PD-L1 on large extracellular vesicles is a predictive biomarker for therapy response in tissue PD-L1-low and -negative patients with non-small cell lung cancer.

Immunotherapy has revolutionized the treatment of patients with non-small cell lung cancer (NSCLC). High expression of tissue PD-L1 (tPD-L1) is currently the only approved biomarker for predicting treatment response. However, even tPD-L1 low (1-49%) and absent (<1%) patients might benefit from immunotherapy but, to date, there is no reliable biomarker, that can predict response in this particular patient subgroup. This study aimed to test whether tumour-associated extracellular vesicles (EVs) could fill this gap. Using NSCLC cell lines, we identified a panel of tumour-related antigens that were enriched on large EVs (lEVs) compared to smaller EVs. The levels of lEVs carrying these antigens were significantly elevated in plasma of NSCLC patients (n = 108) and discriminated them from controls (n = 77). Among the tested antigens, we focused on programmed cell death ligand 1 (PD-L1), which is a well-known direct target for immunotherapy. In plasma lEVs, PD-L1 was mainly found on a population of CD45- /CD62P+ lEVs and thus seemed to be associated with platelet-derived vesicles. Patients with high baseline levels of PD-L1+ lEVs in blood showed a significantly better response to immunotherapy and prolonged survival. This was particularly true in the subgroup of NSCLC patients with low or absent tPD-L1 expression, thus identifying PD-L1-positive lEVs in plasma as a novel predictive and prognostic marker for immunotherapy.

Bronchoscopist-Directed Continuous Flow Propofol Based Analgosedation during Flexible Interventional Bronchoscopy and EBUS.

Sedation techniques in interventional flexible bronchoscopy and endobronchial ultrasound-guided transbronchial-needle aspiration (EBUS-TBNA) are inconsistent and the evidence for required general anesthesia under full anesthesiologic involvement is scarce. Moreover, we faced the challenge of providing bronchoscopic care with limited personnel. Hence, we retrospectively identified 513 patients that underwent flexible interventional bronchoscopy and/or EBUS-TBNA out of our institution between January 2020 and August 2022 to evaluate our deep analgosedation approach based on pethidine/meperidine bolus plus continuous flow adjusted propofol, the bronchoscopist-directed continuous flow propofol based analgosedation (BDcfP) in a two-personnel setting. Consequently, 502 out of 513 patients received BDcfP for analgosedation. We identified cardiovascular comorbidities, chronic obstructive pulmonary disease, and arterial hypertension as risk factors for periprocedural hypotension. Propofol flow rate did not correlate with hypotension. Theodrenaline and cafedrine might be used to treat periprocedural hypotension. Moreover, midazolam might be used to support the sedative effect. In conclusion, BDcfP is a safe and feasible sedative approach during interventional flexible bronchoscopy and EBUS-TBNA. In general, after the implementation of safety measures, EBUS-TBNA and interventional flexible bronchoscopy via BDcfP might safely be performed even with limited personnel.

Risk Factors in HIV-1 Positive Patients on the Intensive Care Unit: A Single Center Experience from a Tertiary Care Hospital.

HIV-positive patients with acquired immunodeficiency syndrome (AIDS) often require treatment on intensive care units (ICUs). We aimed to present data from a German, low-incidence region cohort, and subsequently evaluate factors measured during the first 24 h of ICU stay to predict short- and long-term survival, and compare with data from high-incidence regions. We documented 62 patient courses between 2009 and 2019, treated on a non-operative ICU of a tertiary care hospital, mostly due to respiratory deterioration and co-infections. Of these, 54 patients required ventilatory support within the first 24 h with either nasal cannula/mask (n = 12), non-invasive ventilation (n = 16), or invasive ventilation (n = 26). Overall survival at day 30 was 77.4%. While ventilatory parameters (all p < 0.05), pH level (c/o 7.31, p = 0.001), and platelet count (c/o 164,000/µL, p = 0.002) were significant univariate predictors of 30-day and 60-day survival, different ICU scoring systems, such as SOFA score, APACHE II, and SAPS 2 predicted overall survival (all p < 0.001). Next to the presence or history of solid neoplasia (p = 0.026), platelet count (HR 6.7 for <164,000/µL, p = 0.020) and pH level (HR 5.8 for <7.31, p = 0.009) remained independently associated with 30-day and 60-day survival in multivariable Cox regression. However, ventilation parameters did not predict survival multivariably.

High expression of transcription factor POU2F1 confers improved survival on smokers with lung adenocarcinoma: a retrospective study of two cohorts.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide and its most important risk factor is tobacco smoking. While smoking is associated with inferior outcome in NSCLC patients, smoking also correlates with a higher tumor mutational burden. In contrast to adenocarcinomas (ADC) of non-smokers, that frequently harbor targetable gain-of-function mutations, NSCLC smokers largely present with non-targetable loss-of-function mutations of genes associated with DNA-damage repair. The transcription factor Pit-1, Oct1/2, Unc-86 (POU) domain class 2 transcription factor 1 (POU2F1) is a widely expressed bipotential stabilizer of repressed and inducible transcriptional states and frequently deregulated in cancer. Methods: Via immunohistochemistry, we evaluated POU2F1 protein expression on a tissue micro array of 217 operable stage I-III NSCLC patients. Findings were reproduced in a gene expression database of 1144 NSCLC patients, filtered for POU2F1 mRNA expression. After retroviral overexpression of POU2F1 in A549 cells, we evaluated for clonogenic growth and proliferation. Additionally, CRISPR-Cas9 mediated POU2F1 knockdown in A549 cells was likewise analyzed. Results: High protein expression of POU2F1 in 217 NSCLC patients resulted in improved outcome of smokers with ADC [hazard ratio (HR) 0.30 (0.09-0.99), P=0.035]. Moreover, gene expression analysis confirmed favorable outcome of high POU2F1 mRNA expression in smokers with ADC [HR 0.41 (0.24-0.69), P<0.001]. Other than that, retrovirally induced overexpression of POU2F1 in A549 cells significantly reduced both, clonogenic growth as well as proliferation of NSCLC cells, whereas CRISPR-Cas9 mediated knockdown of the protein did not have any impact. Conclusions: Our data suggest that high expression of POU2F1 mediates a less aggressive cancer phenotype in smokers with ADC NSCLC. Pharmacological induction of genes and signaling pathways controlled by POU2F1 may provide novel avenues for future targeted NSCLC therapies in smokers.

Liquid Biopsies in Lung Cancer.

As lung cancer has the highest cancer-specific mortality rates worldwide, there is an urgent need for new therapeutic and diagnostic approaches to detect early-stage tumors and to monitor their response to the therapy. In addition to the well-established tissue biopsy analysis, liquid-biopsy-based assays may evolve as an important diagnostic tool. The analysis of circulating tumor DNA (ctDNA) is the most established method, followed by other methods such as the analysis of circulating tumor cells (CTCs), microRNAs (miRNAs), and extracellular vesicles (EVs). Both PCR- and NGS-based assays are used for the mutational assessment of lung cancer, including the most frequent driver mutations. However, ctDNA analysis might also play a role in monitoring the efficacy of immunotherapy and its recent accomplishments in the landscape of state-of-the-art lung cancer therapy. Despite the promising aspects of liquid-biopsy-based assays, there are some limitations regarding their sensitivity (risk of false-negative results) and specificity (interpretation of false-positive results). Hence, further studies are needed to evaluate the usefulness of liquid biopsies for lung cancer. Liquid-biopsy-based assays might be integrated into the diagnostic guidelines for lung cancer as a tool to complement conventional tissue sampling.

High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma.

Via immunohistochemistry (IHC) on tissue micro arrays (TMA) clinical and prognostic impact of p53 co-playing 5'-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein expression was evaluated in 252 NSCLC patients. Confirmatory, gene expression database. mRNA levels of NT5DC2 were studied in 1925 NSCLC patients. High protein expression of NT5DC2 resulted in reduced median overall survival (OS) of patients with stage I-III adenocarcinoma (ADC) (Log Rank p = 0.026, HR 2.04 (1.08−3.87)), but not in squamous cell carcinoma (SCC) (p = 0.514, HR 0.87 (0.57−1.33)). Findings on OS were reproduced via gene expression analysis in ADC (p < 0.001, HR 1.64 (1.30−2.08)) and SCC (p = 0.217, HR 0.86 (0.68−1.09)). Yet, NT5DC2 mRNA levels were higher in SCC compared to ADC (p < 0.001) and in pN2 tumors compared to pN0/1 tumors (p = 0.001). Likewise, NT5DC2 protein expression associated with high-grade SCC. Moreover, NT5DC2 expression was positively correlated with p53 protein (p = 0.018) and TP53 gene expression (p < 0.001) and its survival effect was p53 dependent. While p53 expression was negatively associated with the presence of CD34+ cancer associated fibroblasts (CAFs), NT5DC2 expression insignificantly tended to higher levels of SMA+ CAFs (p = 0.065).

Sustained Impairment in Cardiopulmonary Exercise Capacity Testing in Patients after COVID-19: A Single Center Experience.

Background: Following COVID-19, patients often present with ongoing symptoms comparable to chronic fatigue and subjective deterioration of exercise capacity (EC), which has been recently described as postacute COVID-19 syndrome. Objective: To objectify the reduced EC after COVID-19 and to evaluate for pathologic limitations. Methods: Thirty patients with subjective limitation of EC performed cardiopulmonary exercise testing (CPET). If objectively limited in EC or deteriorated in oxygen pulse, we offered cardiac stress magnetic resonance imaging (MRI) and a follow-up CPET. Results: Eighteen male and 12 female patients were included. Limited relative EC was detected in 11/30 (36.7%) patients. Limitation correlated with reduced body weight-indexed peak oxygen (O2) uptake (peakV̇O2/kg) (mean 74.7 (±7.1) % vs. 103.6 (±14.9) %, p < 0.001). Reduced peakV̇O2/kg was found in 18/30 (60.0%) patients with limited EC. Patients with reduced EC widely presented an impaired maximum O2 pulse (75.7% (±5.6) vs. 106.8% (±13.9), p < 0.001). Abnormal gas exchange was absent in all limited EC patients. Moreover, no patient showed signs of reduced pulmonary perfusion. Using cardiac MRI, diminished biventricular ejection fraction was ruled out in 16 patients as a possible cause for reduced O2 pulse. Despite noncontrolled training exercises, follow-up CPET did not reveal any exercise improvements. Conclusions: Deterioration of EC was not associated with ventilatory or pulmonary vascular limitation. Exercise limitation was related to both reduced O2 pulse and peakV̇O2/kg, which, however, did not correlate with the initial severity of COVID-19. We hypothesize that impaired microcirculation or limited peripheral O2 utilization might be causative for prolonged deterioration of EC following acute COVID-19 infection.

Central airway obstruction treatment with self-expanding covered Y-carina nitinol stents: A single center retrospective analysis.

BACKGROUND: Central airway obstruction (CAO) is one of the most challenging, potentially lethal complications in malignant and benign respiratory diseases. Worsening dyspnea is also a relevant cause for reduced quality of life in such patients. Here, we present our data on the application of covered, self-expanding Y-carina nitinol stents due to benign and malignant diseases. METHODS: We retrospectively identified 27 patients who had undergone 31 rigid bronchoscopies with implantation of covered Y-carina nitinol stents over a period of 10 years in order to evaluate indication, clinical course, and outcome. RESULTS: Short-term survival of successfully stented patients with palliative and curative treatment goal did not differ, allowing for diagnosis independent indication. With respect to overall survival, patients with endoluminal obstruction benefited most compared to patients with fistula and/or external compression. Granulation tissue formation (61.3%) and mucus plugging (80.6%) were the most frequent complications. Material defect (6.5%) and migration (3.2%) were rare complications that could be handled by revisional rigid bronchoscopy and stent exchange in some cases. CONCLUSIONS: Implantation of self-expanding covered Y-carina nitinol stents via rigid bronchoscopy is a feasible and safe treatment option for benign and malignant central airway obstruction. Especially in palliative, malignant airway stenosis, stenting might facilitate additional treatment options and optimize dyspnea and eventually quality of life.

Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition.

Treatment of advanced stage anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with ALK-fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage EML4-ALK fused pulmonary adenocarcinoma was initially successfully treated with the second-generation ALK inhibitor alectinib and upon progressions subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress to alectinib was associated with a so far undescribed ALK mutation (p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An off-target KRAS-mutation (p.Q61K) occurred in association with subsequent progression under second-line TKI treatment. Third-line lorlatinib showed limited efficacy but chemoimmunotherapy resulted in disappearance of the KRAS mutant clone and clinical tumor control for another eight months. In conclusion, we suggest molecular profiling of progressive tumor disease also for ALK-positive NSCLC to personalize treatment in a subgroup of ALK-positive patients.

A cardiovascular magnetic resonance imaging-based pilot study to assess coronary microvascular disease in COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and is primarily characterised by a respiratory disease. However, SARS-CoV-2 can directly infect vascular endothelium and subsequently cause vascular inflammation, atherosclerotic plaque instability and thereby result in both endothelial dysfunction and myocardial inflammation/infarction. Interestingly, up to 50% of patients suffer from persistent exercise dyspnoea and a post-viral fatigue syndrome (PVFS) after having overcome an acute COVID-19 infection. In the present study, we assessed the presence of coronary microvascular disease (CMD) by cardiovascular magnetic resonance (CMR) in post-COVID-19 patients still suffering from exercise dyspnoea and PVFS. N = 22 patients who recently recovered from COVID-19, N = 16 patients with classic hypertrophic cardiomyopathy (HCM) and N = 17 healthy control patients without relevant cardiac disease underwent dedicated vasodilator-stress CMR studies on a 1.5-T MR scanner. The CMR protocol comprised cine and late-gadolinium-enhancement (LGE) imaging as well as velocity-encoded (VENC) phase-contrast imaging of the coronary sinus flow (CSF) at rest and during pharmacological stress (maximal vasodilation induced by 400 µg IV regadenoson). Using CSF measurements at rest and during stress, global myocardial perfusion reserve (MPR) was calculated. There was no difference in left ventricular ejection-fraction (LV-EF) between COVID-19 patients and controls (60% [57-63%] vs. 63% [60-66%], p = NS). There were only N = 4 COVID-19 patients (18%) showing a non-ischemic pattern of LGE. VENC-based flow measurements showed that CSF at rest was higher in COVID-19 patients compared to controls (1.78 ml/min [1.19-2.23 ml/min] vs. 1.14 ml/min [0.91-1.32 ml/min], p = 0.048). In contrast, CSF during stress was lower in COVID-19 patients compared to controls (3.33 ml/min [2.76-4.20 ml/min] vs. 5.32 ml/min [3.66-5.52 ml/min], p = 0.05). A significantly reduced MPR was calculated in COVID-19 patients compared to healthy controls (2.73 [2.10-4.15-11] vs. 4.82 [3.70-6.68], p = 0.005). No significant differences regarding MPR were detected between COVID-19 patients and HCM patients. In post-COVID-19 patients with persistent exertional dyspnoea and PVFS, a significantly reduced MPR suggestive of CMD-similar to HCM patients-was observed in the present study. A reduction in MPR can be caused by preceding SARS-CoV-2-associated direct as well as secondary triggered mechanisms leading to diffuse CMD, and may explain ongoing symptoms of exercise dyspnoea and PVFS in some patients after COVID-19 infection.

Detection of Histoplasma DNA from Tissue Blocks by a Specific and a Broad-Range Real-Time PCR: Tools to Elucidate the Epidemiology of Histoplasmosis.

Lack of sensitive diagnostic tests impairs the understanding of the epidemiology of histoplasmosis, a disease whose burden is estimated to be largely underrated. Broad-range PCRs have been applied to identify fungal agents from pathology blocks, but sensitivity is variable. In this study, we compared the results of a specific Histoplasma qPCR (H. qPCR) with the results of a broad-range qPCR (28S qPCR) on formalin-fixed, paraffin-embedded (FFPE) tissue specimens from patients with proven fungal infections (n = 67), histologically suggestive of histoplasmosis (n = 36) and other mycoses (n = 31). The clinical sensitivity for histoplasmosis of the H. qPCR and the 28S qPCR was 94% and 48.5%, respectively. Samples suggestive for other fungal infections were negative with the H. qPCR. The 28S qPCR did not amplify DNA of Histoplasma in FFPE in these samples, but could amplify DNA of Emergomyces (n = 1) and Paracoccidioides (n = 2) in three samples suggestive for histoplasmosis but negative in the H. qPCR. In conclusion, amplification of Histoplasma DNA from FFPE samples is more sensitive with the H. qPCR than with the 28S qPCR. However, the 28S qPCR identified DNA of other fungi in H. qPCR-negative samples presenting like histoplasmosis, suggesting that the combination of both assays may improve the diagnosis.

Tumor infiltrating T cells influence prognosis in stage I-III non-small cell lung cancer.

BACKGROUND: T cell infiltration in non-small cell lung cancer (NSCLC) is essential for the immunological response to malignant tissue, especially in the era of immune-checkpoint inhibition. To investigate the prognostic impact of CD4+ T helper cells (Th), CD8+ cytotoxic (Tc) and FOXP3+ regulatory T (Treg) cells in NSCLC, we performed this analysis. METHODS: By counterstaining of CD4, CD8 and FOXP3 we used immunohistochemistry on tissue microarrays (TMA) to evaluate peritumoral Th cells, Treg cells and Tc cells in n=294 NSCLC patients with pTNM stage I-III disease. RESULTS: Strong CD4+ infiltration was associated with higher tumor stages and lymphonodal spread. However, strong CD4+ infiltration yielded improved overall survival (OS) (P=0.014) in adenocarcinoma (ADC) and large cell carcinoma (LCC) but not in squamous cell carcinoma (SCC). A CD4/CD8 ratio <1 was associated with high grade NSCLC tumors (P=0.020). High CD8+ T cell infiltration was an independent prognostic factor for OS (P=0.040) and progression-free survival (PFS) (P=0.012) in the entire study collective. The OS benefit of high CD8+ infiltration was especially prominent in PD-L1 negative NSCLC (P=0.001) but not in PD-L1 positive tissue (P=0.335). Moreover, positive FOXP3+ expression in tumor infiltrating lymphocytes was associated with increased OS (P=0.007) and PFS (P=0.014) in SCC but not in ADC and LCC (all P>0.05). Here, prognostic effects were prominent in PD-L1 positive SCC (P=0.023) but not in PD-L1 negative SCC (P=0.236). CONCLUSIONS: High proportion of CD8+ Tc cells correlated with improved prognostic outcome in stage I-III NSCLC. Th cells and Treg cells have implications on outcome with respect to tumor histology and biology.

Alpha-1 Antitrypsin Deficiency and Pulmonary Morbidity in Patients with Primary Immunodeficiency Disease: A Single-Center Experience.

Background: Alpha-1 antitrypsin deficiency (AATD) is of importance in the pathogenesis of pulmonary emphysema, chronic obstructive pulmonary diseases (COPD), and bronchiectasis. Various pulmonary disorders are a typical feature of primary immunodeficiency disease (PID). This includes recurrent pulmonary infections, immunodysregulation, and autoinflammatory diseases. As a result, incidence of acute and chronic pulmonary diseases is higher. Interestingly, pulmonary morbidity in PID and AATD share similar features. To study the coexistence of AATD in patients suffering from PID, we performed the underlying investigation. Methods: We evaluated a study group of 149 patients (n = 149) with PID. In total, serum AAT concentrations were available for 110 patients (n = 110). For the identified patients, we analyzed both clinical associations and interactions. Results: Among the investigated patients, reduced serum AAT levels were detected in 7 patients. With regard to the genotype, PI∗ZZ was found in 2 patients, whereas PI∗MZ was observed in 5 patients. Independent of the underlying phenotype, obstructive lung diseases were found in 2 patients with PI∗ZZ and 2 patients with PI∗MZ. Conclusions: In Germany, the estimated percentage for PI∗ZZ and PI∗MZ is 0.01% and 1.9%, respectively. As demonstrated, the ratio in our study group was even higher. We identified seven patients with AATD. Since AATD contributes to pulmonary morbidity in PID patients, systematic underdiagnosis of the coexistence might yield a strong clinical impact. Hence, AAT analysis should be offered to all patients with confirmed PID diagnoses. To strengthen this finding, we suggest the investigation of larger databases.

Prognostic impact of CD34 and SMA in cancer-associated fibroblasts in stage I-III NSCLC.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a crucial step in lung cancer pathogenesis. Among others, cancer-associated fibroblasts (CAFs) are reported to regulate this process. OBJECTIVES: To investigate the prognostic and clinical impact, we analyzed CD34+ and SMA+ CAFs in non-small cell lung cancer (NSCLC). METHODS: Retrospectively, immunohistochemistry was performed to study stromal protein expression of both CD34 and SMA in 304 NSCLC patients with pTNM stage I-III disease. All tissue samples were embedded on tissue microarrays (TMAs). RESULTS: Our analysis revealed an association for CD34+ CAFs with G1/2 tumors and adenocarcinoma histology. Moreover CD34+ CAFs were identified as an independent prognostic factor (both for progression free survival [PFS] and overall survival [OS] in stage I-III NSCLC). Besides, SMA+ expression correlated with higher pTNM-tumor stages and lymphatic spread (pN stage). In turn, SMA-negativity was associated with improved PFS, but no prognostic impact was found on OS. Of interest, neither CD34+ CAFs nor SMA+ CAFs were associated with the primary tumor size, localization and depth of infiltration (pT stage). CONCLUSIONS: CD34 was identified as an independent prognostic marker in pTNM stage I-III NSCLC. Moreover, loss of CD34+ CAFs might influence the dedifferentiation of the NSCLC tumor from its cell origin. Finally, SMA+ CAFs are more prevalent in NSCLC tumors of higher stages and lymphonodal positive NSCLC. KEY POINTS: Expression of CD34 on cancer associated fibroblasts (CAFs) is an independent prognostic factor in stage I-III NSCLC. SMA+ cancer associated fibroblasts are associated with higher tumor stages in NSCLC and might contribute to tumor progression in NSCLC.

Blood clot removal by cryoextraction in critically ill patients with pulmonary hemorrhage.

BACKGROUND: Severe pulmonary hemorrhage is a life-threatening complication in critically ill patients. Due to tracheobronchial obstruction, ventilation is often impaired. Traditionally, rigid bronchoscopy is an option for recanalization. However, in comparison to flexible bronchoscopy, the application of rigid bronchoscopy is more complex. Against this background we evaluated the use of flexible cryo-probes for blood clot removal in critically ill patients. METHODS: Retrospectively, we identified 16 patients (median age: 60 years, 69% male patients), who suffered from severe airway obstruction due to blood clots. All patients required invasive ventilation and 11 patients depended on extracorporeal membrane oxygenation (ECMO). To remove blood clots, flexible bronchoscopic cryoextraction was performed in n=27 cases, whereas rigid bronchoscopy was only needed in two cases. RESULTS: Whereas in 9 cases single flexible cryoextraction was successful immediately, the procedure had to be repeated again in 7 patients. In all cases, tracheobronchial obstruction was treated with success and conditions of invasive ventilation were improved. In no case severe complications were observed. CONCLUSIONS: In consideration of the underlying evaluation, we highly recommend flexible cryoextraction as both a safe and less complex technique for blood clot removal in critically ill patients.

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called 'poly-(ADP)-ribose polymerases' (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of 'enhancer of zeste homolog 2' (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future.

Cyclophosphamide pulse therapy as treatment for severe interstitial lung diseases.

INTRODUCTION: Besides invasive or non-invasive ventilation, treatment of severe forms of interstitial lung diseases (ILD) includes immunosuppressive medication. In case of refractory organ- or life-threatening courses of disease, cyclophosphamide pulse therapy can serve as a rescue treatment option. OBJECTIVES: To investigate therapeutic and prognostic effects of cyclophosphamide for the treatment of severe forms of ILD on intensive care unit (ICU) we performed this analysis. METHODS: Between 2009 and 2017 we identified 14 patients, who were treated on intensive care unit (ICU) with severe forms of ILD. Retrospectively, clinical, radiologic and prognostic data were collected and evaluated. RESULTS: Our analysis demonstrated a prognostic impact of cyclophosphamide on the ILD in general. Whereas pulmonary manifestations of both systemic sclerosis (SSc) and ANCA-associated vasculitis had an improved outcome, a reduced overall survival was found for Goodpasture syndrome (GPS), dermatomyositis (DM), cryptogenic organizing pneumonia (COP) and drug reaction with eosinophilia and systemic symptoms (DRESS; p=0.040, logrank test). Besides, additional plasmapheresis and initiation of cyclophosphamide within ten days following initial diagnosis of ILD were associated with improved prognosis. CONCLUSION: Positive prognostic effects of cyclophosphamide pulse therapy in ICU treated patients suffering from severe respiratory failure due to pulmonary manifestations of both SSc and ANCA-associated-vasculitis were observed. Further prognostic and therapeutic data are needed for cyclophosphamide for this indication in order to prevent patients from its toxic side-effects, who most likely will not benefit from its application.

Soluble Triggering Receptor Expressed on Myeloid Cells 1 in lung cancer.

Soluble Triggering Receptor Expressed on Myeloid Cells 1 (sTREM-1) can be found in the sera of patients with infectious, autoimmune and malignant diseases. The primary objective of this study was to investigate the prognostic significance of sTREM-1 in lung cancer patients. We analyzed the sera of 164 patients with lung cancer of all histologies and all stages at the time of diagnosis. We employed an ELISA using the anti-TREM-1 clone 6B1.1G12 mAb and recombinant human TREM-1. Patient data was collected retrospectively by chart review. In ROC-analysis, a sTREM-1 serum level of 163.1 pg/ml showed the highest Youden-Index. At this cut-off value sTREM-1 was a marker of short survival in patients with NSCLC (median survival 8.5 vs. 13.3 months, p = 0.04). A Cox regression model showed stage (p < 0.001) and sTREM-1 (p = 0.011) to indicate short survival. There were no differences in sTREM-1 serum values among patients with or without infection, pleural effusion or COPD. sTREM-1 was not associated with metastasis at the time of diagnosis and was not a predictor of subsequent metastasis. In SCLC patients sTREM-1 levels were lower than in NSCLC patients (p = 0.001) and did not predict survival. sTREM-1 did not correlate with CRP or the number of neutrophils. In non-small cell lung cancer patients, sTREM-1 in serum has prognostic significance.