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Introduction: Pemetrexed-based immunochemotherapy represents an established standard of care as first line treatment for non-oncogenic driven metastatic non-small cell lung adenocarcinoma (NSCLC/ADC). However, retrospective analyses revealed better outcomes for pemetrexed-free regimens compared to pemetrexed-containing regimens in patients with thyroid transcription factor 1 (TTF-1) negative NSCLC/ADC. The multicenter, phase II, randomized, open-label ANTELOPE trial evaluates whether atezolizumab, carboplatin and nab-paclitaxel is superior to pembrolizumab, cis-/carboplatin and pemetrexed in TTF-1 negative NSCLC/ADC., Methods: Eligible participants are ≥18 years of age, with histologically or cytologically confirmed, treatment-naïve stage IV TTF-1 negative NSCLC/ADC without actionable genomic alterations or PD-L1-overexpression (TPS ≥50%) and will be randomized in a 1:1 fashion to pemetrexed-free (group A) vs. pemetrexed-based (group B) immunochemotherapy. The primary endpoint of this trial is overall survival (OS)., Results: Enrollment will start in Q2 2023 at 30 sites in Germany with a planned inclusion of 136 participants., Conclusion: ANTELOPE will provide efficacy outcomes of the current standard-of-care for the specific subset of TTF-1 negative NSCLC/ADC in a head-to-head comparison of approved immunochemotherapy regimens., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: In ADAURA, adjuvant osimertinib significantly improved disease-free survival versus placebo in resected stage IB to IIIA EGFR-mutated NSCLC. We report in-depth analyses of three-year safety, tolerability, and health-related quality of life (HRQoL) from ADAURA., Methods: Patients were randomized 1:1 to osimertinib 80 mg or placebo once daily for up to 3 years. Safety assessments were performed at baseline, week 2, week 4, week 12, and every 12 weeks until treatment completion or discontinuation, and 28 days after treatment was stopped. The SF-36 survey measured HRQoL at baseline, week 12, week 24, and every 24 weeks until recurrence, treatment completion or discontinuation. Data cutoff: April 11, 2022., Results: Safety and HRQoL analysis sets: osimertinib, n = 337 and n = 339; placebo, n = 343 each. Median (range) total exposure duration was longer with osimertinib versus placebo: 35.8 (0-38) versus 25.1 (0-39) months. Most adverse events (AEs) were first reported within 12 months of starting treatment (osimertinib 97%, placebo 86%). AEs leading to dose reduction, interruption or discontinuation were reported in 12%, 27% and 13% respectively of patients with osimertinib; 1%, 13% and 3% with placebo. Stomatitis and diarrhea were the most common AEs leading to osimertinib dose reduction or interruption; interstitial lung disease was the most common leading to osimertinib discontinuation (per protocol). There were no differences in time to deterioration for SF-36 physical, mental component summaries between osimertinib and placebo., Conclusions: No new safety signals were reported and HRQoL was maintained with 3 years of adjuvant osimertinib treatment. Combined with significant efficacy benefit, these data further support adjuvant osimertinib in stage IB to IIIA EGFR-mutated NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m 2 every 3 weeks) received accelerated approval from the US Food and Drug Administration on the basis of efficacy in patients with small-cell lung cancer (SCLC) who relapsed after first-line platinum-based chemotherapy. The ATLANTIS trial assessed the efficacy and safety of combination lurbinectedin and the anthracycline doxorubicin as second-line treatment for SCLC., Methods: In this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m 2 plus doxorubicin 40·0 mg/m 2 administered on day 1 of 21-day cycles or physician's choice of control therapy (intravenous topotecan 1·5 mg/m 2 on days 1-5 of 21-day cycles; or intravenous cyclophosphamide 1000 mg/m 2 , doxorubicin 45·0 mg/m 2 , and vincristine 2·0 mg on day 1 of 21-day cycles [CAV]) administered until disease progression or unacceptable toxicity. Primary granulocyte-colony stimulating factor prophylaxis was mandatory in both treatment groups. Neither patients nor clinicians were masked to treatment allocation, but the independent review committee, which assessed outcomes, was masked to patients' treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02566993, and with EudraCT, 2015-001641-89, and is complete., Findings: Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (<1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group)., Interpretation: Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control., Funding: PharmaMar., Competing Interests: Declaration of interests SPA has received honoraria from Roche and Bristol Myers Squibb; has received support for attending meetings or travel from Roche; and has a patent for lurbinectedin plus atezolizumab. TEC reports consultant or advisory fees from Astellas Pharma, Janssen, Bristol Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck Sharp & Dohme, Sanofi, Novartis, Servier, and A&D Pharma; and travel support from Pfizer, Sanofi, Boehringer Ingelheim, Merck, Servier, Ipsen, Amgen, A&D Pharma, AstraZeneca, Genentech, Bristol Myers Squibb, Merck Sharp & Dohme Oncology, Eli Lilly, Janssen, Novartis, and Astellas Pharma. LB reports payment or honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; and participation on a data safety monitoring board or advisory board for AstraZeneca and Roche. EFS reports consulting fees paid to his institution from Merck and Eli Lilly; payment or honoraria to his institution from Boehringer Ingelheim, AstraZeneca, and Daiichi Sankyo; and participation on a data safety monitoring board or advisory board for Merck, AstraZeneca, and Merck Sharp & Dohme. AC reports payment or honoraria from Genentech, Takeda, Blueprint Medicines, and Amgen; participation on a data safety monitoring board or advisory board for Ipsen, Odonate Therapeutics, Jazz Pharmaceuticals, Aileron Therapeutics, Janssen, AstraZeneca, and Sanofi; and holds stock or stock options in Merck. IH reports personal payments and payments to her institution from Syneos Health UK. AFF reports a consultancy or advisory role with AstraZeneca, Syros, OncLive, Clinical Care Oncology, Bayer, H3 Biomedicine, Pfizer, Medscape, PeerView, Genentech, Merck, Bristol Myers Squibb, and Boehringer Ingelheim; research funding to her institution from Bayer, Genentech, and AstraZeneca; was an employee and held stock or stock options in Novartis; and received support for this manuscript from PharmaMar. JAL-V, ANi, NV, JG, CK, and AZ are employees of PharmaMar and report stock or stock options in PharmaMar. MC-Y is an employee of PharmaMar. KS reports personal consulting fees from Roche, Bristol Myers Squibb, and Merck Sharp & Dohme; and consulting fees paid to his institution from Amgen. IB reports payment or honoraria from AstraZeneca, Amgen, Takeda, Bristol Myers Squibb, and Pfizer. CFW reports consulting fees from Viatris, Roche, and Alvotech; honoraria for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; meeting or travel support from Bristol Myers Squibb; and honoraria for advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp & Dohme. OJ-V reports consulting fees from Boehringer Ingelheim, Merck Sharp & Dohme, AstraZeneca, Eli Lilly, and Takeda; payment or honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, and Takeda; and meeting or travel support from Merck Sharp & Dohme and Roche. NR reports payment or honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Hoffmann-La Roche, Eli Lilly, Merck Sharp & Dohme, Merck, Pfizer, and Takeda; and meeting or travel support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, and Takeda. MD reports payment or honoraria for lectures and advisory boards from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Sanofi, and Roche. LP-A reports honoraria for scientific advice and speaker fees from Eli Lilly, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Mirati, GlaxoSmithKline, Janssen, and Takeda; participates as external member of the board of Genómica; is a founder and board member of Altum sequencing; and has received institutional support for contracted research from Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In hospitalized patients, the duration of antibiotic therapy for uncomplicated pneumonia is often longer than recommended in clinical guidelines. Consequences include increased risk of Clostridioides difficile infection and the emergence of antibiotic resistance. Reducing the duration of antibiotic therapy is an important goal of antibiotic stewardship (ABS) programs., Objective: To evaluate the impact of a computerized physician order entry (CPOE)-based ABS intervention on treatment duration in respiratory infections and on antibiotic use., Methods: A new type of prescription tool featuring a "soft stop order" was introduced into the CPOE system in the Respiratory Medicine department of a Thorax Center. The effect of this intervention was evaluated after 24 weeks using a retrospective before-and-after study design., Results: A total of 210 patients were evaluated (preintervention group n = 109, postintervention group n = 101). Mean antibiotic treatment duration decreased from 9.59 days to 7.25 days (p < 0.001). It was reduced from 9.93 to 7.21 days (p < 0.001) in community-acquired pneumonia, 10.21 to 7.81 days (p = 0.05) in hospital-acquired pneumonia and 7.81 to 6.83 days (p = 0.14) in COPD exacerbations. The proportion of patients treated according to clinical guidelines increased from 35.8% to 69.3% (p < 0.001). The mean quarterly antibiotic use density was 41.2 RDD/100 PD (recommended daily doses per 100 patient days) before the intervention and decreased to 34.03 RDD/100 PD after the intervention (p = 0.037)., Conclusion: Our study demonstrates the short-term effectiveness of a CPOE-based ABS intervention to reduce antibiotic treatment duration for uncomplicated pneumonia. This approach may be particularly suitable for hospitals with limited ABS resources., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Pembrolizumab is a highly effective standard of care in PD-L1 overexpressing (≥ 50%) non-small-cell lung cancer. However, a substantial share of patients from everyday clinical practice is treated without clear evidence from clinical trials., Patients and Methods: We performed a retrospective multicentric study including all consecutive patients from 6 certified lung cancer centers in Berlin, Germany, having received pembrolizumab as first-line palliative therapy from January 1 until December 31, 2017. Aims were to validate published clinical trials with a special focus on efficacy and outcome in patients with reduced performance status (PS), brain metastases, and steroids., Results: A total of 153 patients were included (median age 69 years, 58% men, 69% adenocarcinoma). Rates for PS ≥ 2, brain metastases, and steroids were 24.8%, 20.9%, and 24.2%, respectively. Median objective response rate, progression-free and overall survival were 48.5%, 8.2 and 22.0 months for all patients and 52.4%, 8.8 and 29.2 months in patients fulfilling the inclusion criteria for the KEYNOTE-024 trial. Patients with a comorbidity-defined PS ≥ 2, symptomatic brain metastases requiring upfront radiotherapy, or baseline steroids had significantly reduced survival. In contrast, durable responses occurred with a tumor-related PS ≥ 2 or asymptomatic brain metastases. Grade 3/4 and 5 immune-related adverse events affected 13.7% and 2.0% of patients., Conclusion: Real-world and clinical trial efficacy with upfront pembrolizumab correspond well. Pembrolizumab may sufficiently control asymptomatic brain metastases and may improve a cancer-related reduced PS. However, the frail share of patients with a comorbidity-defined PS ≥ 2, symptomatic brain metastases, or baseline steroids derives no relevant benefit., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp)., Methods: A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS)., Results: METamp tumors (n = 278) had a high frequency of co-occurring mutations (>80% for all amplification levels), whereas 57.6% of the 59 patients with MET gene and exon 14 (METex14) tumors had no additional mutations. In the METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN < 4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN < 4: 43.2%; GCN ≥ 10: 11.8%). A total of 10.1% of all the METamp tumors with a GCN ≥ 10 had a significant worse OS (4.0 mo; 95% CI: 1.9-6.0) compared with the tumors with GCN < 10 (12.0 mo; 95% confidence interval [CI]: 9.4-14.6). In the METamp NSCLC, OS with immune checkpoint inhibitor (ICI) therapy was significantly better compared with chemotherapy with 19.0 months (95% CI: 15.8-22.2) versus 8.0 months (95% CI: 5.8-10.2, p < 0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147)., Conclusions: METex14, METamp GCN ≥ 10, and METamp GCN < 10 represent the subgroups of MET-dysregulated NSCLC with distinct molecular and clinical features. The patients with METex14 do not seem to benefit from immunotherapy in contrast to the patients with METamp, which is of particular relevance for the prognostically poor METamp GCN ≥ 10 subgroup., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Thyroid transcription factor 1 (TTF-1) is a prognostic biomarker in lung adenocarcinoma; however, TTF-1-positive patients also display more favorable factors like actionable target mutations. In contrast, TTF-1-negative cancer is a poorly described entity. We performed a retrospective study to characterize a TTF-1-negative phenotype and to evaluate outcome depending on the chemotherapy regimen applied in the EGFR/ALK-negative population., Patients and Methods: Phenotypic traits were analyzed in 741 patients with evaluable TTF-1 expression status, among them 529 patients with platinum-based first-line chemotherapy, with disease diagnosed between 2009 and 2016 at a tertiary referral university hospital. The influence of TTF-1 and several cofactors on progression-free survival and overall survival (OS) were analyzed using a 1:1 propensity score matching model, depending on the platinum doublet chemotherapy's incorporating pemetrexed or not, with subsequent Cox regression., Results: TTF-1 negativity implied a distinct cancer phenotype with the predominance of male sex, worse Eastern Cooperative Oncology Group performance status, greater metastatic burden at primary diagnosis, and more adrenal gland metastases. These patients had improved progression-free survival (hazard ratio, 0.42; P = .001) and OS (hazard ratio, 0.40; P < .001) when gemcitabine-, taxane-, or vinorelbine-based regimens were provided instead of pemetrexed. None of the regimens was superior in TTF-1-positive patients with regard to OS. Overall, TTF-1 expression was strongly prognostic with a substantial increase in progression-free survival (hazard ratio, 0.54; P < .001) and OS (hazard ratio, 0.53; P < .001)., Conclusion: TTF-1 negativity is associated with a distinct cancer phenotype. Incorporation of this biomarker may be helpful when choosing an appropriate therapy regimen., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Standard therapy of advanced non-small-cell lung cancer harboring an activating mutation in the epidermal growth factor receptor (EGFR) gene is treatment with tyrosine kinase inhibitors (TKI). However, for rare and compound mutations of the EGFR gene, the clinical evidence of TKI therapy is still unclear., Patients and Methods: A total of 2906 lung cancer samples were analyzed for EGFR mutations during routine analysis between 2010 and 2017. The samples have been investigated by Sanger sequencing and since 2014 by next-generation sequencing., Results: We detected EGFR mutations in 408 specimens (14%). Among these, we found 41 samples with rare and 22 with compound mutations. In these 63 samples, 56 different rare EGFR mutations occurred. Information about the clinical outcome was available for 37. Among those with rare mutations, only one patient harboring the mutation p.G874D had disease that responded to first-generation TKI therapy. In contrast, the disease of all patients with compound mutations responded to first- or second-generation TKI therapy. Furthermore, we collected data on clinical relevance regarding TKI therapy from different databases and from an additional literature search, and only found data for 36 of the 56 detected rare mutations., Conclusion: Information about the clinical outcome of patients with rare and compound EGFR mutations remains limited. At present, second- and third-generation TKIs are available, which may represent new treatment strategies for these patients. Therefore, it is becoming increasingly important to maintain databases concerning rare EGFR mutations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: ROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS)., Patients and Methods: The trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue., Results: Thirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51-85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1-not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7-20.0 versus 24.1 months, 95% CI: 10.1-not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%)., Conclusions: Crizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes., Methods: Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients., Results: We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds., Conclusion: KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subgroup of pulmonary hypertension that differs from all other forms of PH in terms of its pathophysiology, patient characteristics and treatment. For implementation of the European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension in Germany, the Cologne Consensus Conference 2016 was held and last updated in spring of 2018. One of the working groups was dedicated to CTEPH, practical and controversial issues were commented and updated. In every patient with suspected PH, CTEPH or chronic thromboembolic disease (CTED, i.e. symptomatic residual vasculopathy without pulmonary hypertension) should be excluded. Primary treatment is surgical pulmonary endarterectomy (PEA) in a multidisciplinary CTEPH centre. Inoperable patients or patients with persistent or recurrent CTEPH after PEA are candidates for targeted drug therapy. There is increasing experience with balloon pulmonary angioplasty (BPA) for inoperable patients; this option, like PEA, is reserved for specialised centres with expertise in this treatment method., (Copyright © 2018. Published by Elsevier B.V.)

We report a case of tracheal, laryngeal and pulmonary mucormycosis in a patient receiving immunosuppressive medication for an autoinflammatory fever syndrome. Mucormycosis was confirmed by histopathology from tracheal specimens and molecular evidence of Lichtheimia. A surgical approach was not possible because of the multifocal disease pattern and the extent of tracheal involvement. The patient was successfully treated with liposomal amphotericin B followed by posaconazole maintenance therapy. After 9 months, recurrent pulmonary mucormycosis was suspected but emerged as organizing pneumonia without evidence of active fungal infection.

Introduction: To offer patients with EGFR mutation-positive advanced NSCLC appropriate EGFR tyrosine kinase inhibitor treatment, mutation testing of tumor samples is required. However, tissue/cytologic samples are not always available or evaluable. The large, noninterventional diagnostic ASSESS study (NCT01785888) evaluated the utility of circulating free tumor-derived DNA (ctDNA) from plasma for EGFR mutation testing., Methods: ASSESS was conducted in 56 centers (in Europe and Japan). Eligible patients (with newly diagnosed locally advanced/metastatic treatment-naive advanced NSCLC) provided diagnostic tissue/cytologic and plasma samples. DNA extracted from tissue/cytologic samples was subjected to EGFR mutation testing using local practices; designated laboratories performed DNA extraction/mutation testing of blood samples. The primary end point was level of concordance of EGFR mutation status between matched tissue/cytologic and plasma samples., Results: Of 1311 patients enrolled, 1288 were eligible. Concordance of mutation status in 1162 matched samples was 89% (sensitivity 46%, specificity 97%, positive predictive value 78%, and negative predictive value 90%). A group of 25 patients with apparent false-positive plasma results was overrepresented for cytologic samples, use of less sensitive tissue testing methodologies, and smoking habits associated with high EGFR mutation frequency, indicative of false-negative tumor results. In cases in which plasma and tumor samples were tested with identical highly sensitive methods, positive predictive value/sensitivity were generally improved., Conclusions: These real-world data suggest that ctDNA is a feasible sample for EGFR mutation analysis. It is important to conduct mutation testing of both tumor and plasma samples in specialized laboratories, using robust/sensitive methods to ensure that patients receive appropriate treatments that target the molecular features of their disease., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Rearrangements of RET are rare oncogenic events in patients with non-small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC., Methods: Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected., Results: Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53. The median age at diagnosis was 62 years (range, 39-80 years; mean ± SD, 61 ± 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%)., Conclusions: Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Originally reported to occur predominantly in younger women, idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients. We aimed to describe the characteristics of such patients and their survival under clinical practice conditions., Methods: Prospective registry in 28 centers in 6 European countries. Demographics, clinical characteristics, hemodynamics, treatment patterns and outcomes of younger (18-65 years) and elderly (>65 years) patients with newly diagnosed IPAH (incident cases only) were compared., Results: A total of 587 patients were eligible for analysis. The median (interquartile, [IQR]) age at diagnosis was 71 (16) years. Younger patients (n=209; median age, 54 [16] years) showed a female-to-male ratio of 2.3:1 whereas the gender ratio in elderly patients (n=378; median age, 75 [8] years) was almost even (1.2:1). Combinations of PAH drugs were widely used in both populations, albeit less frequently in older patients. Elderly patients were less likely to reach current treatment targets (6 min walking distance>400 m, functional class I or II). The survival rates 1, 2, and 3 years after the diagnosis of IPAH were lower in elderly patients, even when adjusted for age- and gender-matched survival tables of the general population (p=0.006 by log-rank analysis)., Conclusions: In countries with an aging population, IPAH is now frequently diagnosed in elderly patients. Compared to younger patients, elderly patients present with a balanced gender ratio and different clinical features, respond less well to medical therapy and have a higher age-adjusted mortality. Further characterization of these patients is required., Clinical Trials Registration: NCT01347216., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. These guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the use of these drugs in patients with chronic lung disease and PH is not recommended. This recommendation, however, is not always in agreement with medical needs as physicians feel sometimes inclined to also treat other forms of pulmonary hypertension which may affect the quality of life and survival of these patients in a similar manner as in PAH. In June 2010, a consensus conference was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology (DGK, DGP and DGPK). To this end, a number of working groups were initiated, one of which was specifically dedicated to the diagnosis and treatment of PH due to chronic lung disease. This manuscript describes in detail the results and recommendations of this working group which were last updated in October 2011., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The cause of sarcoidosis is unclear. Evidence suggests that there is a genetic susceptibility toward the disease. In this study, we examined whether haplotypes of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 are associated with the onset or the course of sarcoidosis., Methods: Three hundred white patients with sarcoidosis and 381 matched controls were included. Sixty-three haplotype-tagging single nucleotide polymorphisms (SNPs) in the VEGF and VEGFR-1 and VEGFR-2 genes were selected from the HapMap Project phase 2. Mass spectrometry-based SNP genotyping was performed., Results: Sarcoidosis, in general, was significantly associated with three SNPs in the VEGFR-1 gene: rs7337610 (P = .041), rs2296283 (P = .034), and rs12858139 (P = .027). In an acute course (defined as less than two episodes in a lifetime or a course lasting less than 2 years), an association of three SNPs in the VEGF gene was observed: rs833060 (P = .004), rs833068 (P = .008), and rs3025000 (P = .012). In the VEGFR-2 gene, one SNP was associated with an acute course of sarcoidosis (rs7667298, P = .023), whereas two SNPs were associated with a chronic course of sarcoidosis: rs7691507 (P = .029) and rs2125489 (P = .024). We then performed a haplotype analysis. After permutation-based correction, no significant haplotype association for the VEGF receptors was observed. However, we found two haplotypes associated with the onset of sarcoidosis in the VEGF gene. Even after correction for multiple testing, we obtained a P value of .0388. Moreover, patients with a chronic course of the disease showed a P value of .0103 for the same haplotype., Conclusions: There is strong evidence that VEGF and its receptors are involved in the onset of sarcoidosis and influence its course.