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Objectives An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the “real-world” setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany. Patients and methods This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1. Results In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4–10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9–9.2) with druggable ALK alterations. Conclusion Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.

Employing X-ray photon correlation spectroscopy, we measure the kinetics and dynamics of a pressure-induced liquid-liquid phase separation (LLPS) in a water-lysozyme solution. Scattering invariants and kinetic information provide evidence that the system reaches the phase boundary upon pressure-induced LLPS with no sign of arrest. The coarsening slows down with increasing quench depths. The

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

We present experimental data illustrating how heat load affects the performance of a cryogenically cooled monochromator under intense X-ray Free-Electron Laser pulses. The measurements are in good agreement with a depth-uniform model of X-ray dynamical diffraction taking beam absorption and heat deformation of the crystals into account., Comment: 9 pages, 4 figures, to be published in Optics Express

Background Guidelines for metastatic non-small cell lung cancer recommend stratified treatment by biomarker test results. We used CRISP to evaluate treatment and outcome of patients (pts) with targetable molecular alterations. Methods Currently 163 sites in Germany have recruited >3700 pts at start of 1st-line who will be followed until death or end of project. Data from 2204 pts recruited by 133 sites from 12/2015 to 06/2018 was analyzed. Progression-free survival (PFS) was determined in pts observed ≥1 year (recruited Results 94%/65% of 1732/472 pts with non-squamous/squamous tumors were tested for any biomarker. In 2018 test rate was 96%/75% and 49%/33% were tested for all biomarkers (EGFR, ALK, ROS1, BRAF) with approved targeted therapies (aTT). An alteration in EGFR, ALK, ROS1 or BRAF was detected in 9%, 3%, 2%, and 2% of pts, respectively. Details on the type of alteration will be presented. Of pts with druggable EGFR mutation (EGFR+ pts, n = 149) 78% received EGFR-aTT in 1st-line. In 2nd-line, 20% received EGFR-aTT, 15% something else, 11% died prior to 2nd-line, 54% were still in 1st-line. Median PFS of EGFR+ pts was 7.1 months (n = 67, 61% events, 95%-CI 5.2-10.1), in total 46% (n = 31) of pts had died (ous). Of pts with druggable ALK alteration (n = 55), 47% received ALK-aTT in 1st-line. In 2nd-line, 22% received ALK-aTT, 11% something else, 13% died prior to 2nd-line, 54% were still in 1st-line. In the ous (n = 29), 55% (n = 16) of tumors had already progressed, in total 24% (n = 7) of pts had died. All 6 pts with druggable ROS1 alteration received chemotherapy as 1st-line, while 6 of the 9 pts with druggable BRAF mutation and start of treatment in 2017/18 received a BRAF-ATT in 1st-line. Conclusions CRISP presents current real life data from Germany. Pts are frequently tested for molecular alterations. While EGFR-aTT is well established as 1st-line and first data are promising for BRAF-aTT, pts with ALK/ROS alteration do not seem to be routinely treated with 1st-line aTT, reasons are not yet clear and will be further evaluated. Outcome of pts will be further analyzed after longer follow-up. Clinical trial identification NCT02622581. Legal entity responsible for the study AIO-Studien-gGmbH. Funding AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, MSD Sharp & Dohme GmbH, Lilly Deutschland GmbH, Novartis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG, and Takeda Pharma Vertriebs GmbH & Co. KG. Disclosure F. Griesinger: Honoraria (institution), Advisory / Consultancy: Ariad; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myer-Squibb; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Honoraria (institution), Advisory / Consultancy: Clovis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck-Sharp-Dome; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche. N.W. Marschner: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD Sharp & Dohme; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: iOMEDICO. M. Janicke: Leadership role, Full / Part-time employment: iOMEDICO. A. Fleitz: Full / Part-time employment: iOMEDICO. L. Spring: Full / Part-time employment: iOMEDICO. J. Sahlmann: Leadership role, Full / Part-time employment: iOMEDICO. A. Karatas: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MSD Sharp & Dohme; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Roche. A. Hipper: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MSD Sharp & Dohme; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Roche. M. Sebastian: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD Sharp & Dohme; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim Pharma; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer. M. Thomas: Honoraria (institution), Advisory / Consultancy: MSD Sharp & Dohme; Honoraria (institution), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Celgene; Honoraria (institution), Advisory / Consultancy: Novartis. All other authors have declared no conflicts of interest.

Background Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash. Methods This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, > 8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0–1, 2) and age (≤65 years, > 65 years). Results Within the full analysis set (FAS; N = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients (> 65 years). Examination using a multivariate Cox proportional model revealed that an age > 65 years was associated with longer OS (hazard ratio 0.640; p = 0.0327) and PFS (hazard ratio 0.642; p = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3. Conclusions Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals. Trial registration ClinicalTrials.gov Identifier: NCT01782690, retrospectively registered on 4 February 2013.

Korrektur zu 10.1016/j.lungcan.2020.10.012

Background:Immune thrombocytopenia (ITP) is an acquired autoimmune disorder, characterized by increased platelet destruction and impaired platelet production. Therefore, affected patients present with bleeding complications of various severity. However, another frequent complication of ITP is fatigue, which is often underestimated. In Europe the oral thrombopoietin receptor agonist Eltrombopag (EPAG) is licensed for the treatment of patients with persistent and chronic ITP who are refractory to previous treatments. EPAG has previously been shown to elevate platelet count and reduce bleeding complications in ITP patients, but the therapeutic effect on fatigue is unclear. Here we present data from the scheduled 3rd interim analysis of the RISA study. Methods:RISA is an ongoing, single-cohort, non-interventional, multicenter observational study. The individual follow-up period is approximately 24 months. Dosage of EPAG and treatment of patients follows the Summary of Product Characteristic (SmPC) or the routine of treating physicians. Fatigue is assessed at baseline and during the study using the FACIT-Fatigue Scale (Version 4). Annual interim analyses are performed to assess treatment effectiveness and safety. For this interim analysis, an evaluation of patients with prior application of Rituximab is planned. Results:210 patients received at least one dose of EPAG and completed one post baseline assessment. Mean±SD age was 63.1±17.4 years, median (range) duration of ITP was 5.6 (0.0- 44.9) years, 10% were splenectomized, 52.4% were female, median platelet count (range) at baseline was 33.5x109/L (0.0-270.0), 37.6% reported bleeding complications (any grade) within 12 months prior baseline (WHO °I 30% , °II 4.8% , °III 1.9% , °IV 0% , 1% grade missing), 85.2% received prior ITP therapy, and 81.4% had at least one concomitant disease. At least one pre-treatment was given to 179 patients. More than half received prednisolone (46.2%) or prednisone (9%) and 24.3% dexamethasone or immuno globulins (20%). Rituximab as pre-treatment was given to 2.9% of the patients but further analysis is not possible due to the small number. Mean±SD daily dose of EPAG was 45.1±14.4 mg. Treatment with EPAG increased median (range) platelet count to 90x109/L (2.0-617.0) within one month. After two years of treatment median (range) platelet count was 122 (9.0-335.0) (Fig. 1). After one month, 75% of the patients showed treatment response, after 24 months 89 % of the patients exhibited platelet counts above 50x109/L. At baseline mean±SD FACIT-Fatigue Score was 36.3±11.1 and remained unchanged during the two-year observation period (38.0±13.3) (Fig. 1). In a first subgroup analysis, 55 (31%) of 175 patients with an evaluable questionnaire at baseline suffered from severe fatigue (score A total of 166 patients (79%) reported any adverse events (AEs) (n=656), 57 patients (27.1%) experienced 126 serious AEs (SAEs) incl. 9 patients (4.3%) with 12 drug related SAEs. A total of 15 patients (7.1%) were reported to have experienced 27 events with fatal outcome. None of the fatal events was assessed causally related to EPAG. Within the first month of treatment 11 of 202 patients (5.4%) reported bleeding complications (any grade) and after two years 2 of 51 (3.9%). Eleven severe thromboembolic events were observed and 2 mild ones (4 severe and one mild related to EPAG). Discussion:In this 3rd interim analysis it was shown that therapy with EPAG increased the platelet count and reduced bleeding events. No new safety risks were reported despite many concomitant diseases and therapies in these patients. The analysis of the fatigue questionnaire revealed that ITP patients suffer from fatigue, similar to cancer patients and 31% of the patients suffered already from a severe fatigue at baseline. To date, the RISA study could not demonstrate that therapy with EPAG leads to a clinically significant improvement in fatigue. In Germany, ITP patients rarely receive Rituximab prior to EPAG despite their older age and comorbidities. This restrained use of Rituximab is in accordance with the current clinical guidance in Germany. The results in this non-interventional trial are in alignment with the outcomes of other clinical trials with EPAG. Figure Disclosures Meyer: Amgen GmbH:Honoraria;Novartis Pharma GmbH:Honoraria;Grifols Germany:Consultancy, Honoraria.Reiser:Celgene:Consultancy, Honoraria;Roche:Consultancy, Honoraria;BMS:Honoraria;CSL Behring:Honoraria.Plath:Novartis Pharma GmbH:Honoraria.Ballerstädt:Novartis Pharma GmbH:Current Employment.Stark-Lorenzen:Novartis Pharma GmbH:Current Employment.Matzdorff:Novartis Oncology:Consultancy, Other: Honoraria paid to institution;Amgen GmbH:Consultancy, Other: Honoraria paid to institution;Grifols Deutschland GmbH:Consultancy, Other: Honoraria paid to institution;Swedish Orphan Biovitrium GmbH:Consultancy, Other: Honoraria paid to institution;UCB Biopharma SRL:Consultancy, Other: Honoraria paid to institution;Roche Pharma AG:Other: Family stockownership. OffLabel Disclosure: Rituximab has not been licensed for the treatment of ITP and rituximab is not being, and is not intended to be, used to treat patients in this trial. However, some patients have been pretreated with rituximab outside this trial.

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Competition can foster misconduct in any circumstance where the organizer of a contest cannot perfectly monitor contestants' actions or when doing so is prohibitively costly. Although misconduct comprises all actions that are contrary to the interest of the organizer, it is not necessarily the case that it is optimal to prohibit all such behavior. In this paper, we determine the equilibrium level of misconduct chosen by players in a symmetric rank-order tournament between two competitors in which the organizer tolerates some level of misconduct. In addition to showing that zero tolerance may not minimize the level of misconduct in equilibrium, we show that there exists a range of tolerated misconduct where a symmetric mixed strategy equilibrium exists with players cheating (i.e., misconduct above the tolerated level) with some probability. When the gain from misconduct is uncertain and unknown the contest organizer faces a tradeoff: tolerating more misconduct will reduce such behavior when the state of temptation is high, but increase it when temptation is low. (JEL J33, K42)

Objectives The aim of this study was to determine whether noncoronary measures from cardiac computed tomography (CT) may enhance the prognostic value of this imaging technology. Background When cardiac CT is performed for quantification of coronary artery calcium (CAC) score, information on other cardiac and thoracic structures is available. Methods Participants without known cardiovascular disease from the prospective population based Heinz Nixdorf Recall study underwent noncontrast cardiac CT for CAC score quantification. From CT, epicardial adipose tissue (EAT) volume, left ventricular and left atrial (LA) axial area index, ascending and descending aortic diameters, as well as aortic valve, mitral ring, and thoracic aortic calcification (TAC) were assessed. Incident cardiovascular events included myocardial infarction, stroke, and cardiovascular death. The prognostic value of CT-derived parameters was assessed by Cox regression analysis, receiver operating characteristics, and net reclassification improvement. Results From 3,630 subjects (59 ± 8 years of age, 46% male), 241 (6.6%) developed a cardiovascular event during 9.9 ± 2.6 years of follow-up. In multivariable Cox regression analysis including Framingham Risk Score, CAC (as log[CAC + 1]), and CT parameters, LA index (hazard ratio [HR]: 1.22 [95% confidence interval [CI]: 1.05 to 1.41] per SD; p = 0.010) and EAT volume (HR: 1.15 [95% CI: 1.01 to 1.30] per SD; p = 0.031) were significantly associated with incident events. In addition, presence of TAC showed an elevated event rate (HR: 1.33 [95% CI: 0.97 to 1.81]; p = 0.08), whereas all other CT-derived parameters showed no relevant association. The LA index, EAT volume, and presence of TAC together improved the prediction of events over Framingham Risk Score and CAC in receiver operating characteristics analysis (area under the curve: 0.749 to 0.764; p = 0.011), and let to a significant net reclassification improvement (HR: 38.0%; 95% CI: 25.1% to 50.8%). Conclusion Assessment of LA index, EAT volume, and TAC from non–contrast-enhanced cardiac CT improves the prediction of incident hard cardiovascular events above CAC and established risk factors, indicating that quantification of these noncoronary measures may improve the prognostic value of this imaging technology.

Talbot-Lau X-ray imaging (TLXI) provides information about scattering and refractive features of objects-in addition to the well-known conventional X-ray attenuation image. We investigated the potential of TLXI for the detection of hairline fractures in bones, which are often initially occult in conventional 2D X-ray images. For this purpose, hairline fractures were extrinsically provoked in a porcine trotter (post-mortem) and scanned with a TLXI system. In the examined case, hairline fractures caused dark-field and differential-phase signals, whereas they were not evident in the conventional X-ray image. These findings motivate a comprehensive and systematic investigation of the applicability of TLXI for diagnosing hairline fractures.

More than 100 years ago Max von Laue in Munich discovered that X‑rays can be interpreted not only as X‑ray quanta in a particle picture, but also show a wave character. This property has been used for a long time in basic research (e.g. in crystallography for determining the structure of proteins), but so far has had no application in medical imaging. In the last 10 years, however, very impressive technological progress could be made in preclinical research, which also makes the utilization of the wave character of X‑ray light possible for medical imaging. These novel radiography procedures, so-called phase-contrast and dark-field imaging, have a great potential for a pronounced improvement in X‑ray imaging and therefore, also the diagnosis of important diseases. This article describes the basic principles of these novel procedures, summarizes the preclinical research results already achieved exemplified by various organs and shows the potential for future clinical utilization in radiography and computed tomography.

e21236Background: Treatment in non-small cell lung cancer is quickly evolving and new agents make it to the routine practice at a rapid pace. It is of high interest to patients (pts), physicians an...

Objectives This study was conducted to investigate the real-world effectiveness and tolerability of rituximab-containing chemoimmunotherapies, which have become the standard of care for chronic lymphocytic leukaemia (CLL), particularly for physically fit patients. Furthermore, current treatment patterns in clinical practice were documented, and an unselected real-life population was compared with older, comorbid patients. Methods Prospective, multicentre, observational study with rituximab-containing chemoimmunotherapy in CLL patients. Results Of 681 patients in total, 485 were enroled in cohort 1 (unselected) and 196 in cohort 2 (comorbid "slow-go" patients). The median patient age was higher than in most randomised controlled trials (cohort 1: 70 years and cohort 2: 75 years). The most common treatment regimen in both first-line and relapsed patients was rituximab-bendamustine. Two-year progression-free survival rate for first-line therapy was 84.1% for cohort 1 and 69.8% for cohort 2 (with best overall response rate 81.8% for cohort 1 and 76.6% for cohort 2). General and B-symptoms declined during treatment and remained at low level or decreased further until study end. The safety profile observed in randomised clinical trials was confirmed. Conclusion Chemoimmunotherapy with rituximab is feasible and safe in a wide variety of clinical settings in CLL, including the treatment of older patients with comorbidities (ClinicalTrials.gov NCT01178086).

Purpose: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer. Experimental Design: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC. Results: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations. Conclusion: MET amplification is not a mutually exclusive genetic event in therapy-naïve non–small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. Clin Cancer Res; 21(4); 907–15. ©2014 AACR.

Purpose This study described the perceptions of genetic counseling and testing of adults ( N =116) attending a genetic education program. Understanding perceptions of genetic counseling, including the importance of counseling topics, will contribute to patient-focused care as clinical genetic applications for common, complex disorders evolve. Methods Participants completed a survey addressing: the importance of genetic counseling topics, benefits and negative effects of genetic testing, and sharing test results. Results Topics addressing practical information about genetic conditions were rated most important; topics involving conceptual genetic/genomic principles were rated least important. The most frequently identified benefit and negative effect of testing were prevention/early detection/treatment and psychological distress. Participants perceived that they were more likely to share test results with first-degree than other relatives. Conclusions Findings suggest providing patients with practical information about genetic testing and genetic contributions to disease, while also determining whether their self-care abilities would be enhanced by teaching genetic/genomic principles.

Odors and volatile organic compounds (VOCs) are typical products of industrial processes that may cause nuisances and potential environmental threats. Biofiltration is a mature technology that employs a biofilm and a water layer to eliminate odorous and pollutants in the exhaust gases. The purpose of this research was to assess the feasibility of biofiltration to be established in Africa and the Caribbean. After an exhaustive literature review and the utilization of an online survey, several outputs regarding its potential to be implemented in these regions were found. Results indicate that South Africa and Nigeria represent the most feasible countries for a prompt establishment of the technology in Africa. In the case of the Caribbean countries, in the Dominican Rep., Jamaica and Trinidad and Tobago emission targets for some VOCs in particular industrial sectors were found. However, in the case of Cuba this information was very restricted. The preliminary survey indicated that people recognize there are problems with odors, though, biofiltration was practically unknown by the participants. The results of this research indicate that Biofiltration is an emission control technology that has considerable applicability in both regions and its introduction will benefit remarkably several productive sectors in order to enable them to comply with regulations, and towards further implementation of sustainable technologies.

Behavioral studies suggested heightened impact of emotionally laden perceptual input in schizophrenia spectrum disorders, in particular in patients with prominent positive symptoms. De-coupling of prefrontal and posterior cortices during stimulus processing, which is related to loosening of control of the prefrontal cortex over incoming affectively laden information, may underlie this abnormality. Pre-selected groups of individuals with low versus high positive schizotypy (lower and upper quartile of a large screening sample) were tested. During exposure to auditory displays of strong emotions (anger, sadness, cheerfulness), individuals with elevated levels of positive schizotypal symptoms showed lesser prefrontal-posterior coupling (EEG coherence) than their symptom-free counterparts (right hemisphere). This applied to negative emotions in particular and was most pronounced during confrontation with anger. The findings indicate a link between positive symptoms and a heightened impact particularly of threatening emotionally laden stimuli which might lead to exacerbation of positive symptoms and inappropriate behavior in interpersonal situations.

Collagen is a biological macromolecule capable of second harmonic generation, allowing label-free detection in tissues; in addition, molecular orientation can be determined from the polarization dependence of the second harmonic signal. Previously we reported that in-plane orientation of collagen fibrils could be determined by modulating the polarization angle of the laser during scanning. We have now extended this method so that out-of-plane orientation angles can be determined at the same time, allowing visualization of the 3-dimensional structure of collagenous tissues. This approach offers advantages compared with other methods for determining out-of-plane orientation. First, the orientation angles are directly calculated from the polarimetry data obtained in a single scan, while other reported methods require data from multiple scans, use of iterative optimization methods, application of fitting algorithms, or extensive post-optical processing. Second, our method does not require highly specialized instrumentation, and thus can be adapted for use in almost any nonlinear optical microscopy setup. It is suitable for both basic and clinical applications. We present three-dimensional images of structurally complex collagenous tissues that illustrate the power of such 3-dimensional analyses to reveal the architecture of biological structures.

Background & Aims Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. Methods We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naive patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. Results RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. Conclusions We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

Objective We aimed to describe the current management and outcomes of patients with secondary immunodeficiencies (SID) on intravenous (IV) or subcutaneous (SC) immune-globulins (IG) as maintenance therapy to prevent infections. Methods Non-interventional, prospective study (average follow-up 20.5 months). Results Of the 307 SID patients (mean age 63.7 ± 14.4 years, 52% males, in 31% IG newly initiated), 95.4% received IV (mean dosing interval 4.6 weeks, average dose 199 mg/kg per 4 weeks), 4.6% were treated with SC IG therapy (2.6 weeks, 343 mg/kg per 4 weeks). Median IG through level at first documentation was 5.8 g/l and did not differ between IV and SC or between underlying malignancies. In 24.1% of patients, treatment was interrupted temporarily, over a mean of 11.6± 6.3 months. In patients with newly initiated IG treatment the 82% overall infection rate prior to treatment dropped to 21% at 1 year. Conclusions Under clinical practice conditions IG replacement therapy in SID patients was feasible, diminished infection rates and improved quality of life. Average IG doses were relatively low. Tolerability of IV IG treatment was excellent. This article is protected by copyright. All rights reserved.

Focal liver lesions are common incidental findings in abdominal ultrasound diagnostics.Characterization of focal liver lesions solely based on b‑mode and color duplex is not feasible in all cases.Using contrast-enhanced ultrasound (CEUS) it is possible to dynamically visualize the vascularization of focal liver lesions, which enables the characterization of benign and malignant liver tumors. The advantages of CEUS are that ultrasound contrast media do not show renal, hepatic or cardiac toxicity and do not influence the thyroid gland. The approach by fusion of CEUS and contrast-enhanced cross-sectional imaging combines the advantages of both imaging modalities.Using CEUS focal liver lesions can be characterized with a diagnostic accuracy greater than 90%.The use of CEUS has become an important imaging modality to evaluate unclear liver lesions.The use of CEUS provides vital information as a supplement to cross-sectional imaging and it has become an important tool in therapy planning, control and monitoring of malignant liver lesions.

In the daily clinical routine characterization of focal lesions using native B‑mode classical ultrasound and color Doppler can be difficult or insufficient; therefore, additional diagnostic information must be taken into consideration.Standard radiological methods in the daily clinical routine include native B‑mode ultrasound and color Doppler ultrasound.Using sonoelastography it is possible to evaluate and characterize tissue properties and focal lesions regarding their stiffness to acquire additional information on a noninvasive basis.Sonoelastography enables the differentiation between benign and malignant lesions especially in organs that can be easily evaluated using ultrasound. This particularly includes the liver, the thyroid gland, the breasts and the testicles. Regarding the liver, sonoelastography techniques can also be used for evaluation of the tissue flexibility in the diagnostics of fibrosis and cirrhosis.Nowadays, elastography is implemented into every modern ultrasound system and has been established as a supplementary examination technique to the conventional ultrasound techniques.Sonoelastography should be used in cases with unclear findings as an additional noninvasive tool for the differentiation between benign and malignant lesions.

Witnessing the suffering of others, for instance, in hospital emergency rooms but also through televised images in news or reality programs, may be associated with the occurrence of later intrusive memories. The factors contributing to why some people develop intrusive memories and others do not are still poorly understood. N = 121 healthy women were exposed to film scenes showing the suffering of dying, severely injured, and mourning people while their EEG was recorded. Individuals showing greater decreases of functional coupling between prefrontal and posterior cortices (greater decreases of EEG beta coherences) reported more intrusive memories of the witnessed events. This was shown for intrusions in the short term (immediately after viewing the film) as well as in the medium term (intrusive memories over 1 week). The findings illuminate brain mechanisms involved in the encoding of information in ways that make intrusive memories more likely.

Background: Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events. Methods: In 3281 participants (45–74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8±2.2 years after the second CT. The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed. Results: We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events. Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1–Q3, 23–360] versus 8 [0–83], P 5y and 5-year risk factors. An excellent prognosis was found for 921 participants with double-zero CAC b =CAC 5y =0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively. When CAC b progressed from 1 to 399 to CAC 5y ≥400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC 5y =400. Participants with CAC b ≥400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively). Conclusions: CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double-zero CT scan is present or when the subjects are already at high risk.