[Prevention, Diagnosis, Therapy, and Follow-up of Lung Cancer - Interdisciplinary Guideline of the German Respiratory Society and the German Cancer Society - Abridged Version]. / Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms.

The current S3 Lung Cancer Guidelines are edited with fundamental changes to the previous edition based on the dynamic influx of information to this field:The recommendations include de novo a mandatory case presentation for all patients with lung cancer in a multidisciplinary tumor board before initiation of treatment, furthermore CT-Screening for asymptomatic patients at risk (after federal approval), recommendations for incidental lung nodule management , molecular testing of all NSCLC independent of subtypes, EGFR-mutations in resectable early stage lung cancer in relapsed or recurrent disease, adjuvant TKI-therapy in the presence of common EGFR-mutations, adjuvant consolidation treatment with checkpoint inhibitors in resected lung cancer with PD-L1 ≥ 50%, obligatory evaluation of PD-L1-status, consolidation treatment with checkpoint inhibition after radiochemotherapy in patients with PD-L1-pos. tumor, adjuvant consolidation treatment with checkpoint inhibition in patients withPD-L1 ≥ 50% stage IIIA and treatment options in PD-L1 ≥ 50% tumors independent of PD-L1status and targeted therapy and treatment option immune chemotherapy in first line SCLC patients.Based on the current dynamic status of information in this field and the turnaround time required to implement new options, a transformation to a "living guideline" was proposed.

Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study.

AIMS: Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients. METHODS AND RESULTS: This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p < 0.0001) in COVID-19. CONCLUSION: Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes.

Microvascular dysfunction in COVID-19: the MYSTIC study.

RATIONALE: Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. OBJECTIVES: To comprehensively characterize and quantify microvascular alterations in patients with COVID-19. METHODS: Hospitalized adult patients with moderate-to-severe or critical COVID-19 (n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity (VRBC), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS: COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4-6 µm), and also significant reductions of VRBC. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. CONCLUSIONS: Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.

A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer.

CV9201 is an RNActive®-based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400-1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD+CD38hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8-6.3) and 10.8 months (8.1-16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation.

Prospective, Noninterventional Study of Nivolumab in Real-world Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer After Prior Chemotherapy (ENLARGE-Lung).

Nivolumab was the first immune checkpoint inhibitor approved for use in advanced non-small cell lung cancer (NSCLC). This noninterventional, prospective cohort study investigates real-world effectiveness of nivolumab in pretreated NSCLC patients in Germany (Enlarge-Lung/CA209-580). Patients with squamous (SQ) or nonsquamous (NSQ) NSCLC previously treated for locally advanced or metastatic (stage IIIB/IV) disease received nivolumab according to the current Summary of Product Characteristics. Overall survival (OS) was the primary endpoint. Of 907 patients enrolled, 660 patients who were followed for at least 12 months across 79 study centers in Germany, were analyzed. Median OS was 11.2 months [95% confidence interval (CI), 9.1-12.9]; outcomes for the 418 patients with NSQ histology [13.1 mo (95% CI, 10.6-15.6)] were more favorable than outcomes for the 242 patients with SQ histology [8.9 mo (95% CI, 6.4-11.3)]. Patients' age, presence of distant or brain metastases, or line of therapy did not affect outcomes; however, patients with poor performance status (ECOG-PS ≥2, n=80) had shorter median OS [4.7 mo (95% CI, 3.1-5.4)]. This study represents one of the largest real-world cohorts providing outcomes of nivolumab in pretreated NSCLC. The results match well with the published evidence from pivotal clinical trials and demonstrate clinical effectiveness of nivolumab in advanced NSCLC.

Two-year survival with nivolumab in previously treated advanced non-small-cell lung cancer: A real-world pooled analysis of patients from France, Germany, and Canada.

OBJECTIVES: Immune checkpoint inhibitors have become the standard of care for metastatic non-small-cell lung cancer (NSCLC) progressing during or after platinum-based chemotherapy. Real-world clinical practice tends to represent more diverse patient characteristics than randomized clinical trials. We sought to evaluate overall survival (OS) outcomes in the total study population and in key subsets of patients who received nivolumab for previously treated advanced NSCLC in real-world settings in France, Germany, or Canada. MATERIALS AND METHODS: Data were pooled from two prospective observational cohort studies, EVIDENS and ENLARGE, and a retrospective registry in Canada. Patients included in this analysis were aged ≥18 years, had stage IIIB/IV NSCLC, and received nivolumab after at least one prior line of systemic therapy. OS was estimated in the pooled population and in various subgroups using the Kaplan-Meier method. Timing of data collection varied across cohorts (2015-2019). RESULTS: Of the 2585 patients included in this analyses, 1235 (47.8 %) were treated in France, 881 (34.1 %) in Germany, and 469 (18.1 %) in Canada. Median OS for the total study population was 11.3 months (95 % CI: 10.5-12.2); this was similar across France, Germany, and Canada. The OS rate was 49 % at 1 year and 28 % at 2 years for the total study population. In univariable Cox analyses, the presence of epidermal growth factor receptor mutations in nonsquamous disease, liver, or bone metastases were associated with significantly shorter OS, whereas tumor programmed death ligand 1 expression and Eastern Cooperative Oncology Group performance status 0-1 were associated with significantly prolonged OS. Similar OS was noted across subgroups of age and prior lines of therapy. CONCLUSION: OS rates in patients receiving nivolumab for previously treated advanced NSCLC in real-world clinical practice closely mirrored those in phase 3 studies, suggesting similar effectiveness of nivolumab in clinical trials and clinical practice.

Risk stratification of solitary pulmonary nodules by means of PET using (18)F-fluorodeoxyglucose and SUV quantification.

PURPOSE: (18)F-fluorodeoxyglucose (FDG) PET is the most accurate imaging modality in characterizing a solitary pulmonary nodule (SPN). Besides visual image interpretation, semiquantitative analysis using standardized uptake values (SUV) is performed to improve diagnostic accuracy. Mostly, an SUV threshold of 2.5 is applied to differentiate between benign and malignant lesions. In this study we analysed the use different SUV thresholds to predict the post-test probability of malignancy for the individual patient considering his pre-test probability. Furthermore, we investigated the prognostic value of SUV in SPN for survival. METHODS: This retrospective study included 140 consecutive patients who underwent FDG PET for evaluation of SPN. Visual interpretation was performed by two readers. For semiquantitative analysis, maximum SUV (SUV(max)) was measured in all SPN. A final diagnosis was obtained by pathological examination or follow-up of more than 2 years. In a nomogram, positive and negative predictive values (PPV and NPV) were plotted against the hypothetical SUV threshold to determine the optimum SUV threshold. Survival was analysed using the Kaplan-Meier method and log-rank test. RESULTS: The prevalence of malignancy was 57%. The FDG uptake in malignant SPNs was higher than in benign SPNs (SUV 9.7 +/- 5.5 vs 2.6 +/- 2.5, p < 0.01). More than 90% of SPNs with an SUV below 2.0 were benign (sensitivity, specificity, NPV of 96, 55 and 92%). The highest diagnostic accuracy was achieved with an SUV of 4.0 (sensitivity, specificity and accuracy of 85%). Visual interpretation achieved corresponding values of 94, 70 and 84%, respectively. In lung cancer higher FDG uptake (SUV(max) >or= 9.5) was associated with shorter survival (median survival 20 months) and low FDG uptake with longer survival (>75 months). CONCLUSION: FDG PET allows assessment of the individual risk for malignancy in SPNs by considering tumoural SUV and pre-test probability. Higher FDG uptake in lung cancer as measured by SUV analysis is a prognostic factor. In patients with low FDG uptake in an SPN and increased risk during surgery omission of diagnostic thoracotomy may be warranted.

Obstructive sleep apnea syndrome is associated with overactive bladder and urgency incontinence in men.

STUDY OBJECTIVE: To investigate the incidence of overactive bladder (OAB) and urgency incontinence (UI) in men with obstructive sleep apnea syndrome (OSAS). DESIGN: Prospective questionnaire study SETTING: Saarland University Hospital PATIENTS: All male patients who underwent full-night in-laboratory polysomnography between November 2006 and April 2007. INTERVENTIONS: Overactive bladder symptom score (OABSS) and International Consultation on Incontinence Questionnaire, Short-Form (ICIQ-SF). MEASUREMENTS AND RESULTS: OSAS severity was assessed according to the apnea-hypopnea-index (AHI). Return rate of questionnaires was 100% (n=100). Patients with upper airway resistance syndrome (UARS) served as controls. Evaluation of OABSS revealed that patients with moderate and severe OSAS presented with a significantly higher incidence of symptoms of OAB than patients with mild OSAS and UARS (P<0.05). Further, the ICIQ-SF revealed a higher occurrence of UI in patients with severe OSAS than in those with mild OSAS and UARS (P<.05). CONCLUSIONS: Increasing severity of OSAS appears to be associated with an increasing occurrence of overactive bladder and urgency incontinence in men. This relationship may have clinical implications for the treatment of affected patients.

Prevalence Of Chronic Hypercapnia In Severe Chronic Obstructive Pulmonary Disease: Data From The HOmeVent Registry.

Background: Non-invasive ventilation (NIV) has been shown to improve survival and quality of life in COPD patients with chronic hypercapnic respiratory failure. However, the proportion of COPD patients with chronic hypercapnia is not yet known and clinical data enabling better identification of patients are scarce. The HOmeVent registry was initiated to determine the prevalence of chronic hypercapnia in COPD in an outpatient setting and to evaluate the predictors of hypercapnia. Methods: HOmeVent is a multicenter, prospective, observational, non-interventional patient registry that includes COPD patients in GOLD stage 3 or 4. Eligible patients were identified and enrolled in an outpatient setting during routine clinic visits. Assessments included blood gas analyses, pulmonary function testing and quality of life assessment. Results: Ten outpatient clinics in Germany enrolled 231 COPD patients in the registry (135 in GOLD stage 3 (58%) and 96 in GOLD stage 4 (42%)). Arterial carbon dioxide pressure (PaCO2) was ≥45 mmHg in 58 patients (25%); of these, 20 (9%) had PaCO2 ≥50 mmHg. The prevalence of hypercapnia at both cut-off values was numerically higher for patients in GOLD stage 4 versus 3. An increased body mass index, a decreased forced vital capacity and an increased bicarbonate level were significant independent predictors of hypercapnia. The proportion of patients who received NIV was 6% overall and 22% of those with hypercapnia. Conclusion: A relevant proportion of COPD patients in GOLD stage 3 and 4 exhibits chronic hypercapnia and might, therefore, be candidates for long-term domiciliary NIV treatment.

Do genetic factors protect for early onset lung cancer? A case control study before the age of 50 years.

BACKGROUND: Early onset lung cancer shows some familial aggregation, pointing to a genetic predisposition. This study was set up to investigate the role of candidate genes in the susceptibility to lung cancer patients younger than 51 years at diagnosis. METHODS: 246 patients with a primary, histologically or cytologically confirmed neoplasm, recruited from 2000 to 2003 in major lung clinics across Germany, were matched to 223 unrelated healthy controls. 11 single nucleotide polymorphisms of genes with reported associations to lung cancer have been genotyped. RESULTS: Genetic associations or gene-smoking interactions was found for GPX1(Pro200Leu) and EPHX1(His113Tyr). Carriers of the Leu-allele of GPX1(Pro200Leu) showed a significant risk reduction of OR = 0.6 (95% CI: 0.4-0.8, p = 0.002) in general and of OR = 0.3 (95% CI:0.1-0.8, p = 0.012) within heavy smokers. We could also find a risk decreasing genetic effect for His-carriers of EPHX1(His113Tyr) for moderate smokers (OR = 0.2, 95% CI:0.1-0.7, p = 0.012). Considered both variants together, a monotone decrease of the OR was found for smokers (OR of 0.20; 95% CI: 0.07-0.60) for each protective allele. CONCLUSION: Smoking is the most important risk factor for young lung cancer patients. However, this study provides some support for the T-Allel of GPX1(Pro200Leu) and the C-Allele of EPHX1(His113Tyr) to play a protective role in early onset lung cancer susceptibility.

Low-dose MDCT for surveillance of patients with severe homogeneous emphysema after bronchoscopic airway bypass.

OBJECTIVE: The purpose of this study was to evaluate the usefulness of low-dose MDCT for radiologic monitoring of patients who have undergone placement of bronchial stents for airway bypass. SUBJECTS AND METHODS: In a prospective study, seven patients underwent MDCT according to a low-dose protocol (40 mAs, 120 kVp) before and after stent placement. The positions of the stents in the segmental bronchi were analyzed and compared with the bronchoscopic findings, which were reference standard. Patency versus lack of patency of stents was classified with five levels of confidence, and a definitive diagnosis was assigned to each stent. Prediction of stent dislodgment, follow-up findings, and complications occurring during the observation period were recorded. Consensus reading was performed by two radiologists. Statistical analysis was conducted by receiver operating characteristic analysis or four-field table. RESULTS: Seven patients underwent implantation of 37 stents (mean, 5 +/- 2 [SD] stents per patient; range, 2-8 stents). The area under the curve for differentiating patent from occluded stents was 0.995 with resulting sensitivity and specificity of 86.5% and 98.1%. The correct diagnosis of patency was established with MDCT for all but one stent (sensitivity, 94.7%; specificity, 100%). Sensitivity and specificity for prediction of dislodgment were 80% and 91%. Five stents were not identified during inspection bronchoscopy but were found in a regular position at MDCT. Three instances of minor bleeding and one of pneumothorax resolved spontaneously. The mean effective dose of the scan was 1.3 +/- 0.6 mSv. CONCLUSION: Low-dose MDCT is feasible for radiologic monitoring after airway bypass procedure.

A randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Pemetrexed plus cisplatin was approved for first-line treatment of non-small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC. PATIENTS AND METHODS: The patients were randomized (1:1) to 2 parallel arms: pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) or pemetrexed (500 mg/m(2)) plus carboplatin (area under the curve 6) day 1 every 3 weeks (maximum, 6 cycles). Progression-free survival (PFS) was the primary objective; secondary objectives included overall survival (OS), 1-year survival, and safety. RESULTS: Sixty-five patients were randomized to each treatment arm. The patients treated with pemetrexed plus cisplatin had a median age of 64 years and were predominantly men (42 [64.6%]) with nonsquamous histology (53 [81.5%]), stage IV (61 [92.4%]) disease, and a performance status of 0 (40 [61.5%]). Median PFS was 6.0 months, 6-month PFS rate was 50.5%, median OS was 11.7 months, and 1-year survival rate was 47.5%. Drug-related grade 3/4 toxicities included neutropenia (11 [16.9%]), anemia (5 [7.7%]), thrombocytopenia (2 [3.1%]), and nausea (3 [4.6%]). Patients treated with pemetrexed plus carboplatin had a median age of 63 years, were predominantly men (46 [70.8%]) with nonsquamous histology (52 [80.0%]), stage IV (58 [86.6%]) disease, and a performance status of 0 (45 [69.2%]). The median PFS was 4.7 months, the 6-month PFS rate was 34.9%, median OS was 8.9 months, and 1-year survival rate was 39.2%. Drug-related grade 3/4 toxicities included neutropenia (17 [26.2%]), thrombocytopenia (11 [16.9%]), anemia (7 [10.8%]), and nausea (5 [7.7%]). CONCLUSIONS: Both the pemetrexed plus cisplatin and pemetrexed plus carboplatin arms met their primary endpoints and demonstrated efficacy and tolerability as first-line therapy in patients with advanced NSCLC. http://ClinicalTrials.gov: NCT00402051.

F-18-FDG-PET confined radiotherapy of locally advanced NSCLC with concomitant chemotherapy: results of the PET-PLAN pilot trial.

PURPOSE: The integration of fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the process of radiotherapy (RT) planning of locally advanced non-small-cell lung cancer (NSCLC) may improve diagnostic accuracy and minimize interobserver variability compared with target volume definition solely based on computed tomography. Furthermore, irradiating only FDG-PET-positive findings and omitting elective nodal regions may allow dose escalation by treating smaller volumes. The aim of this prospective pilot trial was to evaluate the therapeutic safety of FDG-PET-based RT treatment planning with an autocontour-derived delineation of the primary tumor. METHODS AND MATERIALS: Eligible patients had Stages II-III inoperable NSCLC, and simultaneous, platinum-based radiochemotherapy was indicated. FDG-PET and computed tomography acquisitions in RT treatment planning position were coregistered. The clinical target volume (CTV) included the FDG-PET-defined primary tumor, which was autodelineated with a source-to-background algorithm, plus FDG-PET-positive lymph node stations. Limited by dose restrictions for normal tissues, prescribed total doses were in the range of 66.6 to 73.8 Gy. The primary endpoint was the rate of out-of-field isolated nodal recurrences (INR). RESULTS: As per intent to treat, 32 patients received radiochemotherapy. In 15 of these patients, dose escalation above 66.6 Gy was achieved. No Grade 4 toxicities occurred. After a median follow-up time of 27.2 months, the estimated median survival time was 19.3 months. During the observation period, one INR was observed in 23 evaluable patients. CONCLUSIONS: FDG-PET-confined target volume definition in radiochemotherapy of NSCLC, based on a contrast-oriented source-to-background algorithm, was associated with a low risk of INR. It might provide improved tumor control because of dose escalation.

Diagnostic performance and prognostic impact of FDG-PET in suspected recurrence of surgically treated non-small cell lung cancer.

PURPOSE: The differentiation of recurrent lung cancer and post-therapeutic changes remains a problem for radiological imaging, but FDG-PET allows biological characterisation of tissues by visualising glucose metabolism. We evaluated the diagnostic performance and prognostic impact of FDG-PET in cases of suspected relapse of lung cancer. METHODS: In 62 consecutive patients, 73 FDG-PET scans were performed for suspected recurrence after surgical therapy of lung cancer. FDG uptake by lesions was measured as the standardised uptake value (SUV). PET results were compared with the final diagnosis established by biopsy or imaging follow-up. SUV and clinical parameters were analysed as prognostic factors with respect to survival. RESULTS: FDG-PET correctly identified 51 of 55 relapses and gave true negative results in 16 of 18 remissions (sensitivity, specificity, accuracy: 93%, 89%, 92%). SUV in recurrent tumour was higher than in benign post-therapeutic changes (10.6+/-5.1 vs 2.1+/-0.6, p<0.001). Median survival was longer for patients with lower FDG uptake in recurrent tumour (SUV<11: 18 months, SUV > or = 11: 9 months, p<0.01). Long-term survival was observed mainly after surgical re-treatment (3-year survival rate 38%), even if no difference in median survival for surgical or non-surgical re-treatment was detected (11 vs 12 months, p=0.0627). For patients subsequently treated by surgery, lower FDG uptake predicted longer median survival (SUV<11: 46 months, SUV> or = 11: 3 months, p<0.001). SUV in recurrent tumour was identified as an independent prognostic factor (p<0.05). CONCLUSION: FDG-PET accurately detects recurrent lung cancer. SUV in recurrent tumour is an independent prognostic factor. FDG-PET helps in the selection of patients who will benefit from surgical re-treatment.