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Despite the high prevalence and mortality of lung cancer and proven effectiveness of low-dose computed tomography (LDCT) to reduce mortality, Germany still lacks a national screening program. The German Institute for Quality and Efficiency in Health Care (IQWiG) and the Federal Office for Radiation Protection (BfS) both published positive scientific evaluations recommending a quality-controlled national screening program. IQWiG underlined the importance of a clear risk definition, integrated smoking cessation programs, and quality assurance, highlighting the necessity of procedural optimization.In the HANSE study, former and current smokers aged 55-79 years are assessed for their lung cancer risk by the NELSON and PLCO M2012 risk scores. 5000 high-risk participants, defined as PLCO M2012 6-year risk ≥ 1.58 % or fulfilling NELSON risk inclusion criteria, will be screened by LDCT at baseline and after 12 months. Lung nodules are analyzed by a modified Lung-RADS 1.1 score of the HANSE study, and values of emphysema and coronary calcium are determined and randomly reported to the participants. 7100 low-risk participants serve as a control. All patients are followed-up for up to 10 years. The sensitivity and specificity of the two risk assessments and LDCT screening, effects of the randomized LDCT reporting, efficiency of lung nodule management, and several other factors are assessed to analyze the success and quality of the holistic screening program.The HANSE study is designed as a holistic lung cancer screening study in northern Germany to answer pressing questions for a successful implementation of an effective German lung cancer screening program. · HANSE is designed to address pressing questions for the implementation of lung cancer screening in Germany.. · HANSE compares NELSON and PLCOM2012 risk assessments for optimal definition of the high-risk group. . · HANSE integrates cardiac calcium and pulmonary emphysema scoring in a holistic screening approach.. CITATION FORMAT: · Vogel-Claussen J, Lasch F, Bollmann B et al. Design and Rationale of the HANSE Study: A Holistic German Lung Cancer Screening Trial Using Low-Dose Computed Tomography. Fortschr Röntgenstr 2022; 194: 1333 - 1345., Competing Interests: The authors declare that they have the following conflicts of interest:J. Vogel-Claussen: Research project support by BMBF, Siemens Healthineers, Boehringer Ingelheim, Novartis, GlaxoSmithKline.Speaking fees by Boehringer Ingelheim, Astra Zeneca, Novartis, Siemens Healthineers, Coreline Soft.M. Reck: Speaking and consulting fees by Amgen, AstraZeneca, BMS, Beigene, Boehringer-Ingelheim, Lilly, Merck, MSD, Mirati, Novartis, Pfizer, Roche, Sanofi.B.A. Bollmann: Speaking fees by AstraZeneca, Boehringer Ingelheim, MSD, Bristol-Myers-Sqibb und Roche.G. Schmid-Bindert is an employee of AstraZeneca.The other authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide, and early LC diagnosis can significantly improve outcomes and survival rates in affected patients. Implementation of LC screening programs using low-dose computed tomography CT in high-risk subjects aims to detect LC as early as possible, but so far, adoption of screening programs into routine clinical care has been very slow. In recent years, the use of CT has significantly increased the rate of incidentally detected pulmonary nodules. Although most of those incidental pulmonary nodules (IPNs) are benign, some of them represent early-stage LC. Given the large number of IPNs detected in the range of several millions each year, this represents an additional, maybe even larger, opportunity to drive stage shift in LC diagnosis, next to LC screening programs. Comprehensive evaluation and targeted work-up of IPNs are mandatory to identify the malignant nodules from the crowd, and several guidelines provide radiologists and physicians' guidance on IPN assessment and management. However, IPNs still seem to be inadequately processed due to various reasons including insufficient reporting in the radiological report, missing communication between stakeholders, absence of patient tracking systems, and uncertainty regarding responsibilities for the IPN management. In recent years, several approaches such as lung nodule programs, patient tracking software, artificial intelligence, and communication software were introduced into clinical practice to address those shortcomings. This review evaluates the current situation of IPN management and highlights recent developments in process improvement to achieve first steps toward stage shift in LC diagnosis., (© 2022 S. Karger AG, Basel.)

Background: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor-chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule., Methods: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 on day 1 (arm A), or pemetrexed 500 mg/m 2 (day 1) and cisplatin 40 mg/m 2 (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life., Results: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1-6) and five (1-6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34-1.62), p  = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9 months); [HR = 1.07; (0.68-1.68), p  = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17-2.38); p  = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B., Conclusion: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone., Trial Registration: European Clinical Trials Database (EudraCT) number 2011-001963-37., Competing Interests: Conflict of interest statement: M.M. reports honoraria for advisory boards from MSD, BMS, Roche, Boehringer Ingelheim, Amgen, Astra Zeneca, Novartis, Pfizer and Takeda H.G.K. reports no relevant conflicts of interest F.G. reports research funding to institution from Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Siemens, honoraria for educational lectures from Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, Tesaro/GSK, Amgen, honoraria for advisory boards from Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GSK, Siemens, Tesaro, Amgen N.R. received honoraria for educational lectures and advisory services from Astra Zeneca, Boehringer Ingelheim, BMS, MSD, Pfizer, Roche, and Takeda. M.S. (Sebastian) reports research funding to institution from Astra Zeneca, honoraria for advisory boards from Astra Zeneca, BMS, MSD/Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Johnson & Johnson, Amgen, Tesaro, Eli Lilly, honoraria for educational lectures rom Astra Zeneca, BMS, Novartis, Pfizer, Boehringer Ingelheim, Amgen and Eli Lilly. M.S. (Serke) reports research funding to institution from Astra Zeneca, BMS, Lilly, MSD, Roche, honoraria for educational lectures from Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, honoraria for advisory boards from Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche, Takeda, Abbvie C.F.W. Honoraria for advisory boards from Astra Zeneca, Boehringer Ingelheim, BMS, Chugai, Pfizer, Roche, Takeda: He received consultancy fees from Mylan; Alvotech; Roche and travel grants from IPSEN, BMS and Lilly. M.T. reports Honoraria for Scientific Meetings from Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis Pfizer, Roche, Takeda Advisory-Board Honoraria from Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, Takeda Travelling support from Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, Takeda Research funding to institution from Astra Zeneca, Bristol-Myers Squibb, Roche, Takeda J. E. reports no conflict of interest G. S.-B. reports consultation honoraria from Eli Lilly, Boehringer Ingelheim, Roche, BMS. After completion of study temporarily employed by Eli Lilly from 2015–2017 M. H. Honoraria for advisory boards from Astra Zeneca, Boehringer Ingelheim, BMS, Chugai, Pfizer, Roche and MSD; honoraria for educational lectures from Astra Zeneca, Boehringer Ingelheim and Roche D.C.C. reports personal fees, non-financial support and other from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, MSD Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda M.K. reports no conflict of interest B.D. reports no conflict of interest S.S. reports no conflict of interest S.H. reports no conflict of interest M.S. (Schuler) reports Consultant Honoraria from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Novartis, Roche, Takeda. Honoraria for CME presentations from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, Novartis. Research funding to institution from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis T.H. reports no conflict of interest F.B. reports no conflict of interest W.E.E. reports research funding to institution from BMS, Astra Zeneca and Eli Lilly, honoraria for advisory boards from Astra Zeneca, BMS, MSD/Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Bayer, Johnson & Johnson, Amgen, Daichi Sankyo, Eli Lilly, honoraria for educational lectures from Astra Zeneca, BMS, MSD/Merck, Roche, Pfizer, Boehringer Ingelheim, Takeda, Amgen and Eli Lilly., (© The Author(s), 2021.)

Background: The Lung Volume Reduction Coil Treatment in Patients With Emphysema (RENEW) trial reported improvements in quality of life, pulmonary function, and exercise performance following endobronchial coil treatment., Objectives: The purpose of this post hoc analysis was to identify baseline predictors, including quantitative CT measures, that identify patients most likely to significantly benefit from endobronchial coil therapy., Methods: Quantitative CT analysis by an independent radiology laboratory and a qualitative evaluation by five blinded experts of the baseline thoracic CT imaging were performed. Univariate and multivariate logistic regression analyses were performed to elucidate characteristics associated with clinical response., Results: In total, 125 patients underwent coil treatment and had evaluable 12-month follow-up results. Of these, 78 patients received treatment of lobes with the highest emphysematous destruction determined by quantitative CT analysis (quantitative visual match [QVM]+), and 47 received treatment in at least one lobe that was not the most destroyed (QVM-). From the 78 patients with QVM+ treatment, a subgroup of 50 patients (64%) was identified with baseline residual volume > 200% predicted, emphysema score > 20% low attenuation area, and absence of airway disease. In this subgroup, greater lobar residual volume reduction in the treated lobes was achieved, which was associated with significant mean ± SE improvement in FEV 1 (15.2 ± 3.1%), St. George's Respiratory Questionnaire (-12 ± 2 points), and residual volume (-0.57 ± 0.13 L)., Discussion: This post hoc analysis found that both significant hyperinflation (residual volume ≥ 200% predicted) and CT analysis are critical for patient selection and treatment planning for endobronchial coil therapy. Quantitative CT analysis is important to identify optimal lobar treatment and to exclude patients with insufficient emphysema (< 20% low attenuation area), whereas visual assessment identifies patients with signs of airway disease associated with worse outcomes., Trial Registry: ClinicalTrials.gov; No.: NCT01608490; URL: www.clinicaltrials.gov., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The PneumRx endobronchial coil system for patients with severe emphysema has been shown to improve quality of life, exercise capacity, and pulmonary function in patients with emphysema. A post hoc analysis of the RENEW trial has identified patient characteristics and lobar selection methods associated with improved outcomes, which have to be confirmed prospectively., Methods: The ELEVATE trial is a prospective, multicenter, open label, randomized (2:1), controlled trial comparing outcomes in patients treated with endobronchial coils (treatment) to a medically managed control group (control). The trial aims to enroll 210 patients (140 in the treatment group and 70 in the control group) with severe emphysema. Control patients will be eligible to crossover to coil treatment after 6 months of follow-up. The co-primary effectiveness endpoints are percent change in forced expiratory volume in 1 s and quality of life measured by change in St. George's Respiratory Questionnaire from baseline to 6 months. Secondary objectives are determination of responder rates of clinical endpoints and mean change in other functional and physiologic endpoints. All patients will be followed for 24 months after initial treatment. Adverse events will be collected on an ongoing basis throughout the trial., Discussion: The primary objective of the ELEVATE trial is to prospectively confirm the safety and effectiveness profile of the coil system for the treatment of severe emphysema in consideration of the findings of previous randomized controlled trials. Secondary objectives are the determination of responder rates in all clinical endpoints and mean change in physiologic endpoints., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

In patients with non-small cell lung cancer (NSCLC), the most frequent oncogene driver mutation in Western countries is Kirsten rat sarcoma viral oncogene homolog (KRAS), and KRAS-mutant NSCLC is associated with smoking. There are various sources of biological heterogeneity of KRAS-mutant NSCLC, including different genotypes that may be associated with specific clinical outcomes, the presence of other co-mutations that exhibit different biological features and drug sensitivity patterns, and mutant allelic content. The efficacy of chemotherapy in patients with KRAS-mutant NSCLC is generally poor and numerous novel therapeutic strategies have been developed. These approaches include targeting KRAS membrane associations, targeting downstream signalling pathways, the use of KRAS synthetic lethality, direct targeting of KRAS, and immunotherapy. Of these, immunotherapy may be one of the most promising treatment approaches for patients with KRAS-mutant NSCLC. Recent data also suggest the potential for distinct efficacy of immunotherapy according to the presence of other co-mutations. In view of the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualised and, in future, may require the use of rational combinations of treatment, many of which are currently under investigation., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Techniques for quantitative pulmonary perfusion and ventilation using the Fourier Decomposition method were recently demonstrated. We combine these two techniques and show that ventilation-perfusion (V/Q) imaging is possible using only a single MR acquisition of less than thirty seconds., Methods: The Fourier Decomposition method is used in combination with two quantification techniques, which extract baselines from within the images themselves and thus allows quantification. For the perfusion, a region assumed to consist of 100% blood is utilized, while for the ventilation the zero-frequency component is used. V/Q-imaging is then done by dividing the quantified ventilation map with the quantified perfusion map. The techniques were used on ten healthy volunteers and fifteen patients diagnosed with lung cancer., Results: A mean V/Q-ratio of 1.15 ± 0.22 was found for the healthy volunteers and a mean V/Q-ratio of 1.93 ± 0.83 for the non-afflicted lung in the patients. Mean V/Q-ratio in the afflicted (tumor-bearing) lung was found to be 1.61 ± 1.06. Functional defects were clearly visible in many of the patient images, but 5 of 15 patient images had to be excluded due to artifacts or low SNR, indicating a lack of robustness., Conclusion: Non-invasive, quantitative V/Q-imaging is possible using Fourier Decomposition MRI. The method requires only a single acquisition of less than 30 seconds, but robustness in patients remains an issue., (Copyright © 2015. Published by Elsevier GmbH.)

Objectives: We investigated the feasibility of cisplatin or carboplatin combined with pemetrexed as adjuvant treatment in patients with completely resected Stage IB/II Non-Small-Cell Lung Cancer (NSCLC)., Materials and Methods: Patients in this multicenter, open-label, parallel-group, non-comparative Phase 2 study were randomized (1:1) to pemetrexed (500 mg/m(2)) with either cisplatin (75 mg/m(2)) or carboplatin (AUC5) for 4 cycles of 21 days. The primary endpoint was treatment feasibility (defined as 4 cycles completed with no cycle delay >42 days and ≤2 dose reductions, with a median relative dose intensity (RDI) ≥95% [overall]; and no Grade ≥3 toxicities at the follow-up visit 30 days after last drug administration). Secondary objectives included overall survival (OS) and safety., Results: We randomized 122 patients and treated 118. 71.9% (46/64) of patients in pemetrexed+cisplatin and 88.9% (48/54) in pemetrexed+carboplatin completed 4 cycles (median RDI >97% for all compounds). Neither treatment met the pre-defined feasibility level >60% of patients: 59.4% (95% confidence interval [CI]: 46.4;71.5) pemetrexed+cisplatin; 50.0% (95%CI: 36.1;63.9) in pemetrexed+carboplatin. In a post-hoc analysis considering only safety, both regimens were feasible with 81.3% (95%CI: 69.5;89.9) in pemetrexed+cisplatin and 90.7% (95%CI: 79.7;96.9) in pemetrexed+carboplatin. OS rates for both groups were 82-83% after 3 years and 80-83% after 5 years. Treatment-related Grade ≥3 adverse events (mostly hematological) were experienced by approximately 30% of patients in each group., Conclusion: Although the study did not meet the primary objective, both treatment groups demonstrated good safety-related feasibility and tolerability as adjuvant treatment in patients with completely resected Stage IB/II NSCLC., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Approximately 2% of lung adenocarcinomas have BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations, including V600E and other types. Vemurafenib, dabrafenib, and sorafenib as BRAF inhibitors are currently tested in clinical trials, but access for patients is limited. The aim of this study was to document the clinical course of patients treated outside of clinical trials., Methods: We conducted a retrospective multicenter cohort study in Europe of patients with advanced BRAF-mutant lung cancer treated with known BRAF inhibitors. Data were anonymized and centrally assessed for age, gender, smoking, histology, stage, local molecular diagnostic results, systemic therapies, and survival. Best response was assessed locally by RECIST1.1., Results: We documented 35 patients treated in 17 centers with vemurafenib, dabrafenib, or sorafenib. Median age was 63 years (range 42-85); gender was balanced; 14 (40%) were never smokers; all (100%) had adenocarcinoma; 29 (83%) had V600E; 6 (17%) had other mutations; one of them had a concomitant KRAS mutation. Thirty (86%) patients had chemotherapy in the first line. Overall survival with first-line therapy was 25.3 months for V600E and 11.8 months for non-V600E. Thirty-one patients received one BRAF inhibitor, and four received a second inhibitor. Overall response rate with BRAF therapy was 53%, and disease control rate was 85%. Median progression-free survival with BRAF therapy was 5.0 months, and overall survival was 10.8 months., Conclusions: These results confirm the activity of targeted therapy in patients with BRAF-mutant lung adenocarcinoma. Further trials are warranted to study combination therapies and drug resistance mechanisms.

Background: Switch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC., Methods: Patients with non-progressive disease after 4-6 cycles of chemotherapy were randomised to receive either pazopanib 800mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety., Results: A total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n=50) or placebo (n=52). Median age was 64years in both arms. Median overall survival was 17.4 months for pazopanib and 12.3 months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40-1.28]; p=0.257). Median PFS was 4.3 months versus 3.2 months (HR 0.67, [95% CI 0.43-1.03], p=0.068). PFS rates at 4 months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1-2. Grade 3-4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE., Conclusions: Switch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to investigate the discordance rates of eight known driver mutations among multiple matched intrapulmonary ground-glass nodules (GGNs) in non-small-cell lung cancer (NSCLC) patients., Methods: Tumors from 35 patients with multiple lesions resected, including confirmed NSCLC and at least one GGN, were analyzed for mutations in EGFR, KRAS, HER2, BRAF, and PIK3CA together with fusions in ALK, ROS1, and RET., Results: From 35 patients, a total of 72 lesions (60 were GGNs) were analyzed. These included nine adenocarcinoma in situ, nine minimal invasive adenocarcinoma, and 54 invasive adenocarcinoma. Among them, 33 tumor lesions (45.8 %) were found harboring EGFR mutations: 13 tumors with exon 19 deletion, 18 with L858R on exon 21, and two with both exon 19 del and L858R mutation. There were 5 tumors (6.9 %) harboring EML4-ALK fusion, four HER2 mutations (5.6%), three KRAS mutations (4.2%), one ROS1 fusion and one BRAF mutation. When we used the matched tumors to determine the intertumor discrepancy, only six out of 30 patients harbored identical mutations. The discordance rate of driver mutations was 80% (24 of 30) in those patients harboring at least one of the detected driver mutations. The median disease-free survival was 41.2 months (95% confidence interval: 35.8-52.6 months) and the median overall survival was "still not reached" in this cohort., Conclusions: We found a high discrepancy of driver mutations among NSCLC patients with GGNs and a favorable prognosis after multiple lesions resection, which support surgical resection in this situation as a reasonable approach.

Introduction: To compare dynamic volume perfusion computed tomography (dVPCT) parameters with Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for prediction of therapy response and overall survival (OS) in non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients treated with conventional chemotherapy., Methods: A total of 173 lung cancer patients (131 men; 61 ± 10 years) undergoing dVPCT before (T1) and after chemotherapy (T2) and follow-up were prospectively included. dVPCT-derived blood flow, blood volume, mean transit time, and permeability (PERM) were assessed, compared between NSCLC and SCLC and patients' response to therapy was determined according to RECIST 1.1., Results: One hundred of one hundred and seventy-three patients underwent dVPCT at T1 and T2 within a median of 44 (range, 31-108) days. dVPCT values were differing in NSCLC and SCLC, but were not significantly differing between patients with partial response, stable, or progressive disease. Eighty-five patients (NSCLC = 72 and SCLC = 13) with a follow-up for greater than or equal to 6 months were analyzed for OS. Fifty-six of eighty-five patients died during follow-up. Receiver operating characteristic analysis determined T1/T2 with highest predictive values regarding OS for blood flow, blood volume, mean transit time, and permeability (area under the curve: 0.53, 0.61, 0.54, and 0.53, respectively, all p > 0.05). Kaplan-Meier statistics revealed OS of patient groups assigned according to dVPCT T1/T2 cutoff values was not differing for neither dVPCT parameter, whereas RECIST groups significantly differed in OS (p = 0.02). Cox proportional hazards regression determined progressive disease status to independently predict OS (p = 0.004), while none of the dVPCT parameters did so., Conclusions: dVPCT values, differ between NSCLC and SCLC, are not related to RECIST 1.1 classification and do not improve OS prediction in lung cancer patients treated with conventional chemotherapy.

Epithelial-to-mesenchymal transition (EMT) has profound impacts on cancer progression and also on drug resistance, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Nowadays, there is still no predictive biomarker identified for the use of EGFR-TKIs in non-small cell lung cancer (NSCLC) patients with wild-type EGFR. To clarify the role of EMT phenotype as a predictive marker for EGFR-TKI, we performed a retrospective study in 202 stage IV or recurrent NSCLC patients receiving gefitinib or erlotinib therapy from June 2008 to September 2012 in our institute. Clinical data and EGFR mutational status were collected, while epithelial, epithelial to mesenchymal, not specified or mesenchymal phenotype were classified according to EMT markers such as E-cadherin, fibronectin, N-cadherin and vimentin by immunohistochemistry. Epithelial phenotype was more frequently found in patients with EGFR mutation (p = 0.044). Epithelial phenotype was associated with a significantly higher objective response rate (23.5 vs. 11.1 vs. 0.0 vs. 2.4%, p = 0.011), longer progression-free survival (4.4 vs. 1.9 vs. 1.7 vs. 1.0 months, p < 0.001) and longer overall survival (11.5 vs. 8.9 vs. 4.5 vs. 4.9 months, p < 0.001) compared to epithelial to mesenchymal, not specified and mesenchymal phenotype in the wild-type EGFR subgroup. In the subgroup with EGFR mutation, the trend remained but without a statistically significant difference. In conclusion, epithelial phenotype was more likely expressed in patients with EGFR mutation and was associated with a better outcome in advanced NSCLC patients with wild-type EGFR, which indicates that the EMT phenotype might be a potential marker to guide EGFR-TKI therapy in this population., (© 2014 UICC.)

Objective: The Fourier decomposition (FD) method is a noninvasive method for assessing ventilation and perfusion-related information in the lungs, but the lack of quantifiable values is a drawback. We demonstrate a novel technique for quantification of the FD ventilation maps, compare it to two published methods, and show results from both healthy volunteers and patients diagnosed with lung cancer., Materials and Methods: We quantified the standard FD ventilation images by utilizing additional information, i.e., the zero-frequency component image, which is also obtained from the Fourier analysis. This image acts as a baseline for the changes recorded in the FD ventilation image and can therefore be used to calculate the ventilation. Using this technique, we compared the ventilation values from ten healthy volunteers and ten patients to two previously published methods for quantitative ventilation assessment., Results: All methods showed good overall agreement (mean difference between the methods was 14-38 ml/min). The mean minute ventilation for the FD method was calculated to be 693 ml/min for a 2D slice, which is in the expected range., Conclusion: The zero-frequency component image can be used as a baseline to quantify the FD ventilation maps. Our initial study showed good agreement with published methods in healthy volunteers, but less so in patients with lung cancer.

Purpose: To quantitatively evaluate lung perfusion using Fourier decomposition perfusion MRI. The Fourier decomposition (FD) method is a noninvasive method for assessing ventilation- and perfusion-related information in the lungs, where the perfusion maps in particular have shown promise for clinical use. However, the perfusion maps are nonquantitative and dimensionless, making follow-ups and direct comparisons between patients difficult. We present an approach to obtain physically meaningful and quantifiable perfusion maps using the FD method., Methods: The standard FD perfusion images are quantified by comparing the partially blood-filled pixels in the lung parenchyma with the fully blood-filled pixels in the aorta. The percentage of blood in a pixel is then combined with the temporal information, yielding quantitative blood flow values. The values of 10 healthy volunteers are compared with SEEPAGE measurements which have shown high consistency with dynamic contrast enhanced-MRI., Results: All pulmonary blood flow (PBF) values are within the expected range. The two methods are in good agreement (mean difference = 0.2 mL/min/100 mL, mean absolute difference = 11 mL/min/100 mL, mean PBF-FD = 150 mL/min/100 mL, mean PBF-SEEPAGE = 151 mL/min/100 mL). The Bland-Altman plot shows a good spread of values, indicating no systematic bias between the methods., Conclusion: Quantitative lung perfusion can be obtained using the Fourier Decomposition method combined with a small amount of postprocessing., (Copyright © 2013 Wiley Periodicals, Inc.)

Background and Purpose: Continuous EGFR-TKI treatment beyond progression has shown promising benefit for some patients with acquired resistance to EGFR-TKIs. The aim of this study was to investigate the association of secondary T790M mutation at the time of progression with the efficacy of EGFR-TKI treatment beyond progression., Methods: From March 2011 to March 2013, patients with advanced NSCLC who developed acquired resistance to EGFR-TKI and where a re-biopsy was performed at Tongji University Cancer Institute were included into this study. Scorpion ARMS was used to detect EGFR mutation status., Results: A total of 54 patients were enrolled in this study with a median progression-free survival time (PFS1) of 10.9 months according to RECIST criteria. In all, 53.7% (29/54) had T790M mutation after the failure of EGFR-TKIs; PFS1 was not statistically significantly different between patients with T790M mutation and without (13.0 vs. 10.5 months, p = 0.894). In all, 41 patients received TKI treatment beyond progression, including 22 with local progression to receive additional local therapy and 19 with gradual progression to receive additional chemotherapy. The median progression-free survival time (PFS2) of patients who received EGFR-TKI beyond progression treatment was 3.5 months (95% CI, 2.689-4.311). Patients with T790M mutation had significantly longer PFS2 (6.3 vs. 2.6 months, p = 0.002) and overall survival (39.8 vs. 23.2 months, p = 0.044) than those without., Conclusion: Patients with secondary T790M mutation at the time of progression having gradual or local progression after acquired resistance to EGFR-TKI benefit more from EGFR-TKI treatment beyond progression compared to those without T790M mutation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate dynamic volume perfusion CT (dVPCT) tumor baseline characteristics of three different subtypes of lung cancer in untreated patients., Materials and Methods: 173 consecutive patients (131 men, 42 women; mean age 61 ± 10 years) with newly diagnosed lung cancer underwent dVPCT prior to biopsy. Tumor permeability, blood flow (BF), blood volume (BV) and mean transit time (MTT) were quantitatively assessed as well as tumor diameter and volume. Tumor subtypes were histologically determined and compared concerning their dVPCT results. dVPCT results were correlated to tumor diameter and volume., Results: Histology revealed adenocarcinoma in 88, squamous cell carcinoma in 54 and small cell lung cancer (SCLC) in 31 patients. Tumor permeability was significantly differing between adenocarcinoma, squamous cell carcinoma and SCLC (all p<0.05). Tumor BF and BV were higher in adenocarcinomathan in SCLC (p = 0.001 and p=0.0002 respectively). BV was also higher in squamous cell carcinoma compared to SCLC (p = 0.01). MTT was not differing between tumor subtypes. Regarding all tumors, tumor diameter did not correlate with any of the dVPCT parameters, whereas tumor volume was negatively associated with permeability, BF and BV (r = -0.22, -0.24, -0.24, all p<0.05). In squamous cell carcinoma, tumor diameter und volume correlated with BV (r = 0.53 and r = -0.40, all p<0.05). In SCLC, tumor diameter und volume correlated with MTT (r = 0.46 and r = 0.39, all p<0.05). In adenocarcinoma, no association between morphological and functional tumor characteristics was observed., Conclusions: dVPCT parameters are only partially related to tumor diameter and volume and are significantly differing between lung cancer subtypes., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aim: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was reported to be useful for diagnosis of tuberculosis (TB) lymphadenitis, although its indication remains unclear for suspicious pulmonary TB patients. To clarify the role of EBUS-TBNA for the diagnosis of immunocompetent TB patients with intrathoracic lymphadenopathy, we compared two diagnostic modalities: traditional bronchoscopy alone and EBUS-TBNA combined with bronchoscopy., Methods: We retrospectively studied 175 patients of suspicious pulmonary TB with intrathoracic lymphadenopathy in a single institute (Tongji University, Shanghai, China) from January 2010 to May 2011., Results: Ninety-seven patients underwent traditional bronchoscopy alone while 78 received the combined diagnostic techniques. Sensitivity and specificity were 18.1% and 100%, respectively, in the bronchoscopy group alone, and 80% and 92.3%, respectively, in the EBUS-TBNA combination group (absolute increase in sensitivity, 61.9%; P<0.001; 95% CI, 48.7-75.1%). In the combination group, EBUS-TBNA alone was diagnostic of TB in 42 patients (64.6%, 95% CI, 53-76.2%). Bleeding without hemodynamic instability developed in two patients during the procedure of EBUS-TBNA and no hospitalization prolongation happened in the both arms., Conclusion: Combination of EBUS-TBNA with standard bronchoscopic technique is safe and significantly increases the diagnostic yield in patients of suspicious pulmonary TB with lymphadenopathy.

Background: Multiple biomarker testing is necessary to facilitate individualized treatment of lung cancer patients. More than 80% of lung cancers are diagnosed based on very small tumor samples. Often there is not enough tissue for molecular analysis. We compared three minimal invasive sampling methods with respect to RNA quantity for molecular testing., Methods: 106 small biopsies were prospectively collected by three different methods forceps biopsy, endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA), and CT-guided core biopsy. Samples were split into two halves. One part was formalin fixed and paraffin embedded for standard pathological evaluation. The other part was put in RNA later for immediate RNA/DNA extraction. If the pathologist confirmed the diagnosis of non-small cell lung cancer(NSCLC), the following molecular markers were tested: EGFR mutation, ERCC1, RRM1 and BRCA1., Results: Overall, RNA-extraction was possible in 101 out of 106 patients (95.3%). We found 49% adenocarcinomas, 38% squamouscarcinomas, and 14% non-otherwise-specified(NOS). The highest RNA yield came from endobronchial ultrasound guided needle aspiration, which was significantly higher than bronchoscopy (37.74 ± 41.09 vs. 13.74 ± 15.53 ng respectively, P = 0.005) and numerically higher than CT-core biopsy (37.74 ± 41.09 vs. 28.72 ± 44.27 ng respectively, P = 0.244). EGFR mutation testing was feasible in 100% of evaluable patients and its incidence was 40.8%, 7.9% and 14.3% in adenocarcinomas, squamouscarcinomas and NSCLC NOS subgroup respectively. There was no difference in the feasibility of molecular testing between the three sampling methods with feasibility rates for ERCC1, RRM1 and BRCA1 of 91%, 87% and 81% respectively., Conclusion: All three methods can provide sufficient tumor material for multiple biomarkers testing from routinely obtained small biopsies in lung cancer patients. In our study EBUS guided needle aspiration provided the highest amount of tumor RNA compared to bronchoscopy or CT guided core biopsy. Thus EBUS should be considered as an acceptable option for tissue acquisition for molecular testing.

Background: Serum expression of cytokines may provide information about the clinical outcome of advanced non-small cell lung cancer (NSCLC) patients. This study aimed to investigate the relationship between serum cytokine levels and the clinical outcome of erlotinib treatment in a second or third line setting in patients with advanced NSCLC., Methods: A total of 162 patients with advanced NSCLC who received erlotinib as either second or third line therapy were enrolled in this study. Blood samples were collected before the initiation of erlotinib treatment, and the levels of IL-1, IL- 2R, IL-6, and tumor necrosis factor (TNF)-α were assessed by enzyme-linked immunosorbent assay (ELISA). Cutoff points were defined as the median levels of IL-1 (low (≥26.5 pg/ml) and high (>26.5 pg/ml)), IL-2R (low ( = 115 pmol/L) and high (>15 pmol/L)), IL-6 (low (≤49.5 pg/ml) and high (>49.5 pg/ml)), and TNF-α (low (≤48.5 pg/ml) and high (>48.5 pg/ml)). Kaplan-Meier analysis was used to estimate the survival time, and Cox regression analyses were used to correlate cytokines and baseline clinical characteristics with clinical outcomes, including time to progression (TTP) and overall survival (OS)., Results: Between January 2007 and May 2011, 162 patients were enrolled. Their median age was 58 years. In this group, 109 were males and 53 were females, 74 were former or current smokers and 88 were non-smokers. A total of 122 patients had adenocarcinoma, 27 had squamous cell carcinoma, and 13 had tumors with other types of histology. And 139 patients had an Eastern cooperative oncology group (ECOG) performance status of 0-1, while 23 scored at 2-3. Expression of IL-1, IL-2R, and IL-6 was not significantly associated with age, gender, ECOG performance status, smoking status, or histology and stage of tumor. Only TNF-α was associated with smoking status (P = 0.045). Survival analysis showed that patients with low levels of either IL-6 or TNF-α had a statistically longer TTP and OS than patients with high expression (P < 0.05). These cytokines remained significant upon multivariate analysis (P < 0.05)., Conclusion: IL-6 or TNF-α may serve as potential predictive biomarker for the efficacy of erlotinib.

Objectives: The aim was to determine if combined pemetrexed, cisplatin, and cetuximab was efficacious and safe as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC)., Patients and Methods: In this single-arm, multicenter clinical trial, patients with Stage IIIB/IV nonsquamous NSCLC received first-line therapy consisting of pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on Day 1 (21-day cycles) plus weekly cetuximab (400 mg/m(2) loading dose, then 250 mg/m(2)) for 4-6 cycles. Non-progressing patients received maintenance therapy consisting of pemetrexed and cetuximab as above until disease progression. All patients received vitamin supplementation, dexamethasone, and antihistamine prophylaxis. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), 1-year survival rate, translational research (TR) and safety., Results: Of the 113 patients receiving study drug, 109 were protocol-qualified. All patients completed ≥1 cycle of induction, and 51 (45%) and 49 (43%) patients completed ≥1 cycle of maintenance with pemetrexed and cetuximab, respectively. The ORR (n = 109) was 38.5% (80% confidence interval [CI], 32.3-45.1%), all partial responses. Median PFS was 5.8 (80% CI, 4.4-6.7) months. One-year survival rate was 45% (80% CI, 39-51%). In exploratory analyses, there was some preliminary evidence of potential prognostic relationships with efficacy outcomes for epidermal growth factor receptor and thyroid transcription factor-1 protein expression, but not for KRAS mutation or for thymidylate synthase or folate receptor-alpha protein expression. Seventy-three (64.6%) patients had study drug-related Grade 3/4 adverse events (AEs). Drug-related serious AEs were reported in 31 (27.4%) patients. There were 3 (2.7%) potentially drug-related deaths on-study or within 30 days of follow up., Conclusion: Pemetrexed, cisplatin, and cetuximab appeared efficacious and tolerable in advanced nonsquamous NSCLC patients. The TR outcomes are hypothesis-generating given the study's size and nonrandomized nature., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Recently, differences in tumor biology have been observed between Asian and Caucasian lung cancer patients, resulting in different sensitivities to targeted therapy. To date, all registered third-generation chemotherapeutic agents have been investigated mainly in Caucasians, but little is known whether this data can be transferred to an Asian population. The aim of this study was to provide evidence about the efficacy of chemotherapy in a Chinese population., Methods: Three thousand one hundred patients with advanced non-small-cell lung cancer NSCLC, treated between 2002 and 2009 with a platinum-based doublet first-line chemotherapy, including vinorelbine, gemcitabine, docetaxel or paclitaxel, were included for retrospective survival analysis., Results: Overall survival (OS) was 12.1 months and progression free survival (PFS) was four months for all patients. No advantage in OS was seen for any of the four compounds. Gemcitabine was associated with a better PFS compared to the other three (P < 0.001). Docetaxel led to higher response rates, but this finding didn't reach statistical significance (P = 0,054). Chinese patients appear to have longer survival times compared to historical data in Caucasians., Conclusion: Our retrospective analysis suggests, that there is no difference in efficacy of third-generation chemotherapy between Asians and Caucasians., (© 2012 Tianjin Lung Cancer Institute and Wiley Publishing Asia Pty Ltd.)

Objectives: A growing interest in monitoring cardiac output (CO) noninvasively has emerged; however, its determination has been difficult using the standard approaches. The aim of this study was to evaluate the accuracy and precision of pulse contour analysis (PCA) compared with cardiac magnetic resonance imaging (CMR)., Design: A single-center prospective study., Setting: A university hospital., Participants: Thirty-nine consecutive stable patients undergoing CMR., Interventions: CO was determined twice by PCA using the Nexfin monitoring system (BMEYE BV, Amsterdam, The Netherlands). Measurements were performed after 10 minutes of rest in a stable supine position immediately before or after the CMR examination., Measurements and Main Results: There was a mean bias of 0.2 ± 1.9 L/min between CMR and PCA and a reproducibility of 0.2 ± 0.6 L/min for PCA. Between 4.8 and 6.3 L/min (second quartile of COCMR), there was a good agreement (mean bias = -0.2 ± 1.3 L/min). Comparing quartile 1 (-1.3 ± 2.0 L/min) overestimating and quartiles 3 (1.4 ± 0.9 L/min) and 4 (0.9 ± 2.0 L/min) underestimating CO, a statistically significant difference was found. The reproducibility was not affected by the quartile (p = 0.23, analysis of variance), whereas there was a significant difference between the nonoutlier and outlier group when using the Mann-Whitney U test (p = 0.02)., Conclusions: Noninvasive PCA allows the safe and economic measurement of CO, yet it still has major limitations. Although the agreement with CMR was acceptable, there was a clinically unacceptable variation; absolute values should not be used interchangeably. These results suggest that therapeutic interventions and clinical decisions should not be based on noninvasive PCA measurements at the present time., (Copyright © 2013 Elsevier Inc. All rights reserved.)