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OA Förderung 2023

Treatment concepts for patients with localized and locally advanced non-small cell lung cancer (NSCLC) are based on local treatment, surgery and/or radiotherapy, with curative intent. An adjuvant systemic treatment is added after primary resection of an operable NSCLC primarily to reduce the systemic risk of relapse. Locally advanced stages with mediastinal lymph node involvement carry a substantial risk of local and distant recurrence and require multimodal treatment strategies in an interdisciplinary approach. Recently, immunotherapy with programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) checkpoint inhibitors is increasingly being integrated into adjuvant, neoadjuvant or perioperative treatment concepts.Therapiekonzepte für Patienten mit lokalisierten und lokal fortgeschrittenen nicht-kleinzelligen Lungenkarzinomen („non-small cell lung cancer“ [NSCLC]) basieren auf einer Lokaltherapie (Operation oder Strahlentherapie) in kurativer Intention. Nach primärer Resektion eines operablen NSCLC soll durch eine adjuvante Systemtherapie in erster Linie das systemische Rezidivrisiko gesenkt werden. Lokal fortgeschrittene Stadien mit mediastinaler Lymphknotenbeteiligung weisen ein erhebliches lokales und systemisches Rezidivrisiko auf. Hier ist die interdisziplinäre Umsetzung multimodaler Therapiekonzepte gefragt. Eine Immuntherapie mit Programmed-cell-death-1(PD-1)/Programmed-cell-death-1-ligand-1(PD-L1)-Checkpointinhibitoren ergänzt in zunehmendem Maße die neoadjuvanten, adjuvanten oder perioperativen Therapiekonzepte.

Objectives Preoperative planning of lung resection extent is decisive for preoperative functional work-up and selection for multimodal treatment. It is mainly based on preoperative chest CT. We aimed at evaluating chest CT adequacy to predict the extent of lung resection and hypothesized a relation with CT interpreters’ level of experience. Materials and Methods A pseudonymized CT library was built from patients who had curative intent lung resection for centrally located NSCLC. CT library was interpreted by 20 thoracic surgery residents or attendings. Interpreters were blinded to intraoperative findings and scored one point when lung resection was adequately planned. Points were summed up in a score from 0 to 20. Interpreters’ experience was evaluated through nine variables: age, position (resident vs. attending), years of experience in evaluating chest CTs, number of anatomic resections and sleeve resections attended as first assistant or performed as surgeon in presence of a teaching assistant or as main surgeon/teaching assistant. Variables characterizing interpreters’ experience were divided into equal sized groups. Independent sample T-test and one-way ANOVA/Tukey post hoc tests were used to compare scores between groups. Results CT library included 20 patients. Lung resections were lobectomy (n = 7, 35 %), sleeve lobectomy (n = 10, 50 %), sleeve bilobectomy (n = 2, 10 %), pneumonectomy (n = 1, 5%). Twenty interpreters scored a median of 10 (4–14). Attending surgeons had significantly higher mean scores (11.2 ± 1.3) compared to residents (7.7 ± 2.3, p = 0.001). All scores were significantly different between groups related to interpreters’ levels of experience, except for interpreters’age. Conclusion Preoperative CT evaluation for predicting intraoperative lung resection for centrally located NSCLC strongly depends on interpreters’ experience.

Malignant pleural mesothelioma is a rare type of cancer, whose incidence, however, is increasing and will presumably continue to rise in the coming years. Key features of this disease comprise its mantle-shaped, pleura-associated, often multifocal growth, which cause diagnostic challenges. A growing number of mesotheliomas are being treated with novel immunotherapies for which no image derived general response criteria have been established. However, recent studies indicate that FDG-PET/CT could be superior for response assessment compared to CT-based criteria. This article aims at providing an overview of response assessment criteria dedicated to malignant pleural mesothelioma, such as mRECIST, iRECIST, and PERCIST. In addition, the potential future role of PET/CT in the management of malignant pleural mesothelioma will also be discussed.

Background Leiomyosarcoma (LMS) most frequently metastasizes to the lung. Metastatic LMS is considered incurable. Selected patients may benefit from pulmonary metastasectomy (PM) within multimodal therapy. This study analyzed the prognostic relevance of clinicopathologic factors in these patients. Methods Patients with metastatic LMS to the lung treated in our center from 2004 to 2020 were included in this single-center retrospective study. Overall survival (OS), progression-free survival (PFS), and prognostic factors were analyzed. Results The study had 64 patients (33 males, 52%) with metastatic LMS to the lung. The 5-year OS was 55% after the diagnosis of pulmonary metastases. Age older than 60 years at the primary tumor diagnosis, primary tumor larger than 70 mm, and five or more lung metastases were associated with poorer OS. Of the 64 patients, 44 underwent PM. The postoperative mortality rate was 0%. The patients selected for PM were younger and had smaller primary tumors, fewer metastases, and metastases that more often were metachronous. Metastasis grade (G1 vs. G2/3) and size (20-mm cutoff) were significant prognostic factors for OS (p = 0.05) and PFS (p = 0.028) after PM, respectively. The 44 patients who underwent PM had a survival benefit compared with the patients who were selected but did not undergo PM (n = 6) and the patients who were not selected for PM (n = 14). Three patients (7%) were alive and free of disease at the last follow-up visit respectively 5.5, 9, and 12 years after PM. Conclusions For patients with leiomyosarcoma, PM is safe. Despite aggressive multimodal treatment, most patients will experience recurrence and eventually die of their disease. However, a small subgroup of patients could potentially be cured after PM.

The pivotal PACIFIC trial defined durvalumab consolidation as the new standard of care in patients with stage III non-small-cell lung cancer treated with definitive radiochemotherapy. The authors characterized the durvalumab effect after induction chemotherapy according to the ESPATUE trial and definitive radiochemotherapy. All consecutive patients with stage III non-small-cell lung cancer receiving definitive radiochemotherapy between January 2017 and February 2020 were included. Primary end points were progression-free survival and overall survival. Altogether, 160 patients (75 PD-L1-positive, 62 PD-L1-negative, 23 unknown) received definitive radiochemotherapy, 146 (91%) of whom received prior induction chemotherapy. Durvalumab consolidation showed high effectiveness overall and in the good-risk group according to the PACIFIC trial (log-rank test: p < 0.005). Hazard ratios for progression-free survival and overall survival were at the lower limits of those in the PACIFIC trial. These results were robust to adjustment for potential confounders by propensity score weighting. Eastern Cooperative Oncology Group (ECOG) performance status was the most important pretreatment prognostic factor. Tweetable abstract High effectiveness according to the PACIFIC and ESPATUE trials: patients were treated with induction chemotherapy, definitive radiochemotherapy and consolidation immunotherapy. A durable and remarkable tumor response was achieved in the real-world clinical routine. Plain language summary The PACIFIC trial is the major landmark trial for stage III non-small-cell lung cancer (NSCLC) patients treated with combined chemoradiation and defined immunotherapy as maintenance treatment and the new standard of care in patients with stage III NSCLC. Here the authors report a retrospective study comparing consecutive stage III NSCLC patients receiving induction chemotherapy and definitive chemoradiation with or without durvalumab consolidation in a high-volume lung cancer center. After induction chemotherapy, chemoradiation and immune checkpoint inhibition, a durable and remarkable tumor response can be achieved in the clinical routine. Consolidation immunotherapy with durvalumab can be confirmed as a strong innovative therapeutic option in NSCLC in almost all subgroups of patients.

Simple Summary Neoadjuvant immunotherapy is a novel approach for lung cancer patients in stages where curative intent treatment is possible. The rationale is a based on the idea that recognition by the immune system is activated by the entire tumor prior to surgical resection. Promising pathologic response rates have been reported and the impact on survival is currently investigated in ongoing studies. Abstract In early-stage lung cancer, recurrences are observed even after curative resection. Neoadjuvant immunotherapy might be a promising approach to eliminate micrometastasis and to potentially reduce recurrence rates and improve survival. Early trials have shown encouraging rates of pathologic response to neoadjuvant therapy and have demonstrated that surgery can be safely performed after neoadjuvant immunotherapy with various agents and in combination with chemo-(radio)therapy. However, whether these response rates translate into improved disease-free survival rates and overall survival rates remains to be determined by ongoing phase III studies.

Background Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare entity occurring in less than 4% of all lung cancers. Due to its low differentiation and high glucose transporter 1 (GLUT1) expression, LCNEC demonstrates an increased glucose turnover. Thus, PET/CT with 2-[18F]-fluoro-deoxyglucose ([18F]FDG) is suitable for LCNEC staging. Surgery with curative intent is the treatment of choice in early stage LCNEC. Prerequisite for this is correct lymph node staging. This study aimed at evaluating the diagnostic performance of [18F]FDG PET/CT validated by histopathology following surgical resection or mediastinoscopy. N-staging interrater-reliability was assessed to test for robustness of the [18F]FDG PET/CT findings. Methods Between 03/2014 and 12/2020, 46 patients with LCNEC were included in this single center retrospective analysis. All underwent [18F]FDG PET/CT for pre-operative staging and subsequently either surgery (n = 38) or mediastinoscopy (n = 8). Regarding the lymph node involvement, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for [18F]FDG PET/CT using the final histopathological N-staging (pN0 to pN3) as reference. Results Per patient 14 ± 7 (range 4–32) lymph nodes were resected and histologically processed. 31/46 patients had no LCNEC spread into the lymph nodes. In 8/46 patients, the final stage was pN1, in 5/46 pN2 and in 2/46 pN3. [18F]FDG PET/CT diagnosed lymph node metastasis of LCNEC with a sensitivity of 93%, a specificity of 87%, an accuracy of 89%, a PPV of 78% and a NPV of 96%. In the four false positive cases, the [18F]FDG uptake of the lymph nodes was 33 to 67% less in comparison with that of the respective LCNEC primary. Interrater-reliability was high with a strong level of agreement (κ = 0.82). Conclusions In LCNEC N-staging with [18F]FDG PET/CT demonstrates both high sensitivity and specificity, an excellent NPV but a slightly reduced PPV. Accordingly, preoperative invasive mediastinal staging may be omitted in cases with cN0 disease by [18F]FDG PET/CT. In [18F]FDG PET/CT cN1-cN3 stages histological confirmation is warranted, particularly in case of only moderate [18F]FDG uptake as compared to the LCNEC primary.

Endobronchial ultrasound-guided transbronchial needle aspirations (EBUS-TBNAs) are well established for staging lung cancer. A growing number of publications report on lymphoma diagnosis via EBUS-TBNA-acquired cytology; however current guidelines recommend histologic diagnosis. Research on the value of EBUS-TBNA-acquired cytology versus surgical-acquired histology in the diagnosis of lymphoma is lacking.We conducted a retrospective review of patients with mediastinal lymphoma diagnosed between 2010 and 2016. Mediastinal lymphadenopathy was accessible through both EBUS-TBNAs and surgical procedures. All data were extracted from our clinic's medical database and analyzed.Fifty-one patients newly diagnosed with lymphoma in the mediastinum were identified (median age, 43.5 years; mean age, 48.6 ± 20.6 years). A minimally invasive procedure was performed as a first diagnostic step in 29 patients, whereas surgical biopsy was performed in the remaining 22. The time to final diagnosis was significantly longer if a minimally invasive procedure was performed first compared with a surgical procedure (mean, 44 days [median, 38 days] vs 16 days [median, 8 days]; p0.030). The number of procedures to obtain a final diagnosis ranged from one to five (median, 2 procedures per patient) in the EBUS-TBNA group. This was significantly higher than that in the surgical group (median, 1 procedure per patient; p0.00005).We demonstrate that surgical biopsies are safe and well tolerated for lymphoproliferative disease diagnosis and lead to a final diagnosis in the shortest possible time. Unnecessary procedures were significantly reduced if a surgical biopsy was performed as the first step.

Background:Large cell neuroendocrine carcinomas of the lung (LCNEC) is a rare entity occurring in less than 4% of all lung cancers. Due to its low differentiation and high glucose transporter 1 (GLUT1) expression LCNEC demonstrates an increased glucose turnover. Thus, PET/CT with 2-[18F]-fluoro-deoxyglucose (FDG) is suitable for LCNEC staging. Surgery with curative intent is the treatment of choice in early stage LCNEC. Prerequisite for this is correct lymph node staging. This study aimed at evaluating the diagnostic performance of FDG PET/CT validated by histopathology following surgical resection or mediastinoscopy. N-staging interrater-reliability was assessed to test for robustness of the FDG PET/CT findings.Methods:Between 03/2014 and 12/2020 46 patients with LCNEC were included in this single center retrospective analysis. All underwent FDG PET/CT for pre-operative staging and subsequently either surgery (n=38) or mediastinoscopy (n=8). Regarding the lymph node involvement, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for FDG PET/CT using the final histopathological N-staging (pN0 to pN3) as reference.Results:Per patient 14 ± 7 (range 4 - 32) lymph nodes were resected and histologically processed. 31/46 patients had no LCNEC spread into the lymph nodes. In 8/46 patients final stage was pN1, in 5/46 pN2 and in 2/46 pN3. FDG PET/CT diagnosed lymph node metastasis of LCNEC with a sensitivity of 93%, a specificity of 87%, an accuracy of 89%, a PPV of 78% and a NPV of 96%. Interrater-reliability was high with a strong level of agreement (κ=0.82).Conclusions:In LCNEC N-staging with FDG PET/CT demonstrates both high sensitivity and specificity, an excellent NPV but a slightly reduced PPV. Accordingly, preoperative invasive mediastinal staging may be omitted in cases with cN0 disease by FDG PET/CT. In FDG PET/CT cN1-cN3 stages histological confirmation is warranted, particularly in case of only moderate FDG uptake.

Aims Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study. Methods and results Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours. Conclusions Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches.

Background The optimal treatment for patients with locally advanced non-small-cell lung-cancer (NSCLC) cT4 cN0/1 cM0 is still under debate. The purpose of this study was to examine the long-term survival of cT4 cN0/1 cM0 NSCLC patients undergoing induction chemotherapy and concurrent radiochemotherapy before surgery. Methods All consecutive patients with confirmed NSCLC (cT4 cN0/1 cM0) treated with neoadjuvant chemotherapy, concurrent radiochemotherapy (RT/CTx) (45–46 Gy) and surgical resection between 2000 and 2015 were included. According to the UICC guidelines (8th edition), T4 stage was reanalysed by an expert radiologist. The mediastinal staging was performed by systematic EBUS-TBNA or mediastinoscopy. The primary end-point was overall-survival (OS). The power to detect an increase of early tumour-associated mortality (hazard ratio > 3.5) within the first 5 years after treatment in comparison to late deaths beyond 96 months was >80%. Results Overall, 67 patients were treated with concurrent RT/CTx. T4 criteria were fulfilled by all patients, and multiple T4 criteria by 53 patients. Seventy percent of patients had an initial PET/CT staging. The median follow-up period was 134 months. OS rates at 2, 5, 10 and 15 years were 83.6 ± 4.5%, 65.4 ± 5.9%, 53.3 ± 6.3% and 36.6 ± 6.8%, respectively. A total of 44.8% of patients achieved a pathologic complete response. In multivariable analysis, ypT category was the most predictive factor. OS at 5 years for ypT0 (n = 31) was 80.5%, and ypT1 (n = 11) was 62.5%. Main sites of failure were brain and pulmonary metastases in seven and three patients, respectively. The intercurrent annual death rate was estimated from the survival curve beyond 96 months and was found to be 4.75% (95% CI 2.40–9.27%). No significant increased mortality was observed during the first 5 years (annual death rate: 8.31% [95% CI 5.60–12.24%], hazard-ratio = 1.72 [95% CI 0.81–3.65]). Conclusions The effectiveness of this trimodality schedule is high in patients with cT4 cN0/1 cM0 NSCLC with excellent local control rates. Considering the annual death rate beyond 8 years of survival as an intercurrent death rate due to comorbidity, this treatment schedule reduces annual mortality to background even in the first 5 years after therapy.

Background: Large cell neuroendocrine carcinomas (LCNEC) are rare pulmonary malignancies. Reported survival rates are heterogeneous and the optimal therapeutic strategy is still debated. The prognosis of LCNEC is generally inferior compared to other non-small lung cancers. In early stages, surgery is recommended but might not be sufficient alone. Methods: We retrospectively analyzed all consecutive LCNEC patients operated at three institutions with curative intent between May 2005 and January 2017. Data retrieved from individual clinical databases were analyzed with the aim to identify prognostic parameters. Results: A total of 251 patients with LCNEC underwent curative intent surgery during the observation period. The median age was 64 years, 156 patients (62.2%) were male and 88.4% were smokers. The pathologic AJCC stage was I in 136 patients, II in 77, III in 33, and IV in 5 patients. Median followup was 26 months. Lymphatic vessel invasion (P=0.031) was identified as significant prognostic factor by multivariable analysis. There was a trend towards decreased survival in patients with blood vessel invasion (P=0.067). Even in earlier tumor stages, adjuvant chemotherapy had a positive effect on survival. The overall 1-, 3- and 5-year survival rates were 79.2%, 48.6% and 38.8% respectively. Conclusions: Lymphatic invasion (L1) is an independent prognostic factor. Surgery in LCNEC is beneficial in early tumor stages and platinum-based adjuvant chemotherapy may help in achieving better long-term outcomes resulting in most obvious survival differences in stage Ib. CA extern

Background and objectives Primary pulmonary sarcoma (PPS) accounts for less than 1.1% of all pulmonary tumors. Few outcome data are reported. We evaluated outcome and prognostic factors in our series. Methods We retrospectively reviewed all patients who underwent resection for PPS in our center from 2002 to 2018. Survival was calculated from the date of surgery until last follow-up. Impact on survival of gender, type of lung resection, completeness of resection, grade, size, and TNM staging for lung cancer and soft tissue sarcoma (STS) was assessed. Results Thirteen patients were included. Eight (61.5%) patients received neoadjuvant treatment. Median tumor size at diagnosis was 11.5 cm (1-30 cm). Type of lung resection was wedge (n = 2, 15%), lobectomy (n = 4, 31%), intrapericardial (n = 3, 23%), and extrapleural pneumonectomies (n = 4, 31%). In-hospital mortality was 8%. Overall 5-year survival was 60%. Median disease-free survival was 17 months. Tumor size was a predictor for survival (P = .02) and recurrence (P = .05). Gender (P = .04) and type of lung resection (P = .04) were predictors of survival. T stage for STS of trunk and extremity, and TNM stage for lung cancer were predictors for recurrence (P = .03 and P = .04, respectively). Conclusion Surgical resection within a multimodality therapy concept in highly selected patients can offer good long-term outcome.

Malignant pleural effusion (MPE) confers dismal prognosis and has limited treatment options. While immune-checkpoint inhibition (ICI) proved clinical efficacy in a variety of malignancies, data on the prognostic role of PD-L1 in MPE is scarce. We retrospectively studied PD-L1 tumour proportion score and Ki-67 index in pleural biopsies or cytologies from 123 patients (69 lung cancer, 25 mesothelioma, and 29 extrathoracic primary malignancies). Additionally, the impact of C-reactive protein (CRP) and platelet count was also analysed. Median overall survival (OS) after MPE diagnosis was 9 months. Patients with PD-L1 positive tumours (≥1%) had significantly shorter OS than patients with negative PD-L1 status (p = 0.031). CRP and Ki-67 index were also prognostic and remained independent prognosticators after multivariate analysis. Interestingly, Ki-67 index and CRP influenced the prognostic power of PD-L1. Finally, patients receiving ICI tended to have a longer median OS and CRP - but not PD-L1 - was a significant prognosticator in this subgroup. In summary, histological and circulating biomarkers should also be taken into account as potential biomarkers in ICI therapy and they may have an impact on the prognostic power of PD-L1. Our findings might help personalizing immune-checkpoint inhibition for patients with MPE and warrant further prospective validation.

OBJECTIVESPulmonary metastasectomy for malignant melanoma requires an individualized therapeutic decision. Due to recently developed novel treatment options, the prognosis of patients with melanoma has improved significantly. Validated prognostic factors that identify patients who are most likely to benefit from metastasectomy are urgently needed.METHODSWe retrospectively reviewed all consecutive patients with melanoma undergoing complete pulmonary metastasectomy between January 2010 and December 2016. The impact of age, sex, extrapulmonary metastases, preoperative systemic therapy, number of metastases, laterality and largest diameter of metastasis on survival after metastasectomy was analysed.RESULTSA total of 29 male and 32 female patients were included in the study. The median follow-up time was 25.6 months. The mean number of resected metastases was 1.7 ± 1.1 (range 1–5). Ten patients had repetitive pulmonary metastasectomies. The median survival time was 31.3 months with a 2-year survival rate of 54%. Bilateral metastases or multiple nodules were not associated with a significantly decreased overall survival rate after metastasectomy. Shorter overall survival times were observed in male patients [hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.42–5.92; P = 0.0035] and in patients with nodules larger than 2 cm (HR 3.18, 95% CI 1.45–6.98; P = 0.004). In multivariable analysis, both gender and tumour size remained significant independent prognostic factors.CONCLUSIONSExcellent overall survival rates after pulmonary metastasectomy for melanoma metastases were observed in patients with a metastatic diameter less than 2 cm and in female patients. In view of improved long-term outcome due to novel treatment options, the selection of patients for pulmonary metastasectomy based on prognostic factors will become increasingly important.

Background Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term “BRCAness”. An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis. Methods We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members. Results A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM. Conclusions Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients’ clinical management and outcome. Electronic supplementary material The online version of this article (10.1186/s12885-019-5314-0) contains supplementary material, which is available to authorized users.

The majority of patients with lung cancer are diagnosed in a metastatic state, in which prognosis is rather poor. Chemotherapy can improve median overall survival by only a few months, but a small percentage of these patients suffer only from oligometastatic diseases and may therefore be treated with curative intend. In this study, we compared two groups of patients with oligometastatic lung cancer, who received palliative treatment or multimodal treatment with a surgical approach. We conducted a retrospective review of all patients with synchronous extrapulmonary oligometastatic disease diagnosed between 2010 and 2013. All data were extracted from the medical database of our department and further analysed. There were 52 patients diagnosed with oligometastatic lung cancer between 2010 and 2013. A cohort of 32 patients was treated surgically in a multimodal approach, but 19 patients refused surgery. These patients were treated by palliative chemotherapy or other palliative treatments, such as radiochemotherapy etc. Median overall survival was 18 months in the surgically treated group and 6 months in the palliative group (p

Previously, our group demonstrated that nuclear expression of E3 ubiquitin ligase (MDM2) in malignant pleural mesothelioma (MPM) is significantly associated with decreased overall survival. A possible explanation may be that overexpression of MDM2 leads to a proteasomal degradation of TP53 that eventually results in a loss of TP53-induced apoptosis and senescence. It is well known from other tumor entities that restoration of TP53 activity, e.g., by MDM2 inhibition, results in an instant TP53-induced stress and/or DNA damage response of cancer cells. Nutlin-3A (acis-imidazoline analogue) has been described as a potent and selective MDM2 inhibitor preventing MDM2-TP53-interaction by specific binding to the hydrophobic TP53-binding pocket of MDM2. In the present study, the effects of MDM2 inhibition in MPM via Nutlin-3A and standard platinum based chemotherapeutic agents were comparatively tested in three MPM cell lines (NCI-H2052, MSTO-211H, and NCI-H2452) showing different expression profiles of TP53, MDM2, and its physiological inhibitor of MDM2—P14/ARF. Ourin vitroexperiments on MPM cell lines revealed that Nutlin-3A in combination with cisplatin resulted in up to 9.75 times higher induction of senescence (p=0.0050) and up to 5 times higher apoptosis rate (p=0.0067) compared to the commonly applied cisplatin and pemetrexed regimens. Thus Nutlin-3A, a potent inhibitor of MDM2, is associated with a significant induction of senescence and apoptosis in MPM cell lines, making Nutlin-3A a promising substance for a targeted therapy in the subgroup of MPM showing MDM2 overexpression.

// Fabian D. Mairinger 1, * , Jan Schmeller 1, * , Sabrina Borchert 1 , Michael Wessolly 1 , Elena Mairinger 1 , Jens Kollmeier 2 , Thomas Hager 1 , Thomas Mairinger 3 , Daniel C. Christoph 4, 5 , Robert F.H. Walter 1, 6 , Wilfried E.E. Eberhardt 4, 6 , Till Plones 7 , Jeremias Wohlschlaeger 1, 8 , Bharat Jasani 9 , Kurt Werner Schmid 1 and Agnes Bankfalvi 1 1 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany 3 Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany 4 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 5 Department of Internistic Oncology, Kliniken Essen Mitte, Essen, Germany 6 Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 7 Department of Thoracic Surgery and Thoracical Endoscopy, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 8 Department of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany 9 Department of Pathology, Targos Molecular Pathology GmbH, Kassel, Germany * These authors have contributed equally to this work Correspondence to: Fabian D. Mairinger, email: fabian.mairinger@uk-essen.de Keywords: malignant pleural mesothelioma; metallothionein; overall survival; prognostic biomarker; platin-based chemotherapy; Pathology Received: August 18, 2017 Accepted: March 11, 2018 Published: April 27, 2018 ABSTRACT Background: Malignant pleural mesothelioma (MPM) is a biologically highly aggressive tumor arising from the pleura with a dismal prognosis. Cisplatin is the drug of choice for the treatment of MPM, and carboplatin seems to have comparable efficacy. Nevertheless, cisplatin treatment results in a response rate of merely 14% and a median survival of less than seven months. Due to their role in many cellular processes, methallothioneins (MTs) have been widely studied in various cancers. The known heavy metal detoxifying effect of MT-I and MT-II may be the reason for heavy metal drug resistance of various cancers including MPM. Methods: 105 patients were retrospectively analyzed immunohistochemically for their MT expression levels. Survival analysis was done by Cox-regression, and statistical significance determined using likelihood ratio, Wald test and Score (logrank) tests. Results: Cox-regression analyses were done in a linear and logarithmic scale revealing a significant association between expression of MT and shortened overall survival (OS) in a linear (p=0.0009) and logarithmic scale (p=0.0003). Reduced progression free survival (PFS) was also observed for MT expressing tumors (linear: p=0.0134, log: p=0.0152). Conclusion: Since both, overall survival and progression-free survival are negatively correlated with detectable MT expression in MPM, our results indicate a possible resistance to platin-based chemotherapy associated with MT expression upregulation, found exclusively in progressive MPM samples. Initial cell culture studies suggest promoter DNA hypomethylation and expression of miRNA-566 a direct regulator of copper transporter SLC31A1 and a putative regulator of MT1A and MT2A gene expression, to be responsible for the drug resistance.

BACKGROUND Lung cancer is highly aggressive and tends to metastasize early. Therefore, accurate mediastinal staging is important for therapeutic decision making. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a minimally invasive procedure for mediastinal lymph node sampling and cancer staging. Classical EBUS-TBNA cytology has been combined with molecular staging techniques to improve sensitivity and specificity. This study aimed to assess mRNA integrity in samples acquired by EBUS-TBNA in the clinics. As proof-of-principle experiments, we also investigated whether stable miRNA could be detected in these samples. METHODS Integrity of mRNA isolated from tumor-positive EBUS-TBNA samples was assessed by calculating the RNA integrity number (RIN). In addition, 4 microRNAs were investigated (miRNA 21, miRNA 155, miRNA 200c, and miRNA 34a) because their relation to lung cancer has been documented recently. A group of patients with benign mediastinal lymphadenopathy served as a control. RESULTS mRNA isolated from EBUS-TBNA samples was nearly completely degraded if handled under clinical conditions (RIN

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.