Helios Klinikum Emil von Behring

Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.
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\nMethods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.
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\nFindings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.
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\nInterpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.

BackgroundWe designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma.MethodsEURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030.FindingsBetween April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate.InterpretationEURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting.FundingUK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.

PURPOSE: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. PATIENTS AND METHODS: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). RESULTS: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. CONCLUSION: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

RATIONALE: Numerous studies have been published on the new Mycobacterium tuberculosis (MTB)-specific IFN-gamma release assays. However, their prognostic value for progression from latent tuberculosis infection (LTBI) to active TB has yet to be established. OBJECTIVES: To compare the QuantiFERON-TB Gold In-Tube assay (QFT) with the tuberculin skin test (TST) in recently exposed close contacts of active TB cases with respect to their development of TB disease within 2 years. METHODS: Close contacts (n = 601) of MTB-positive source cases underwent both TST and QFT testing and were subsequently observed for 103 (+/-13.5) weeks. Risk factors for MTB infection were evaluated by multivariate analysis. MEASUREMENTS AND MAIN RESULTS: For the TST, 40.4% (243/601) of contacts were positive at a 5-mm cutoff, whereas only 66 (11%) were QFT positive. QFT positivity, but not TST, was associated with exposure time (P < 0.0001). Six contacts progressed to TB disease within the 2-year follow-up. All were QFT positive and had declined preventive treatment, equating to a progression rate of 14.6% (6/41) among those who were QFT positive. The progression rate for untreated TST-positive subjects was significantly lower (P < 0.003), at 2.3% (5 of 219), and one subject who progressed was TST negative. CONCLUSIONS: Results suggest that QFT is a more accurate indicator of the presence of LTBI than the TST and provides at least the same sensitivity for detecting those who will progress to active TB. The high rate of progression to active TB of those who are QFT positive (14.6%), which is far greater than the 2.3% found for those who are TST positive, has health and economic implications for enhanced TB control, particularly if this higher progression rate is seen in studies of other at-risk populations.

In light of the marked global health impact of tuberculosis (TB), strong focus has been on identifying biosignatures. Gene expression profiles in blood cells identified so far are indicative of a persistent activation of the immune system and chronic inflammatory pathology in active TB. Definition of a biosignature with unique specificity for TB demands that identified profiles can differentiate diseases with similar pathology, like sarcoidosis (SARC). Here, we present a detailed comparison between pulmonary TB and SARC, including whole-blood gene expression profiling, microRNA expression, and multiplex serum analytes. Our analysis reveals that previously disclosed gene expression signatures in TB show highly similar patterns in SARC, with a common up-regulation of proinflammatory pathways and IFN signaling and close similarity to TB-related signatures. microRNA expression also presented a highly similar pattern in both diseases, whereas cytokines in the serum of TB patients revealed a slightly elevated proinflammatory pattern compared with SARC and controls. Our results indicate several differences in expression between the two diseases, with increased metabolic activity and significantly higher antimicrobial defense responses in TB. However, matrix metallopeptidase 14 was identified as the most distinctive marker of SARC. Described communalities as well as unique signatures in blood profiles of two distinct inflammatory pulmonary diseases not only have considerable implications for the design of TB biosignatures and future diagnosis, but they also provide insights into biological processes underlying chronic inflammatory disease entities of different etiology.

OBJECTIVE: The study was performed to validate the CURB, CRB and CRB-65 scores for the prediction of death from community-acquired pneumonia (CAP) in both the hospital and out-patient setting. DESIGN: Data were derived from a large multi-centre prospective study initiated by the German competence network for community-acquired pneumonia (CAPNETZ) which started in March 2003 and were censored for this analysis in October 2004. SETTING: Out- and in-hospital patients in 670 private practices and 10 clinical centres. SUBJECTS: Analysis was done for n = 1343 patients (n = 208 out-patients and n = 1135 hospitalized) with all data sets completed for the calculation of CURB and repeated for n = 1967 patients (n = 482 out-patients and n = 1485 hospitalized) with complete data sets for CRB and CRB-65. INTERVENTION: None. 30-day mortality from CAP was determined by personal contacts or a structured interview. RESULTS: Overall 30-day mortality was 4.3% (0.6% in out-patients and 5.5% in hospitalized patients, P < 0.0001). Overall, the CURB, CRB and CRB-65 scores provided comparable predictions for death from CAP as determined by receiver-operator-characteristics (ROC) curves. However, in hospitalized patients, CRB misclassified 26% of deaths as low risk patients. Availability of the CRB-65 score (90%) was far superior to that of CURB (65%), due to missing blood urea nitrogen values (P < 0.001). CONCLUSIONS: Both the CURB and CRB-65 scores can be used in the hospital and out-patients setting to assess pneumonia severity and the risk of death. Given that the CRB-65 is easier to handle, we favour the use of CRB-65 where blood urea nitrogen is unavailable.

BACKGROUND: Diagnosis of childhood tuberculosis (TB) is challenging. The widely used tuberculin skin test (TST) may produce -positive results because of cross-reactivity with nontuberculous mycobacteria or bacille Calmette-Guerin vaccination, resulting in unnecessary treatment. Two recently developed interferon- gamma release assays (IGRAs) show good diagnostic accuracy for active TB in adults; pediatric data are limited, particularly in areas with a low incidence of TB. We assessed the diagnostic accuracy of IGRAs for TB in children in an area with a low incidence of TB. METHODS: In a hospital-based study, the diagnostic accuracy of the TST and 2 IGRAs (T SPOT-TB [T-SPOT; Oxford Immunotec] and QuantiFERON-TB Gold In-Tube [QFT-IT; Cellestis]) were assessed in a cohort of 73 children (median age, 39 months); 28 children with bacteriologically confirmed TB were compared with children without TB (23 with bacteriologically confirmed nontuberculous mycobacterial lymphadenitis and 22 with other nonmycobacterial respiratory tract infections). RESULTS: The specificity for TB of QFT-IT was 100% (95% confidence interval [CI], 91%-100%), and the specificity of T-SPOT was 98% (95% CI, 87%-100%), both of which were considerably higher than the specificity of TST (58%; 95% CI, 42%-73%). The specificity of the TST was 10.5% (95% CI, 1%-33%) in children with nontuberculous mycobacterial lymphadenitis and was 100% (95% CI, 83%-100%) in children with other nonmycobacterial respiratory tract infections. The sensitivity of both QFT-IT and T-SPOT was 93% (95% CI, 77%-99%), and the sensitivity of the TST was 100% (95% CI, 88%-100%). Agreement between the IGRAs was 95.6% ( kappa =0.91); 6.8% of the IGRAs showed indeterminate results. CONCLUSIONS: Both IGRAs showed high diagnostic value in bacteriologically confirmed childhood TB. Their advantage in this study, when performed in addition to the TST, was the ability to distinguish -positive TST results caused by nontuberculous mycobacterial disease, thereby reducing overdiagnosis of TB and guiding clinical management.

Background. Highly pathogenic avian H5N1 influenza viruses preferentially infect alveolar type II pneumocytes in human lung. However, it is unknown whether this cellular tropism contributes to high viral virulence because the primary target cells of other influenza viruses have not been systematically studied.

Community-acquired pneumonia remains a major cause of mortality in developed countries. There is much discrepancy in the literature regarding factors influencing the outcome in the elderly population. Data were derived from a multicentre prospective study initiated by the German Competence Network for Community-Acquired Pneumonia. Patients with community-acquired pneumonia (n = 2,647; 1,298 aged < 65 yrs and 1,349 aged > or = 65 yrs) were evaluated, of whom 72.3% were hospitalised and 27.7% treated in the community. Clinical history, residence status, course of disease and antimicrobial treatment were prospectively documented. Microbiological investigations included cultures and PCR of respiratory samples and blood cultures. Factors related to mortality were included in multivariate analyses. The overall 30-day mortality was 6.3%. Elderly patients exhibited a significantly higher mortality rate that was independently associated with the following: age; residence status; confusion, urea, respiratory frequency and blood pressure (CURB) score; comorbid conditions; and failure of initial therapy. Increasing age remained predictive of death in the elderly. Nursing home residents showed a four-fold increased mortality rate and an increased rate of gram-negative bacillary infections compared with patients dwelling in the community. The CURB score and cerebrovascular disease were confirmed as independent predictors of death in this subgroup. Age and residence status are independent risk factors for mortality after controlling for comorbid conditions and disease severity. Failure of initial therapy was the only modifiable prognostic factor.

BACKGROUND: The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is described as a potential biomarker for NSCLC (non-small cell lung cancer). Diagnostic biomarkers need to be detectable in easily accessible body fluids, should be characterized by high specificity, sufficient sensitivity, and robustness against influencing factors. The aim of this study was to evaluate the performance of MALAT1 as a blood based biomarker for NSCLC. RESULTS: MALAT1 was shown to be detectable in the cellular fraction of peripheral human blood, showing different expression levels between cancer patients and cancer-free controls. For the discrimination of NSCLC patients from cancer-free controls a sensitivity of 56% was calculated conditional on a high specificity of 96%. No impact of tumor stage, age, gender, and smoking status on MALAT1 levels could be observed, but results based on small numbers. CONCLUSIONS: The results of this study indicate that MALAT1 complies with key characteristics of diagnostic biomarkers, i.e., minimal invasiveness, high specificity, and robustness. Due to its relatively low sensitivity MALAT1 might not be feasible as a single biomarker for the diagnosis of NSCLC in the cellular fraction of blood. Alternatively, MALAT1 might be applicable as a complementary biomarker within a panel in order to improve the entire diagnostic performance.

The present guideline provides a new and updated concept of treatment and prevention of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2009.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment as well as primary and secondary prevention.

Supraglottic airway devices (SAD) play an important role in the management of patients with difficult airways. Unlike other alternatives to standard tracheal intubation, e.g. videolaryngoscopy or intubation stylets, they enable ventilation even in patients with difficult facemask ventilation and simultaneous use as a conduit for tracheal intubation. Insertion is usually atraumatic, their use is familiar from elective anaesthesia, and compared with tracheal intubation is easier to learn for users with limited experienced in airway management. Use of SADs during difficult airway management is widely recommended in many guidelines for the operating room and in the pre-hospital setting. Despite numerous studies comparing different SADs in manikins, there are few randomised controlled trials comparing different SADs in patients with difficult airways. Therefore, most safety data come from extended use rather than high quality evidence and claims of efficacy and particularly safety must be interpreted cautiously.

•Pralsetinib produced an ORR of 72% in treatment-naive patients with RET fusion–positive NSCLC.•Pralsetinib was generally well tolerated and there were no new safety signals.•The confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting is ongoing BackgroundRET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion–positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study.Patients and methodsARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator’s decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety.ResultsBetween 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion–positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion–positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs.ConclusionsPralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion–positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending. RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion–positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator’s decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion–positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion–positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion–positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

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Moxifloxacin is the most active fluoroquinolone against Mycobacterium tuberculosis in vitro. However, data about the efficacy in patients are not available. We enrolled 17 patients with tuberculosis in a prospective, randomized study. After 5 days of monotherapy with either moxifloxacin or isoniazid, we detected significant decreases in mean CFU per milliliter in sputum in both groups. The calculated early bactericidal activities for isoniazid and moxifloxacin were 0.209 and 0.273 log(10) CFU per ml of sputum per day, respectively. According to the data from our study, moxifloxacin exhibits an early bactericidal activity that is comparable to that of isoniazid.

Acute respiratory distress syndrome (ARDS) and pneumonia are closely correlated in the critically ill patient. Whereas ARDS is often complicated by nosocomial pneumonia, pulmonary infection is also the most frequent single cause of ARDS. The prevalence of pneumonia during the course of ARDS seems to be particularly high, but whether persons with ARDS are more susceptible to pneumonia or simply have more risk factors remains unknown because of methodological limitations. Recent research suggests that host factors have a major bearing on the development of ARDS. To date, sepsis seems to be the principal link between pneumonia and ARDS. However, prospective observational data on this supposed sequence are not available. The individual role of specific pathogens for the development of ARDS is difficult to assess, because prospective studies are missing. Respiratory viruses have received particular attention, but this review suggests that infections with coronavirus and avian influenza virus (H5N1) are associated with a high incidence of ARDS.

OBJECTIVES: Owing to novel therapy strategies in epidermal growth factor receptor (EGFR)-mutated patients, molecular analysis of the EGFR and KRAS genome has become crucial for routine diagnostics. Till date these data have been derived mostly from clinical trials, and thus collected in pre-selected populations. We therefore screened 'allcomers' with a newly diagnosed non-small cell lung carcinoma (NSCLC) for the frequencies of these mutations. DESIGN: A cohort study. SETTING: Lung cancer centre in a tertiary care hospital. PARTICIPANTS: Within 15 months, a total of 552 cases with NSCLC were eligible for analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Frequency of scrutinising exons 18, 19 and 21 for the presence of activating EGFR mutation and secondary codon 12 and 13 for activating KRAS mutations. RESULTS: Of the 552 patients, 27 (4.9%) showed a mutation of EGFR. 19 of these patients (70%) had deletion E746-A750 in codon 19 or deletion L858R in codon 21. Adenocarcinoma (ACA) was the most frequent histology among patients with EGFR mutations (ACA, 22/254 (8.7%) vs non-ACA, 5/298 (1.7%); p<0.001). Regarding only ACA, the percentage of EGFR mutations was higher in women (16/116 (14%) women vs 6/138 (4.3%) men; p=0.008). Tumours with an activating EGFR mutation were more likely to be from non-smokers (18/27; 67%) rather than smoker (9/27; 33%). KRAS mutation was present in 85 (15%) of all cases. In 73 patients (86%), the mutation was found in exon 12 and in 12 cases (14%) in exon 13. Similarly, ACA had a higher frequency of KRAS mutations than non-ACA (67/254 (26%) vs 18/298 (6.0%); p<0.001). CONCLUSIONS: We found a lower frequency for EGFR and KRAS mutations in an unselected Caucasian patient cohort as previously published. Taking our results into account, clinical trials may overestimate the mutation frequency for EGFR and KRAS in NSCLC due to important selection biases.

This abridged version is based on an interdisciplinary guideline which corresponds to development stage 3 (S3) of guidelines according to the classification of the Association of the Scientific Medical Societies in Germany (AWMF). The guideline development process is characterized by the combination of formal evidence-search, formal consensus, logic (algorithms), decision and outcome analysis, and interdisciplinary development with the cooperation of 15 German and Austrian medical societies. [Table 1] shows the relationship between levels of evidence, consensus, and resulting recommendation grades of the recommendations of this guideline. The recommendation grades A – D are added to the recommendations in the abridged version. For the evidence levels, see the full version [1].

OBJECTIVE: To examine whether acute dysglycaemia predicts death in people admitted to hospital with community acquired pneumonia. DESIGN: Multicentre prospective cohort study. SETTING: Hospitals and private practices in Germany, Switzerland, and Austria. PARTICIPANTS: 6891 patients with community acquired pneumonia included in the German community acquired pneumonia competence network (CAPNETZ) study between 2003 and 2009. MAIN OUTCOME MEASURES: Univariable and multivariable hazard ratios adjusted for sex, age, current smoking status, severity of community acquired pneumonia using the CRB-65 score (confusion, respiratory rate >30/min, systolic blood pressure ≤ 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age ≥ 65 years), and various comorbidities for death at 28, 90, and 180 days according to serum glucose levels on admission. RESULTS: An increased serum glucose level at admission to hospital in participants with community acquired pneumonia and no pre-existing diabetes was a predictor of death at 28 and 90 days. Compared with participants with normal serum glucose levels on admission, those with mild acute hyperglycaemia (serum glucose concentration 6-10.99 mmol/L) had a significantly increased risk of death at 90 days (1.56, 95% confidence interval 1.22 to 2.01; P<0.001), and this risk increased to 2.37 (1.62 to 3.46; P<0.001) when serum glucose concentrations were ≥ 14 mmol/L. In sensitivity analyses the predictive value of serum glucose levels on admission for death was confirmed at 28 days and 90 days. Patients with pre-existing diabetes had a significantly increased overall mortality compared with those without diabetes (crude hazard ratio 2.47, 95% confidence interval 2.05 to 2.98; P<0.001). This outcome was not significantly affected by serum glucose levels on admission (P = 0.18 for interaction). CONCLUSIONS: Serum glucose levels on admission to hospital can predict death in patients with community acquired pneumonia without pre-existing diabetes. Acute hyperglycaemia may therefore identify patients in need of intensified care to reduce the risk of death from community acquired pneumonia.

BACKGROUND AND PURPOSE: There have been few long-term studies on the outcome of chondrosarcoma and the findings regarding prognostic factors are controversial. We examined a homogeneous group of patients with primary central chondrosarcoma of bone who were treated according to a uniform surgical protocol at our institution, in order to determine the factors that influence survival and identify potential improvements to our therapeutic algorithm. PATIENTS AND METHODS: We performed a retrospective analysis of 115 patients with primary central chondrosarcoma of bone who presented with localized disease and who had a minimum follow-up of 5 years after diagnosis. 68 tumors were localized in the extremities and 47 in the axial skeleton or pelvis. 59 patients had a high-grade (II and III) and 56 a low-grade (I) tumor. 94 patients underwent surgical resection with adequate (wide or radical) margins, while 21 patients had inadequate (marginal or intralesional) margins. RESULTS: Tumor grade and localization were found to be statistically significant independent predictors of disease-related deaths in multivariate analysis. The quality of surgical margins did not influence survival. The AJCC staging system was able to predict prognosis in patients with chondrosarcoma of the extremities, but not in those with tumors of the axial skeleton and pelvis. Long-term survival after secondary metastatic disease was only observed when metastases were resected with wide margins. Patients with metastases who received further treatment with conventional chemotherapy, radiotherapy, and/or further surgery had significantly better survival compared to those who received best supportive care. INTERPRETATION: The outcome in patients with primary central chondrosarcoma of bone who present with localized disease is mostly affected by tumor-related parameters.