients varies between 30 and 70% depending on the type of primary tumor, the immunohistochemical staining procedure used and especially on the primary monoclonal antibody. The detection of disseminated tumor cells in lymph nodes or bone marrow by immunocytochemistry is associated with a poorer prognosis in lung cancer. In conclusion, the immunohistochemical detection of disseminated tumor cells in lymph nodes can help to obtain a more exact identification of patients with an unfavorable prognosis. Whether the identified patients will gain from an adjuvant therapy, has to be evaluated in further studies.

Current therapy for small cell lung cancer (SCLC) consists of chemotherapy with or without radiotherapy. Radiotherapy is generally accepted as an essential treatment component of limited stage disease. However, the local failure rate after chemo- and radiotherapy is still high and ranges from 30 to 70%. Furthermore, despite having obtained a complete radiographic response, up to 75% of these patients will have residual disease in the tumor specimen, if resection is performed. Therefore, more effective means are needed to eradicate the primary tumor and to obtain an improved local disease control. Recent phase two trials of multimodal regimens for stage I–IIIA SCLC demonstrate that in selected patients with early stage SCLC the combination of surgery and chemotherapy with or without radiotherapy is feasible with low morbidity and mortality rates. The combination therapy results in satisfying long term outcome depending on the pathological tumor stage and a local disease control is achieved in almost all patients. It is remarkable that the pneumonectomy rate has decreased over the past decades from almost 100 to 27–39%. In order to confirm these promising results, a German multicenter prospective randomized phase III trial has been designed for patients with stage I–IIIA SCLC consisting of induction chemotherapy, followed by surgery, adjuvant thoracic radiotherapy and prophylactic cranial radiation compared to thoracic radiotherapy and prophylactic cranial radiation.

In view of the high incidence of early distant tumor relapses in apparently completely resected (R0, M0) non-small cell lung cancer (NSCLC), there is a need for an adjuvant therapy. Considering the low tumor burden in these patients, an adjuvant therapy with monoclonal antibodies (i.e., the 17-1A MAb) might be appropriate. The purpose of our study was to test whether the 17-1A antigen is expressed on primary and metastatic NSCLC carcinoma cells. Using immunohistochemistry, the expression of 17-1A was analysed in primary tumors (n = 60) and in lymph node metastases (n = 7) of patients with NSCLC. Additionally, we investigated in 6 patients the expression of 17-1A on disseminated tumor cells in the bone marrow, which were detected by the pan-cytokeratin MAb A45-B/B3 using a double-labeling technique. The 17-1A antigen was homogeneously expressed in 47 (78.3%) out of 60 primary NSCLCs. The expression of 17-1A was independent from the tumor histology, the grade of differentiation, and other clinicopathological parameters (ploidy status, TNM-stage). Lymph node metastases were positive in 4 (57.4%) out of 7 cases. The double-labeling experiments demonstrated that 17-1A is coexpressed on disseminated tumor cells in the bone marrow in 5 (83%) out of 6 patients. The 17-1A antigen is expressed on the majority of primary, metastatic, and disseminated NSCLC cells. Patients with 17-1A-positive tumors might benefit from an adjuvant therapy with MAb 17-1A after completely resected NSCLC.

Accurate diagnosis of tracheobronchial injuries in children is difficult due to the paucity of clinical presentation and the variety of clinical symptoms. They are potentially life threatening in blunt chest trauma. We report here on a clinical case of a boy who was injured during outdoor activity. We describe intraoperative findings of the massive tracheobronchial lesion and its successful repair using a pericardial patch technique and postoperative recovery. Such a serious tracheobronchial injury with a positive outcome has not been reported so far. Clinical and technical steps are described and discussed.

Aim: To compare the number of lung metastases seen preoperatively on computed tomography in patients with a previous history of malignant disease with the number of resected pulmonary nodules and the number of histologically proven lung metastases. Patients and methods: Between 1998 and 2003, we operated on 281 patients with suspected lung metastases. The histology of the primary tumour, the number of preoperatively diagnosed nodules, the number of lesions removed during surgery and the number of histologically confirmed metastases of 276 patients are presented. Results: Resection of lung metastases was performed in 276 patients. The median age was 62 years (21—86 years). The mean number of nodules seen on the CT scan was 1.9 (total: 515 nodules), 2.9 pulmonary lesions were removed (total: 835 nodules) and 2.1 nodules were confirmed as lung metastases (total: 560). In 39%, the number of lesions found and removed during the operation was higher than counted on the preoperative CTscan. These extra nodules found during the operation were confirmed as lung metastases in 16% of all patients. A benign solitary lesion was found in 15.2% of the patients and in 7.9% a primary carcinoma of the lung was diagnosed. In patients with a solitary nodule we found no metastasis in 16.4%, one lung metastasis in 76.7% and more than one lung metastasis in 6.9%. In patients with more than one nodule on the preoperative CTscan, an identical number of lung metastases were histologically confirmed in 35% of the patients, a larger number in 27.4% and a smaller number in 37.6%. Conclusions: In patients with a previous history of malignant disease, 15.2% of the pulmonary lesions are benign. Video-assisted thoracoscopic surgery (VATS) is a safe diagnostic and therapeutic method for solitary lesions, with little discomfort for the patient. In patients with more than one nodule on the CT scan, manual exploration of the lung is necessary to detect further lesions. # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

e.lim@rbht.nhs.uk Academic Division of Thoracic Surgery, The Royal Brompton Hospital, London, SW3 6NP, UK (EL); Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle University, Newcastle upon Tyne, UK (PJM); Division of Thoracic Surgical Oncology, Istituto Nazionale Tumori, Fondazione Pascale, IRCCS, Naples, Italy (GR); St James’s University Hospital, Leeds, UK (AB); Service de Chirurgie Thoracique, Hopitaux Universitaires de Strasbourg, Strasbourg, France (GM); Istanbul University, Istanbul Medical School Department of Thoracic Surgery, Istanbul, Turkey (AT); University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany (BP); School of Medicine and University Hospital, Salamanca University, Salamanca, Spain (GV); Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland (WW)

OBJECTIVE: To evaluate the effectiveness of lymphadenectomy in the treatment of non-small cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: The extent of lymphadenectomy in the treatment of NSCLC is still a matter of controversy. Although some centers perform mediastinal lymph node sampling (LS) with resection of only suspicious lymph nodes, others recommend a radical, systematic mediastinal lymphadenectomy (LA) to improve survival and to achieve a better staging. METHODS: In a controlled, prospective, randomized clinical trial, the effects of LA on recurrence rates and survival were analyzed, comparing LS and LA in 169 patients with operable NSCLC. RESULTS: After a median follow-up of 47 months, LA did not improve survival in the overall group of patients (hazard ratio: 0.78; 95% confidence interval: 0.47-1.24). Although recurrences rates tended to be reduced among patients who underwent LA, these decreases were not statistically significant (hazard ratio: 0.82; 95% confidence interval: 0.54-1.27). However, analysis of subgroups of patients according to histopathologic lymph node staging revealed that LA appears to prolong relapse-free survival (p = 0.037) with a borderline effect on overall survival (p = 0.058) in patients with limited lymph node involvement (pN1 disease or pN2 disease with involvement of only one lymph node level); in patients with pN0 disease, no survival benefit was observed. CONCLUSIONS: Radical systematic mediastinal lymphadenectomy does not influence disease-free or overall survival in patients with NSCLC and without overt lymph node involvement. However, a small subgroup of patients with limited mediastinal lymph node metastases might benefit from a systematic lymphadenectomy.

Current methods of disease staging often fail to detect small numbers of tumor cells in lymph nodes. Metastatic relapse may arise from these few cells.We studied 1308 lymph nodes from 68 patients with esophageal cancer without overt metastases who had undergone radical en bloc esophagectomy. A total of 399 lymph nodes obtained from 68 patients were found to be free of tumor by routine histopathological analysis and were studied further for isolated tumor cells by immunohistochemical analysis with the monoclonal anti-epithelial-cell antibody Ber-EP4. This antibody did not stain lymph nodes from 24 control patients without carcinoma.Of the 399 "tumor free" lymph nodes, 67 (17 percent), obtained from 42 of the 68 patients, contained Ber-EP4-positive tumor cells. Fifteen of 30 patients who were considered free of lymph-node metastases by histopathological analysis had such cells in their lymph nodes, and 5 of the 15 had small primary tumors. Ber-EP4-positive cells found in "tumor free" nodes were independently predictive of significantly reduced relapse-free survival (P=0.008) and overall survival (P=0.03). They predicted relapse both in patients without nodal metastases (P=0.01) and in those with regional lymph-node involvement (P=0.007). All 12 patients whose lymph nodes were negative on both histopathological and immunohistochemical analysis and who were available for follow-up survived without recurrence. The presence of micrometastatic tumor cells in bone marrow had no additional prognostic value.Immunohistochemical examination of lymph nodes may improve the pathological staging of esophageal cancer.

Background: The effect of pleurectomy/decortication or extrapleural pleuropneumonectomy on pulmonary function has not yet been evaluated. The aim of this study was to determine the parameters of pulmonary function before and after pleurectomy/decortication or extrapleural pleuropneumonectomy. Methods: We conducted a review of 48 patients with unilateral malignant pleural mesothelioma who underwent pleurectomy/decortication or extrapleural pleuropneumonectomy. Data including medical history, histology, survival, and pre- and postoperative pulmonary function were extracted from the medical database of the University Medical Center Freiburg, or sought by telephone interview with the general practitioner or patients. Results: 25 patients underwent extrapleural pleuropneumonectomy and 23 had pleurectomy/decortication. Pulmonary function was not significantly reduced in the pleurectomy/decortication group postoperatively. In the extrapleural pleuropneumonectomy group, the median preoperative total lung capacity of 4.8 L (77.7%) differed significantly from the postoperative total lung capacity of 3.5 L (55.3%; p Conclusions: Pleurectomy/decortication preserved good pulmonary function, whereas extrapleural pleuropneumonectomy significantly reduced pulmonary function, which may lead to dyspnea and influence the quality of life of these patients.

Background. A major reason for the high incidence of tumor recurrences in patients with apparently resectable non-small cell lung cancer is presumably early tumor cell dissemination, which is clearly underestimated by current staging procedures. Methods. In this prospective study we assessed the frequency and prognostic significance of early lymphatic tumor cell spread to regional lymph nodes staged as tumor free by conventional histopathology by applying an immunohistochemical assay using monoclonal antibody Ber-Ep4. Results. Ber-Ep4 positive cells were demonstrated in 27 (21.6%) of 125 patients and in 35 (6.2%) of 565 lymph nodes, respectively. Immunohistochemical analysis resuited in an up-staging in 24 of 27 patients. In patients previously staged as having pN0 disease, tumor cells were detected in 11/70 cases (15.7%). Univariate and multivariate survival analysis showed that the detection of minimal nodal tumor cell dissemination was associated with a reduced disease-free survival (log rank test, p = 0.0001; Cox regression model, p = 0.001). Conclusions. The use of immunohistochemistry enables one to identify many patients with regional tumor cell dissemination at the time of operation. These patients might benefit from an adjuvant therapeutic regimen.

Early microdissemination of tumour cells determines the prognosis of patients with apparently localised non-small cell lung cancer (NSCLC). Monoclonal antibodies to epithelial antigens can now be used to detect single carcinoma cells present in mesenchymal secondary organs such as bone marrow or lymph nodes. The present study was designed to obtain insights into the potential role of the immune system in lymphatic and haematogenous microdissemination of NSCLC cells. Using immunohistochemical staining of primary NSCLC, we assessed the expression pattern of molecules mediating an efficient cellular immune response, that is, MHC class I and class II antigens and the intercellular adhesion molecule-1 (ICAM-1). All 58 patients evaluated were staged as free of overt metastases by conventional clinico-pathological screening. Isolated tumour cells in bone marrow or lymph nodes were identified with mAb CK2 to cytokeratin component No. 18 and mAb BerEp-4 to glycoproteins of 34 and 39 kd present on epithelial cells, respectively. MHC class I expression on primary tumours was reduced or absent in 6/10 (60.0%) patients with isolated cancer cells in lymph nodes as compared to 6/33 tumours (18.1%) without such tumour cell dissemination (P = 0.01). MHC class II molecules on primary tumours were detected in 1/10 (10.0%) patients with micrometastases to regional lymph nodes and in 10/33 (30.3%) patients without such a tumour cell spread. None of the 10 patients with nodal microdissemination expressed ICAM-1 on their primary NSCLC, while such expression was detectable in 12/33 (36.4%) patients without this dissemination (P = 0.01). In contrast, the detection of tumour cells in bone marrow was not correlated to the expression of any of these immunoregulatory molecules. Our data suggest that escape caused by deficient expression of MHC class I antigens and ICAM-1 on tumour cells may support homing or survival of disseminated tumour cells in lymphoid tissue.

OBJECTIVES: Since the introduction of video-assisted lobectomy for non-small-cell lung cancer (NSCLC) into clinical practice, it has been discussed controversially whether mediastinal lymphadenectomy can be performed as effectively as an open procedure via thoracotomy. Therefore, we address this issue in a prospective randomized trial conducted in our institution. METHODS: In total, 66 patients with completely staged clinical Stage I NSCLC were included and randomized either into a videoassisted group (n= 34) or into the conventional lobectomy group (n= 32). The video-assisted thoracoscopic (VATS) lobectomy was performed by using a 4- to 5-cm utility incision in the fourth or fifth intercostal space and two additional 10-mm ports without rib spreading. The conventional lobectomy was done via an anterolateral thoracotomy. Lymph nodes were classified according to the International Association for the Study of Lung Cancer classification; for right-sided tumours, lymph nodes number 2R, 4R, 7, 8, 9, 10, 11 and 12 were dissected, and for left-sided tumours, lymph nodes number 5, 6, 7, 8, 9, 10, 11 and 12. For the subsequent analyses, lymph nodes were grouped into different zones consisting of Zone 1 (2R and 4R), Zone 2 (7), Zone 3 (8R and 9R), Zone 4 (10R, 11R and 12R), Zone 5 (4L), Zone 6 (5 and 6), Zone 7 (8L and 9L) and Zone 8 (10L, 11L and 12L). RESULTS: Both groups were comparable with respect to different clinical pathological parameters (age, tumour size and comorbidity). In the video-assisted group, 2 patients were excluded due to conversion to an open thoracotomy. The number of mediastinal lymph nodes removed was as follows: VATS (right side) 24.0 lymph nodes/patient, open right-sided 25.2 lymph nodes/patient, VATS (left side) 25.1 lymph nodes/patient and open left-sided 21.1 lymph nodes/patient. With respect to the zones mentioned above, we found the following results: VATS vs open (mean number of lymph nodes/patient): Zone 1: 9 vs 8.5; Zone 2: 6.3 vs 5.6; Zone 3: 2.4 vs 3.2; Zone 4: 6.5 vs 6.9; Zone 5: 0 vs 0.5; Zone 6: 3.2 vs 3.7; Zone 7: 4.6 vs 3.2 and Zone 8: 10.5 vs 8.9. There were no statistically significant differences between the procedures, either with respect to the overall number of lymph nodes or with respect to the number of lymph nodes in each zone. CONCLUSIONS: Mediastinal lymph node dissection can be performed as effectively by the video-assisted approach as by the open thoracotomy approach. Furthermore, the video-assisted approach allows a better visualization of different lymph node zones.

Background: Chemotherapy with radiation has to be considered the standard therapy for limited-stage small cell lung cancer but surgical resection is possible in a small subgroup in which it may improve survival. Surgery is not recommended as the standard treatment, but a few small studies have demonstrated a benefit of surgery in highly selected cases of limited-stage small cell lung cancer. Methods: We conducted a retrospective study of 29 patients with limited-stage small cell lung cancer undergoing surgical resection in our department. There were 7 (24%) women and 22 (76%) men with a median age of 62 years (range, 46–82 years). Medical history, histology and survival status were extracted from the medical database of the University Medical Center Freiburg. Results: The median overall survival was 20.7 months. In 15 patients who received neoadjuvant treatment, the median survival was 89.4 months. Karnofsky performance status and neoadjuvant chemotherapy had a significant influence on median survival ( p Conclusions: We concluded that surgical resection can be beneficial in a highly selected group of patients as a part of a multidisciplinary approach. In addition, surgical resection is safe with acceptable mortality and morbidity.

Lung cancer is one of the leading causes of cancer related death worldwide with more than a million deaths per year. The poor prognosis is due to its high aggressiveness and its early metastasis. Although the exact mechanisms are still unknown, the process of epithelial to mesenchymal transition (EMT) seems to be involved in these neoplastic processes. We already demonstrated that serum levels of CCL18, a primate specific chemokine, are highly elevated in patients with lung cancer and correlate with their survival time of patients with adenocarcinoma of the lung. Therefore, we hypothesized that CCL18 may be directly involved in pathological processes of lung cancer, e.g. EMT. We investigated the effect of CCL18 on A549, an adenocarcinoma cell line of the lung, on EMT and other cell functions like proliferation, chemotaxis, invasion, chemoresistance and proliferation. Exposure of A549 lung cancer cells to CCL18 in various concentrations decreases the epithelial marker E-cadherin, whereas FSP-1, a marker of the mesenchymal phenotype increases. Accordingly, CCL18 induced the transcriptional EMT regulator SNAIL1 in a dose dependent fashion. In contrast, an increasing CCL18 concentration was associated with a decline of cell proliferation rate. In addition, CCL18 induced chemotaxis of these cells and increased their chemoresistance. Therefore, CCL18 may be an interesting therapeutic target for NSCLC.