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Objectives A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled. Material and methods Patients with resectable NSCLC stage II/IIIA were included. Two cycles of pembrolizumab (200 mg intravenously once every 3 weeks) were administered prior to surgery. The primary objectives were to assess the feasibility and safety of neoadjuvant pembrolizumab therapy and to evaluate antitumor activity. We analyzed the clinical parameters as well as pathological and radiological tumor response data. Results The NSCLC histology was adenocarcinoma for 13 patients and squamous cell carcinoma for 2 patients. All patients but two underwent 2 cycles of pembrolizumab prior to surgery. Four patients (27 %) presented a major pathologic response. Significant tumor target response in positron emission tomography computed tomography (PET-CT) was detected in all 4 pathologic responders. Nevertheless, the PET findings mismatched the tumor load in some patients. A PD-L1 expression ≥10 % in the pretreatment biopsy was associated with at least major pathologic response. Five patients (33 %) presented grade 2–3 treatment related adverse events (TRAE), the overall postoperative morbidity was 7 % and 30-day mortality was 0 %. Conclusion Neoadjuvant pembrolizumab is a feasible therapy in surgical lung cancer patients. It was associated with tolerable toxicity and did not compromise tumor resection.

The literature reports that hospital caseload volume is associated with survival for lung cancer resection. The aim of this study is to explore this association in a nationwide setting according to individual hospital caseload volume of every inpatient case in Germany.This retrospective analysis of nationwide hospital discharge data in Germany between 2014 and 2017 comprises 121,837 patients of whom 36,051 (29.6 %) underwent surgical anatomic resection. Hospital volumes were defined according to the number of patient resections for lung cancer in each hospital, and patients were categorized into 5 quintiles based on hospital caseload volume. A logistic regression model accounting for death according to sex, age, comorbidity, and resection volume was calculated, and effect modification was evaluated using the Mantel-Haenszel method.In-house mortality ranged from 2.1 % in very high-volume centers to 4.0 % in very low-volume hospitals (p 0.01). In multivariable logistic regression analysis, lower in-house mortality in very high-volume centers performing140 anatomic lung resections per year was observed compared with very low-volume centers performing27 resections (OR, 0.58; CI, 0.46 to 0.72; p 0.01). This relationship also held for failure to rescue rates (12.9 vs 16.7 %, p = 0.01), although a greater number of extended resections were performed (23.1 vs. 14.8 %, p 0.01).Hospitals with high volumes of lung cancer resections performed surgery with a higher ratio of complex procedures and achieved reduced in-house mortality, fewer complications, and lower failure to rescue rates.

Intrapulmonale Rundherde stellen in der Regel einen Zufallsbefund im Rontgenbild oder Computertomogramm des Thorax dar. Sie sind definiert als relativ gut abgegrenzte Lasionen von bis zu 3 cm Durchmesser, die allseits von Lungengewebe umgeben sind. Die Wahrscheinlichkeit fur das Vorliegen eines malignen Tumors steigt mit ihrer Grose. Rundherde ab 1 cm Durchmesser bedurfen der aktiven Abklarung. Zur Behandlung solitarer maligner Tumoren steht fur Patienten ohne nennenswert erhohtes Operations- und Narkoserisiko der chirurgische Eingriff an erster Stelle. Patienten, die aus funktionellen Grunden fur einen solchen nicht geeignet sind, konnen mit Radiofrequenzablation (RFA) oder die stereotaktische Radiotherapie (SBRT) behandelt werden. In diesen Fallen mussen vor Therapiebeginn die Malignitat nachgewiesen oder zumindest uber einen begrenzten Zeitraum eine Grosenzunahme der Lasion dokumentiert worden sein. In Bezug auf die lokale Tumorfreiheit ist die Operation unter den Voraussetzungen einer R0-Resektion den anderen Verfahren uberlegen.

Background: Surgical lung biopsy (SLB) is recommended for patients with nonclassified interstitial lung disease (nILD) if high resolution computed tomography and/or transbronchial lung biopsy did not achieve a definitive diagnosis. Current literature suggests better patient tolerability and less postoperative complications if surgery is performed under spontaneous ventilation. Objectives: We conducted a propensity score matching (PSM) analysis of our nILD patients undergoing SLB under spontaneous ventilation or general anesthesia to investigate postprocedural AE-ILD, 30-/90-day mortality and perioperative variables in two academic high-volume centers (Hannover, Heidelberg). Methods: All patients undergoing SLB for nILD under general anesthesia (GAVATS) and spontaneous ventilation (NIVATS) at both centers from February 2013 until April 2021 were analyzed retrospectively. Data of 132 patients were used for PSM resulting in 40 pairs. Results: There was one death in the NIVATS group 60 days after SLB and one AE-ILD in each cohort. Chest tube indwelling time, chest tube total effusion, length of hospital stay, and operative time were all in favor of NIVATS. Conclusions: In our PSM analysis, NIVATS is associated with faster postprocedural recovery. However, a reduction in postoperative AE-ILD or 30-/90-day mortality was not observed.

The exact role and type of surgery for malignant pleural mesothelioma (MPM) remains controversial. This study aimed at analyzing a 20-year single center perioperative experience in MPM surgery at our high-volume thoracic surgery center and comparing the overall survival after trimodal extrapleural pneumonectomy (EPP) and extended pleurectomy and decortication combined with hyperthermic intrathoracic chemoperfusion (EPD/HITOC) and adjuvant chemotherapy with that after chemotherapy (CTx) alone.Patients with epithelioid MPM treated with neoadjuvant chemotherapy, EPP and adjuvant radiotherapy within a trimodal concept or EPD/HITOC in combination with adjuvant chemotherapy between 2001 and 2018 were included in this retrospective analysis. Surgical cohorts were compared to patients treated with standard chemotherapy.Overall, 182 patients (69 EPP, 57 EPD/HITOC, 56 CTx) were analyzed. Due to occupational exposure to asbestos for most of the patients, 154 patients (84.6%) were male. The patients in the surgical cohorts were significantly younger than those in the CTx cohort. There was no significant difference between the proportion of patient age and side. The median overall survival of the EPD/HITOC cohort with 38.1 months was significantly longer than that of the EPP and CTx cohorts (24.0 and 15.8 months). Better survival was significantly associated with an ECOG 0 performance status, age below 70 years, and negative lymph node status. In the multivariate analysis, EPD/HITOC was significantly associated with improved overall survival. Perioperative morbidity was lower in the EPD/HITOC group than in the EPP cohort.EPD/HITOC is feasible and safe for localized epithelioid pleural mesothelioma. Changing the surgical approach to a less radical lung-sparing technique may improve overall survival compared to trimodal EPP.

EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce.We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases.Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p 0.01), and shorter OS for patients receiving both treatments (p 0.05). More tumour CD8Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival.

Das maligne Pleuramesotheliom ist ein seltener, aggressiv wachsender Tumor der Pleura, der haufig mit einer Asbestexposition assoziiert ist. Die uberwiegend mannlichen Patienten haben oft Begleiterkrankungen, wodurch das Behandlungsmanagement erschwert wird. Es gibt mehrere multimodale Therapiekonzepte, die sich vor allem hinsichtlich des Umfangs und der Art einer chirurgischen Therapie unterscheiden, sofern sie dem Tumorstadium entsprechend indiziert ist.

e21141 Background: First-line pembrolizumab monotherapy is a standard treatment for metastatic non-small-cell lung cancer (NSCLC) with high PD-L1 expression (TPS ≥50%). However, many patients do not respond, and reliable biomarkers are lacking. Methods: Blood samples of 33 patients with metastatic NSCLC were analyzed at baseline (BL) and after four cycles of pembrolizumab monotherapy (FU). The expression of 12 genes involved in tumor-specific immune responses ( FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, MKI67, TBX21) in whole blood RNA was quantified by RT-PCR in absolute terms using plasmids as standards. Results: Gene expression was significantly higher after immunotherapy for 11/12 genes analyzed ( FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, TBX21 with fold changes [FC] 1.99 – 5.45; all p < 0.001). Blood neutrophil and total leukocyte counts were significantly decreased (ANC BL:7.65/nl vs. FU:5.36/nl, p = 0.024; Leu BL:10.65/nl vs. FU:7.78/nl, p = 0.032), while lymphocyte counts did not change (ALC BL:1.41/nl vs. FU:1.47/nl, p = 0.267). Increases in the expression of RORgt, FASLv1, PRF1, PD1, CD247, GZMB and TBX21 remained significant (FC 1.9 – 3.7; all p < 0.001) even after correction for the blood lymphocyte/leukocyte ratio (Ly/Lc BL:0.151 vs. FU:0.197, p = 0.003). Patients with long-term response (LTR, i.e. lasting > 6 months) had significantly higher increases in the expression of 8 genes ( RORgt, FOXP3, IFNγ, FASLv1, GATA3, PD1, CD247, TBX21) compared with patients with rapid disease progression within 3 months (RP) (FC 2.34 – 4.62, all p < 0.05). There were no significant differences (FU-BL) between LTR and RP regarding ANC (RP:-1.00/nl vs. LTR:-2.63/nl, p = 0.50), ALC (RP:-0,14/nl vs. LTR:+0,12/nl, p = 0,33) or Ly/Lc (RP:0.015 vs. LR:0.0542, p = 0.259). Conclusions: Pembrolizumab monotherapy of metastatic NSCLC causes significant increases in the blood expression for several genes including FAS, RORgt, FOXP3, IFNγ, FASLv1, PRF1, GATA3, PD1, CD247, GZMB, TBX21, as well as a decrease in circulating neutrophiles and total leucocytes. Long-term responders have more pronounced blood gene expression changes, which appear to correlate with long-term benefit, in contrast to blood count changes, which are not indicative. These results are currently being validated in a larger prospective study.

Background: Epidermal growth factor receptor-mutated (EGFR+) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging. Methods: EGFR+ NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib. Results: A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x, p Conclusion: Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR+ NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR+ NSCLC in the future.

Background: Lung-sparing cytoreductive surgery by extended pleurectomy and decortication (EPD) in combination with hyperthermic intrathoracic chemoperfusion (HITOC) forms a promising treatment strategy for malignant pleural mesothelioma and recurrent pleural thymic malignancies. Objectives: The objective of this study was to scrutinize the surgical procedure and perioperative patient management with emphasis on perioperative morbidity and local tumor control. Methods: In 2014, a standardized EPD and HITOC procedure was implemented at the Thoraxklinik Heidelberg. This retrospective analysis included clinical data of consecutive patients with pleural mesothelioma and pleural metastasized malignancies treated by EPD and HITOC. The surgical procedure, perioperative management, lung function data, and progression-free survival (PFS) were analyzed. Results: In the time range between April 2, 2014 and July 2018, 76 patients with pleural malignancies have been treated with EPD and HITOC, and were analyzed retrospectively. It included 61 patients with pleural mesothelioma and 15 patients with pleural metastases of thymic malignancies (12), non-small cell lung cancer (1), colorectal carcinoma (1), and sarcoma (1). Perioperative morbidity following EPD and HITOC treatments represented 23.7% of overall malignancies, while 30- and 90-day mortality were 0 and 1.3%, respectively. Median PFS lasted 18.4 months for mesothelioma and 72.2 months for thymic malignancies. Conclusion: Combining EPD with HITOC can be performed in patients with either pleural mesothelioma or pleural metastases resulting in low perioperative morbidity and mortality as well as remarkable local tumor control.

Simple Summary Diagnostic subtyping of non-small cell lung cancer is paramount for therapy stratification. Our study shows that the subtyping into pulmonary adenocarcinoma and pulmonary squamous cell carcinoma by mass spectrometry imaging is rapid and accurate using limited tissue material. Abstract Subtyping of non-small cell lung cancer (NSCLC) is paramount for therapy stratification. In this study, we analyzed the largest NSCLC cohort by mass spectrometry imaging (MSI) to date. We sought to test different classification algorithms and to validate results obtained in smaller patient cohorts. Tissue microarrays (TMAs) from including adenocarcinoma (ADC, n = 499) and squamous cell carcinoma (SqCC, n = 440), were analyzed. Linear discriminant analysis, support vector machine, and random forest (RF) were applied using samples randomly assigned for training (66%) and validation (33%). The m/z species most relevant for the classification were identified by on-tissue tandem mass spectrometry and validated by immunohistochemistry (IHC). Measurements from multiple TMAs were comparable using standardized protocols. RF yielded the best classification results. The classification accuracy decreased after including less than six of the most relevant m/z species. The sensitivity and specificity of MSI in the validation cohort were 92.9% and 89.3%, comparable to IHC. The most important protein for the discrimination of both tumors was cytokeratin 5. We investigated the largest NSCLC cohort by MSI to date and found that the classification of NSCLC into ADC and SqCC is possible with high accuracy using a limited set of m/z species.

Background Synaptophysin, chromogranin and CD56 are recommended markers to identify pulmonary tumors with neuroendocrine differentiation. Whether the expression of these markers in pulmonary adenocarcinoma and pulmonary squamous cell carcinoma is a prognostic factor has been a matter of debate. Therefore, we investigated retrospectively a large cohort to expand the data on the role of synaptophysin, chromogranin and CD56 in non-small cell lung cancer lacking morphological features of neuroendocrine differentiation. Methods A cohort of 627 pulmonary adenocarcinomas (ADC) and 543 squamous cell carcinomas (SqCC) lacking morphological features of neuroendocrine differentiation was assembled and a tissue microarray was constructed. All cases were stained with synaptophysin, chromogranin and CD56. Positivity was defined as > 1% positive tumor cells. Data was correlated with clinico-pathological features including overall and disease free survival. Results 110 (18%) ADC and 80 (15%) SqCC were positive for either synaptophysin, chromogranin, CD56 or a combination. The most commonly positive single marker was synaptophysin. The least common positive marker was chromogranin. A combination of ≤2 neuroendocrine markers was positive in 2–3% of ADC and 0–1% of SqCC. There was no significant difference in overall survival in tumors with positivity for neuroendocrine markers neither in ADC (univariate: P = 0.4; hazard ratio [HR] = 0.867; multivariate: P = 0.5; HR = 0.876) nor in SqCC (univariate: P = 0.1; HR = 0.694; multivariate: P = 0.1, HR = 0.697). Likewise, there was no significant difference in disease free survival. Conclusions We report on a cohort of 1170 cases that synaptophysin, chromogranin and CD56 are commonly expressed in ADC and SqCC and that their expression has no impact on survival, supporting the current best practice guidelines.

Objectives Large cell neuroendocrine carcinoma of the lung (LCNEC) is associated with an unfavorable prognosis and only few patients are eligible for surgery. In most patients, chemotherapy is recommended alone or in addition to resection. Novel immunotherapies blocking the PD-L1 pathway have been introduced into therapeutic regimens for NSCLC with great success. In order to evaluate a possible efficacy of an anti-PD-L1 therapy, we analyzed the frequency of PD-L1 expression in LCNEC. Material and methods We retrospectively reviewed data from 76 patients with LCNEC treated in our institution between 1998 and 2010. The expression of PD-L1 was examined on the tumor cells and the tumor surrounding tissue by immunohistochemistry. An expression of >1% was considered as positive. Statistical analysis was performed to determine significant predictors for survival. Results 56 of 76 patients with LCNEC were treated with a potentially therapeutic surgical approach. Tumor-specific survival (TSS) of the entire cohort was 29% at five years. 17 patients (22.3%) had PD-L1 positive tumors and 12 of these had no additional PD-L1 expression in the adjacent immune cell infiltrate. Tumor-flanking immune cells were found PD-L1 positive 28 patients; 16 of these had no additional expression on the tumor cells. The most considerable difference in survival was found when comparing patients with isolated PD-L1 expression on tumor cells and PD-L1 negative immune cell infiltrate to their counterpart (positive immune-cell infiltrate and PD-L1 negative tumor cell surface; 5-year TSS: 0% vs. 60%; p Conclusion PD-L1 expression in LCNEC was associated with poorer survival whereas PD-L1 expression in the tumor microenvironment seemed to have a beneficial effect. Therapeutic approaches have to be evaluated in future.

The programmed death-ligand 1 (PD-L1) plays a crucial role in immunomodulatory treatment concepts for end-stage non-small cell lung cancer (NSCLC). To date, its prognostic significance in patients with curative surgical treatment but regional nodal metastases, reflecting tumor spread beyond the primary site, is unclear. We evaluated the prognostic impact of PD-L1 expression in a surgical cohort of 277 consecutive patients with pN1 NSCLC on a tissue microarray. Patients with PD-L1 staining (clone SP263) on &gt, 1% of tumor cells were defined as PD-L1 positive. Tumor-specific survival (TSS) of the entire cohort was 64% at five years. Low tumor stage (p &lt, 0.0001) and adjuvant therapy (p = 0.036) were identified as independent positive prognostic factors in multivariate analysis for TSS. PD-L1 negative patients had a significantly better survival following adjuvant chemotherapy than PD-L1 positive patients. The benefit of adjuvant therapy diminished in patients with PD-L1 expression in more than 10% of tumor cells. Stratification towards histologic subtype identified PD-L1 as a significant positive predictive factor for TSS after adjuvant therapy in patients with adenocarcinoma, but not squamous cell carcinoma. Routine PD-L1 assessment in curative intent treatment may help to identify patients with a better prognosis. Further research is needed to elucidate the predictive value of PD-L1 in an adjuvant setting.

Background: Mitochondria are considered relevant players in many tumour entities and first data indicate beneficial effects of mitochondria-targeted antioxidants in both cancer prevention and anticancer therapies. To further dissect the potential roles of mitochondria in NSCLC we comprehensively analysed somatic mitochondrial mutations, determined the spatial distribution of mitochondrial DNA within complete tumour sections and investigated the mitochondrial load in a large-scale approach. Methods: Whole mitochondrial genome sequencing of 26 matched tumour and non-neoplastic tissue samples extended by reviewing published data of 326 cases. Systematical stepwise real-time PCR quantification of mitochondrial DNA covering 16 whole surgical tumour sections. Immunohistochemical determination of the mitochondrial load in 171 adenocarcinoma and 145 squamous cell carcinoma. Results: Our results demonstrate very low recurrences (max. 1.7%) and a broad distribution of 456 different somatic mitochondrial mutations. Large inter- and intra-tumour heterogeneity were seen for mitochondrial DNA copy numbers in conjunction with a correlation to the predominant histological growth pattern. Furthermore, tumour cells had significantly higher mitochondrial level compared to adjacent stroma, whereas differences between tumour entities were negligible. Conclusions: Non-evident somatic mitochondrial mutations and highly varying mitochondrial DNA level delineate challenges for the approach of mitochondria-targeted anticancer therapies in NSCLC.

Objective Lymph node (LN) metastases predict survival in patients with non-small cell lung cancer (NSCLC) treated with curative surgery. Nevertheless, prognostic differences within the same nodal (N) status have been reported. Consequently, the International Association for the Study of Lung Cancer (IASLC) proposed to stratify patients with limited nodal disease (pN1) from low (pN1a) to high (pN1b) nodal tumor burden. This study aimed to validate the IASLC proposal in a large single-center surgical cohort of patients with pN1 NSCLC. Material and Methods Data from 317 patients with pN1 NSCLC treated between January 2012 and December 2016, were retrospectively analyzed. Associations between distribution of LN metastases and survival were analyzed for different classification models—toward nodal extension (pN1a: one station involved; pN1b: multiple stations involved) and toward location (pN1 in the hilar [LN#10/11] or peripheral zone [LN#12-14]). Results Tumor-specific survival (TSS) in the entire pN1 cohort was 67.1% at five years. Five-year TSS rates for pN1a and pN1b patients were comparable (67.6% vs. 66.5%, p = 0.623). Significant survival differences from pN1a to pN1b were observed only in patients with adenocarcinoma histology and completed adjuvant chemotherapy (5-year TSS: pN1a, 80.4% vs. pN1b, 49.6%; p = 0.005). TSS for LN metastases in the hilar zone/peripheral zone or in both zones was 68.2% and 59.9%, respectively (p = 0.068). In multivariate analysis, adjuvant chemotherapy, squamous cell histology, and nodal disease limited to one zone nodal disease were identified as independent beneficial prognostic factors (p Conclusion pN1 in only one region (hilar or lobar) was associated with better outcome than metastatic affection of both regions after surgery and adjuvant therapy. A stratification towards single (pN1a) and multiple (pN1b) N1-metastases was found of prognostic relevance only in adenocarcinoma. Prospective multicenter analysis of prognostic subgroups in N1 NSCLC is required to evaluate its clinical impact for consideration in future TNM classification.

Patients with nonsmall cell lung cancer and limited metastatic disease have been defined as oligometastatic if local ablative therapy of all lesions is amenable. Evidence from different clinical retrospective series suggests that this subgroup harbours better prognosis than other stage IV patients. However, most reports have included patients with inconsistent numbers of metastases in different locations treated by a variety of invasive and noninvasive therapies. As long as further results from randomised clinical trials are awaited, treatment decision follows an interdisciplinary debate in each individual case. Surgery and radiotherapy should capture a dominant role in the treatment course offering the option of a curative-intended local therapy in combination with a systemic therapy based on an interdisciplinary decision. This review summarises the current treatment standard in oligometastatic lung cancer with focus on an ablative therapy for both lung primary and distant metastases in prognostically favourable locations.

Intrapulmonale Rundherde stellen in der Regel einen Zufallsbefund im Rontgenbild oder Computertomogramm des Thorax dar. Sie sind definiert als relativ gut abgegrenzte Lasionen von bis zu 3 cm Durchmesser, die allseits von Lungengewebe umgeben sind. Die Wahrscheinlichkeit fur das Vorliegen eines malignen Tumors steigt mit ihrer Grose. Rundherde ab 1 cm Durchmesser bedurfen der aktiven Abklarung. Zur Behandlung solitarer maligner Tumoren steht fur Patienten ohne nennenswert erhohtes Operations- und Narkoserisiko der chirurgische Eingriff an erster Stelle. Patienten, die aus funktionellen Grunden fur einen solchen nicht geeignet sind, konnen mit Radiofrequenzablation (RFA) oder Einzeitbestrahlung (SBRT) behandelt werden. In diesen Fallen mussen vor Therapiebeginn die Malignitat nachgewiesen oder zumindest uber einen begrenzten Zeitraum eine Grosenzunahme der Lasion dokumentiert worden sein. In Bezug auf die lokale Tumorfreiheit ist die Operation unter den Voraussetzungen einer R0-Resektion den anderen Verfahren uberlegen.

Reliable entity subtyping is paramount for therapy stratification in lung cancer. Morphological evaluation remains the basis for entity subtyping and directs the application of additional methods such as immunohistochemistry (IHC). The decision of whether to perform IHC for subtyping is subjective, and access to IHC is not available worldwide. Thus, the application of additional methods to support morphological entity subtyping is desirable. Therefore, the ability of convolutional neuronal networks (CNNs) to classify the most common lung cancer subtypes, pulmonary adenocarcinoma (ADC), pulmonary squamous cell carcinoma (SqCC), and small-cell lung cancer (SCLC), was evaluated. A cohort of 80 ADC, 80 SqCC, 80 SCLC, and 30 skeletal muscle specimens was assembled, slides were scanned, tumor areas were annotated, image patches were extracted, and cases were randomly assigned to a training, validation or test set. Multiple CNN architectures (VGG16, InceptionV3, and InceptionResNetV2) were trained and optimized to classify the four entities. A quality control (QC) metric was established. An optimized InceptionV3 CNN architecture yielded the highest classification accuracy and was used for the classification of the test set. Image patch and patient-based CNN classification results were 95% and 100% in the test set after the application of strict QC. Misclassified cases mainly included ADC and SqCC. The QC metric identified cases that needed further IHC for definite entity subtyping. The study highlights the potential and limitations of CNN image classification models for tumor differentiation.

Immunotherapies targeting the PD1/PD-L1 pathway have had a large impact on the treatment of advanced NSCLC. Concerning multimodality tumor therapy, only few trials until today have been performed investigating neoadjuvant treatment with anti PD-1 immunotherapy prior to curative intent surgery. Aim of the NEOMUN investigator initiated trial (EudraCT-Number: 2017–000105-20; ClinicalTrials.gov Identifier: NCT03197467) is to assess feasibility and safety of pre-surgical anti PD-1 treatment in order to improve long term survival. The study is designed as an open-label, single arm, prospective, monocenter, phase II study including 30 patients with NSCLC stage II/IIIA suitable for curative intent surgery. Investigational drug is Pembrolizumab. After 2 cycles of immunotherapy (a 200 mg q3w i.v.), tumor resection with lobectomy or bilobectomy will be performed. Primary objectives are to assess the feasibility and safety of a neoadjuvant immunotherapy and to assess antitumor activity of Pembrolizumab with regard to clinical and pathological tumor response. Secondary objective is disease free and overall survival. Exploratory objective is to analyze potential predictive biomarkers and to evaluate the therapeutic efficacy of Pembrolizumab by extended immune cell and cytokine analysis of tumor tissue. The study protocol was approved by the local ethics committee and the federal authority. Start of patient enrollment is scheduled for June 2018. The NEOMUN trial will be one of the first clinical trials investigating a multimodal treatment strategy including neoadjuvant immunotherapy using Pembrolizumab as an investigational drug. Assessing the safety and therapeutic potential of neoadjuvant immunotherapy in connection with lung surgery will be of great interest for thoracic surgeons. Prospectively, the NEOMUN study has been registered on www.clinicaltrials.gov ; NCT03197467 (first post: June 23rd, 2017).

Multiregional analysis provided first indications for morphological and molecular heterogeneity in lung adenocarcinomas (ADCs), but comprehensive morpho-molecular comparisons are still lacking. The purpose of our study was to investigate the spatial distribution of EGFR and KRAS alterations systematically throughout whole tumor cross-sections in correlation with the tumor cell content and the histopathological patterns. Central sections of 19 ADCs were subdivided into 467 segments of 5 mm × 5 mm. We determined the predominant histological growth pattern and the allele frequencies of driver gene mutations by digital PCR in every segment. We further quantified the absolute cell counts and proportions of tumor and non-neoplastic cells in all segments to normalize the mutant allele frequencies. Driver gene mutations could be detected in99% of the tumor containing segments, with high levels of inter- and intratumor heterogeneity regarding the mutant allele frequency (range: 0.04-19.36). Different patterns for the distribution of the variant allele frequency within a tumor were recognizable. While some cases showed ubiquitously low or high levels, others revealed regions with focally elevated frequencies. Differences between KRAS and EGFR alterations were not significant. The great majority of the analyzed tumor sections (16/19) exhibited two or more morphological growth patterns. Mutant allele frequencies were significantly higher in segments with a predominant solid pattern compared to all other histologies (p 0.01). Our data indicate that driver gene mutations are present with high levels of inter- and intratumor heterogeneity throughout the whole tumor, with a correlation between the allele frequencies and histological growth patterns.

Background: Only few reports exist on malignant thoracic neoplasms that require cardiopulmonary bypass during resection. We aimed to investigate the early and late clinical outcome of these patients. Methods: Patients with thoracic malignancies that underwent surgery between 2002 and 2014 were analyzed. All patients had cardiopulomonary bypass support during resection. Clinical and perioperative data was retrospectively reviewed for outcome and overall survival. Results: Fifteen patients (12 female, mean age of 55 ± 15 years, range 24 to 80 years) were identified. Eleven (8 female) were diagnosed with primary thoracic malignomas and four with metastases. Three patients died early postoperatively. Patients diagnosed with sarcoma had a significantly worse outcome than non-sarcoma patients (83.3 ± 15.2 % after 1 year, 31.3 ± 24.5 % after 5 years vs. 83.3 ± 15.2 % after 1 year, 0 ± 0 % after 5 years, p = 0.005). Conclusions: Malignancies with extension into cardiac structures or infiltration of great vessels can be resected with cardiopulmonary bypass support and tolerable risk. Carefully selected patients can undergo advanced operative procedures with an acceptable 1-year-survival, but only few patients achieved good long-term outcome.

Background. Large cell neuroendocrine carcinoma (LCNEC) represents a rare entity in non-small cell lung cancer, with only partially understood biology and poor survival. A diagnosis is difficult to obtain on the basis of small biopsy specimens, but surgical procedures may be indicated in only a small fraction of patients. The aim of this study was to assess the clinical and immunohistochemical features of patients with LCNEC to identify predictors of outcome and long-term survival. Methods. The clinical and pathologic data of 57 surgical patients with LCNEC between March 2003 and December 2012 were retrospectively reviewed. The tumor specimens wereexaminedforexpressionofneuronalspecificenolase, synaptophysin, CD 56, chromogranin-A, and the somatostatin receptor by immunohistochemistry. Statistical analysiswasperformedtodeterminesignificantpredictors for overall survival and recurrence-free survival. Results. Fifty-seven patients (41 men, 16 women) underwent thoracic operations with curative intent. Complete resection was achieved in 91% of cases. The results of staining for CD56, synaptophysin, neuronal specific enolase, chromogranin-A, and somatostatin were positive in 86%, 81%, 68%, 61%, and 21%, respectively. Recurrence occurred in 28 patients (49%). Overall survival and recurrence-free survival were 50% and 45%, respectively, after 3 years. Advanced nodal status (N1, p < 0.025; N2, p < 0.02) and simultaneous expression of CD56 and chromogranin-A (p < 0.04) were significantly associated with poorer outcome. Conclusions. LCNEC is a rare neuroendocrine pulmonary malignancy that is associated with poor prognosis and high recurrence rates. Surgical treatment can achieve satisfactory results in selected cases. Neuroendocrine marker profiles may predict prognosis and may influence the decision for adjuvant therapy or follow-up intervals. (Ann Thorac Surg 2015;99:983–90) 2015 by The Society of Thoracic Surgeons

Large cell neuroendocrine carcinoma (LCNEC) represents a rare entity in non-small cell lung cancer, with only partially understood biology and poor survival. A diagnosis is difficult to obtain on the basis of small biopsy specimens, but surgical procedures may be indicated in only a small fraction of patients. The aim of this study was to assess the clinical and immunohistochemical features of patients with LCNEC to identify predictors of outcome and long-term survival.The clinical and pathologic data of 57 surgical patients with LCNEC between March 2003 and December 2012 were retrospectively reviewed. The tumor specimens were examined for expression of neuronal specific enolase, synaptophysin, CD 56, chromogranin-A, and the somatostatin receptor by immunohistochemistry. Statistical analysis was performed to determine significant predictors for overall survival and recurrence-free survival.Fifty-seven patients (41 men, 16 women) underwent thoracic operations with curative intent. Complete resection was achieved in 91% of cases. The results of staining for CD56, synaptophysin, neuronal specific enolase, chromogranin-A, and somatostatin were positive in 86%, 81%, 68%, 61%, and 21%, respectively. Recurrence occurred in 28 patients (49%). Overall survival and recurrence-free survival were 50% and 45%, respectively, after 3 years. Advanced nodal status (N1, p0.025; N2, p0.02) and simultaneous expression of CD56 and chromogranin-A (p0.04) were significantly associated with poorer outcome.LCNEC is a rare neuroendocrine pulmonary malignancy that is associated with poor prognosis and high recurrence rates. Surgical treatment can achieve satisfactory results in selected cases. Neuroendocrine marker profiles may predict prognosis and may influence the decision for adjuvant therapy or follow-up intervals.

Background Sleeve pneumonectomy is a challenging therapeutic strategy for patients with non-small cell lung cancer (NSCLC) invading the carina. The aim of this study was to illustrate common indications and individual concepts for surgery and to investigate oncologic outcomes and complications. Methods Sixty-four consecutive sleeve pneumonectomies were performed between September 2000 and November 2011. All patients had histologically proven central NSCLC. Data were retrospectively reviewed for indications, complications, and factors influencing long-term survival. Results Sixty-four patients underwent sleeve pneumonectomy for curative (n = 50, 78%) or palliative therapy (n = 14, 22%). Complete resection was achieved in 83%. Pathologic N2 disease was found in 41%. Complications occurred in 41%, with severe anastomotic problems in 8% of cases. Thirty-day mortality was 3% (n = 2). Outcome was significantly influenced by pathologic nodal status with 5-year survival rates of 70%, 35%, and 9% for N0, N1, and N2 subgroups, respectively. Patients with multilevel N2 disease and contraindications for chemotherapy or radiotherapy had a mean survival of 13 months after palliative surgery. Conclusions Sleeve pneumonectomy for central NSCLC invading the carina or proximal main bronchus can be performed with tolerable risk and encouraging survival rates in selected cases. Palliative sleeve pneumonectomy displays an option in the absence of alternative therapeutic strategies.

Das Pneumoperikard ist eine seltene Komplikation nach Eingriffen in der Herz-Thorax-Chirurgie oder bei Katheterinterventionen. Bei kardialer Kompression mit hamodynamischer Relevanz infolge einer Perikardtamponade sind die schnelle klinisch-radiologische Diagnostik und Perikarddrainage unabdingbar. Wir beobachteten ein neu aufgetretenes Pneumoperikard drei Wochen nach Unterlappenektomie und Lymphknotendissektion bei nichtkleinzelligem Lungenkarzinom. Durch zugige therapeutische Drainage und Ursachenfindung konnte ein lebensbedrohlicher Verlauf abgewendet werden.

Background Unicameral (or simple) bone cysts (UBC) are benign tumours most often located in long bones of children and adolescents. Pathological fractures are common, and due to high recurrence rates, these lesions remain a challenge to treat. Numerous surgical procedures have been proposed, but there is no general consensus of the ideal treatment. The aim of this investigation therefore was to study the long-term outcome after surgical treatment in UBC. Methods A retrospective analysis of 46 patients surgically treated for UBC was performed for short and mid-term outcome. Clinical and radiological outcome parameters were studied according to a modified Neer classification system. Long-term clinical information was retrieved via a questionnaire at a minimum follow-up of 10 years after surgery. Results Forty-six patients (17 female, 29 male) with a mean age of 10.0 ± 4.8 years and with histopathologically confirmed diagnosis of UBC were included. Pathological fractures were observed in 21 cases (46%). All patients underwent surgery for UBC (35 patients underwent curettage and bone grafting as a primary therapy, 4 curettage alone, 3 received corticoid instillation and 4 decompression by cannulated screws). Overall recurrence rate after the first surgical treatment was 39% (18/46), second (17.4% of all patients) and third recurrence (4.3%) were frequently observed and were addressed by revision surgery. Recurrence was significantly higher in young and in male patients as well as in active cysts. After a mean of 52 months, 40 out of 46 cysts were considered healed. Prognosis was significantly better when recurrence was observed later than 30 months after therapy. After a mean follow-up of 15.5 ± 6.2 years, 40 patients acknowledged clinically excellent results, while five reported mild and casual pain. Only one patient reported a mild limitation of range of motion. Conclusions Our results suggest satisfactory overall long-term outcome for the surgical treatment of UBC, although short-and mid-term observation show a considerable rate of recurrence independent of the surgical technique.