Older patients with EGFR mutation-positive non-small cell lung cancer treated with afatinib in clinical practice: A subset analysis of the non-interventional GIDEON study.

INTRODUCTION: Lung cancer is most common in older patients; despite this, older patients are historically under-represented in clinical studies. Here we present data from GIDEON, a study undertaken in Germany in patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) receiving first-line afatinib. GIDEON enrolled a high proportion of patients aged ≥70 years, providing an opportunity to study afatinib use in older patients. MATERIALS AND METHODS: In GIDEON (NCT02047903), a prospective non-interventional study, patients with EGFRm+ NSCLC received first-line afatinib in routine clinical practice until disease progression, death or intolerable adverse events. Key objectives were twelve-month progression-free survival (PFS) rate and objective response rate (ORR). Overall survival (OS) and safety were also assessed. This post hoc analysis explores outcomes of patients grouped by age (≥70 and <70 years). RESULTS: In the 152 patients enrolled in GIDEON (69.7% female, 64.5%/22.4%/13.2% with Del19/L858R/other exon 18-21 mutations, 33.6% with brain metastases), the median age was 67 years (range 38-89) and 43.4% were aged ≥70 years. In the ≥70 years age group and the <70 years age group, twelve-month PFS rate was 58.9% and 43.9%, median PFS was 17.2 months and 10.6 months, ORR was 72.0% and 76.5%, twelve-month OS rate was 79.1% and 79.2%, 24-month OS rate was 52.0% and 61.7%, and median OS was 30.4 months and 27.4 months, respectively. In the ≥70 years age group and the <70 years age group, grade ≥3 adverse drug reactions (ADRs) were observed in 34.8% and 40.7% of patients, respectively; the most common were diarrhea (13.6% and 14.0%), acneiform dermatitis (7.6% and 7.0%), stomatitis (1.5% and 4.7%) and maculopapular rash (1.5% and 4.7%). DISCUSSION: Patients with EGFRm+ NSCLC aged ≥70 years showed clinical benefit from first-line afatinib with no unexpected safety signals, supporting the use of afatinib in this setting.

Prognostic factors in nonsmall cell lung cancer: insights from the German CRISP registry.

INTRODUCTION: Understanding prognosis, especially long-term outcome, in advanced nonsmall cell lung cancer (NSCLC) is crucial to inform patients, guide treatment and plan supportive and palliative care. METHODS: Prognostic factors influencing overall survival (OS) and progression-free survival (PFS) in 2082 patients with wild-type (WT)-NSCLC (629 M1a, 249 M1b, 1204 M1c) are reported. Patients were included in the prospective German CRISP registry recruiting in >150 centres. Analysis for pre-therapeutic factors was based on results from Cox proportional hazard models. RESULTS: Current M-descriptors of the Union for International Cancer Control-8 staging system were validated: M1a and M1b patients had significantly longer median time to events compared to M1c (OS/PFS 16.4/7.2 months, 17.8/6.7 months and 10.9/5.4 months, respectively). OS and PFS were influenced by number and location of metastatic organ systems. M1c and four or more metastatic organs involved had shorter OS and PFS than M1c with one to three organs (OS hazard ratio (HR) 1.69, p<0.001; PFS HR 1.81, p<0.001). M1b-liver metastases had shorter OS/PFS than M1b involving other organs (OS HR 2.70, p=0.006; PFS HR 2.48, p=0.007). Based on number of involved organs (orgsys) and liver metastases, two risk groups (low-risk: M1a, M1b-non-liver, M1c-1-3-orgsys-non-liver; high-risk: M1c-liver, M1b-liver, M1c-4+-orgsys) with significantly different prognoses could be amalgamated (median OS/PFS 14.3/6.5 months and 7.7/4.1 months, respectively). Other favourable factors were female gender and Eastern Cooperative Oncology Group stage 0, with age showing no impact. Those with T1- or N0-status were associated with longer OS than T2-4 or N2-3. CONCLUSION: In this large observational dataset, we further defined factors for outcome in WT-NSCLC, including increased number of involved metastatic organ systems and liver metastases, as those with overall poorer prognosis and reduced survival chance.

Afatinib as first-line treatment in patients with EGFR-mutated non-small cell lung cancer in routine clinical practice.

BACKGROUND: Lung cancer is a leading cause of cancer-related death in Germany and worldwide. Non-small cell lung cancer (NSCLC) comprises ~80% of lung cancer diagnoses; in White patients, around 10% of NSCLC cases are epidermal growth factor receptor mutation-positive (EGFRm+). Head-to-head clinical trials have demonstrated superior efficacy with second-/third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) versus first-generation EGFR TKIs in EGFRm+ NSCLC. Data from routine clinical practice are necessary to confirm that clinical trial findings are transferable to real-world populations. METHODS: In NCT02047903, a prospective non-interventional study in Germany, patients with EGFRm+ NSCLC received first-line afatinib until disease progression or intolerable adverse events. Key objectives were progression-free survival (PFS) rate at 12 months, objective response rate (ORR) and overall survival (OS). Safety/tolerability was also assessed. RESULTS: Of 152 patients, 106 (69.7%) were female, 20 (13.1%) patients had an uncommon EGFR mutation and 51 patients (33.6%) had brain metastases. A starting dose of <40 mg was received by 39 (25.7%) patients. Overall, the 12-month PFS rate was 50.2% while the median PFS was 12.2 months. The ORR was 74.6% and the median OS was 30.4 months. In patients with brain metastases and uncommon mutations, the median PFS was 10.5 and 10.7 months, and the ORR was 77.3% and 83.3%, respectively. Treatment effectiveness was similar in patients with a starting dose of <40 mg (median PFS: 16.4 months; ORR, 81.3%) and a starting dose of 40 mg (median PFS: 10.8 months; ORR, 72.1%). Adverse drug reactions were manageable and consistent with the known afatinib safety profile. CONCLUSION: The results support clinical trial data for afatinib in routine clinical practice, including in patients generally excluded from clinical trials. Outcomes were positive in patients with uncommon EGFR mutations and in those with brain metastases. Treatment benefit was also seen in patients receiving a <40 mg afatinib starting dose, supporting patient-tailored dosing.

Safety and efficacy of clip-based vs. suture mediated vascular closure for femoral access hemostasis: A prospective randomized single center study comparing the StarClose and the ProGlide device.

OBJECTIVES: This study is the first head-to-head analysis of StarClose vs. ProGlide in patients undergoing 5F or 6F percutaneous coronary catheterization or peripheral artery interventions. BACKGROUND: The clip based StarClose and the suture mediated ProGlide vascular closure device are well established for femoral hemostasis in endovascular therapy. However, until now no prospective randomized study compared the safety and efficacy of the two devices. METHODS: This prospective, randomized, single-center study enrolled 505 patients (69.6 ± 11.2 years) resulting in 538 procedures due to more than one intervention in several patients: We analyzed 422 cardiac catheterization and 116 peripheral artery interventions via a common femoral artery access. Patients were randomized to StarClose or ProGlide (1:1). In-hospital complications (major bleeding, hematoma, pseudoaneurysm, vessel occlusion, and arteriovenous fistula) and device failure were recorded. The puncture site was assessed by ultrasound in all patients prior to discharge. RESULTS: Overall complication rate was 3.9%. There were more complications after utilization of StarClose compared to ProGlide (5.6 vs. 2.2%, P = 0.064), which was significant in adjusted logistic regression analysis with a 2.9-fold increased risk of complications for StarClose (P < 0.05). In the subgroup of coronary catheterizations there were significantly more complications for StarClose compared to ProGlide (1.4 vs. 5.2%, P < 0.05) with a 4.7-fold increased risk. Device failure rate was not significantly different between the two devices. CONCLUSION: In this first randomized trial comparing the two closure systems complication rate was higher for StarClose with equal efficacy compared to ProGlide. © 2017 Wiley Periodicals, Inc.

Deactivation vs. asynchronous pacing - prospective evaluation of a protocol for rhythm management in patients with magnetic resonance conditional pacemakers undergoing adenosine stress cardiovascular magnetic resonance imaging.

BACKGROUND: Cardiovascular Magnetic Resonance (CMR) imaging with adenosine stress is an important diagnostic tool in patients with known or suspected coronary artery disease (CAD). However, the method is not yet established for CAD patients with pacemakers (PM) in clinical practice. A possible reason is that no recommendations exist for PM setting (paused pacing or asynchronous mode) during adenosine stress. We elaborated a protocol for rhythm management in clinical routine for PM patients that considers heart rate changes under adenosine using a test infusion of adenosine in selected patients. METHODS: 47 consecutive patients (mean age 72.3 ± 10,0 years) with MR conditional PM and known or suspected CAD who underwent CMR in clinical routine were studied in this prospective observational study. PM indications were sinus node dysfunction (SND, n = 19; 40,4%), atrioventricular (AV) block (n = 26; 55.3%) and bradyarrhythmia in permanent atrial fibrillation (AF, n = 2; 4.3%). In patients with SND, normal AV-conduction and resting HR >45 bpm at the time of CMR and in AF the PM was deactivated for the scan. In intermittent AV-block a test infusion of adenosine was given prior to the scan. All patients with permanent higher degree sinuatrial or AV-block or deterioration of AV-conduction in the adenosine test were paced asynchronously during CMR, in patients with preserved AV-conduction under adenosine the pacemaker was deactivated. CMR protocol included cine imaging, adenosine stress perfusion and late gadolinium enhancement. RESULTS: The adenosine test was able to differentiate between mandatory PM stimulation during CMR and safe deactivation of the device. In patients with permanent sinuatrial or AV-block (n = 11; 23.4%) or deterioration of AV conduction in the adenosine test (n = 5, 10.6%) asynchronous pacing above resting heart rate did not interfere with intrinsic rhythm, no competitive stimulation was seen during the scan. 10 of 15 (66,7%) patients with intermittent AV-block showed preserved AV-conduction under adenosine. As in SND and AF deactivation of the PM showed to be safe during CMR, no bradycardia was observed. CONCLUSION: Our protocol for rhythm management during adenosine stress CMR showed to be feasible and safe and may be recommended for pacemaker patients undergoing routine CMR.

Insertion of miniaturized cardiac monitors outside the catheter operating room: experience and practical advice.

Minor surgical procedures are increasingly being performed as outpatient procedures in settings outside hospital operating rooms (ORs). In electrophysiology, the recent miniaturization of insertable cardiac monitors (ICMs) has enabled the routine insertion of the device as a minimally invasive procedure without the need of a catheter OR. However, a shift to office-based environments for minor surgical procedures is associated with some concerns, particularly with respect to patient- and procedure-related safety in the new setting. In the present document, the authors provide practical advice on facilities, practices, and adaptations necessary when performing ICM insertions in office settings, based on available recommendations as well as their own experience with the use of the novel Reveal LINQ ICM. The main differences from in-hospital implant settings are simplified requirements of room, equipment, and insertion procedures, while ensuring and maintaining an adequate, sterile environment. Patient selection is important: certain groups of patients are recommended to be treated in the catheter OR (e.g. those at increased risk for bleeding or very frail elderly individuals). Insertion in alternative positions, as is sometimes performed for cosmetic reasons, should be referred to dedicated hospitals. Quality assurance and internal quality control are critical in the new procedural landscape, and it is important not to trivialize minor surgical procedures. Operators' sharing of experiences and lessons learned, e.g. in the form of registries, should be encouraged.

A Long-Term Follow-Up Investigation of Endobronchial Valves in Emphysema (the LIVE Study): Study Protocol and Six-Month Interim Analysis Results of a Prospective Five-Year Observational Study.

BACKGROUND: Randomized controlled trials indicate that significant lung volume reduction (ELVR) can be obtained with Zephyr® valves by occluding the target lobe in the absence of collateral ventilation, leading to relevant functional benefits in advanced emphysema patients. OBJECTIVES: To observe the long-term effects of endobronchial valve (EBV) implantation in emphysema patients screened by Chartis assessment in the context of daily pulmonology practice. METHODS: The LIVE Study is a prospective, observational, open-label, single-arm, multicenter trial conducted in Germany. 498 patients included in this interim analysis were enrolled between July 2, 2012, and September 16, 2014. The 6-month follow-up visit data were recorded for 343 patients (safety population), and complete data sets were available for 321 treated patients (efficacy population) - 56.4% male, age: 64.5 years, forced expiratory volume in 1 s (FEV1) % predicted: 31.3%, residual volume (RV) % predicted: 252%. RESULTS: Efficacy results at 6 months: FEV1 (l) increased by +100 ml (+11.9%), RV (l) decreased by -0.42 liter, and the COPD Assessment Test score decreased by -3.14 points (each p < 0.0001). Safety outcomes: A total of 66 adverse events (AEs; with 50 serious AEs - SAEs) were reported in 55 patients (16%) during the hospital stay for EBV placement - pneumothorax (35 cases), chronic obstructive pulmonary disease (COPD) exacerbation (5 cases), and pneumonia (4 cases). During the subsequent 6-month follow-up window, 170 SAEs were recorded in 125 patients (36.4%), predominantly COPD exacerbation (53% of the SAEs). CONCLUSION: The current results of this large-scale German observational study performed in the context of daily practice further demonstrates that ELVR with Zephyr® valves is an effective and well-tolerated treatment option in advanced emphysema.

Infection of a bronchogenic cyst after ultrasonography-guided fine needle aspiration.

Standard recommendation for therapy of benign mediastinal cysts is surgery. Endobronchial ultrasound fine needle aspiration (EBUS-FNA) has been used by some researchers as a diagnostic tool. This approach may be associated with severe life-threatening complications. We describe a case of life-threatening purulent pericardial effusion with tamponade by infection of a bronchogenic cyst after EBUS-FNA.

Gender-related differences in patients with ST-elevation myocardial infarction: results from the registry study of the ST elevation myocardial infarction network Essen.

BACKGROUND: The Myocardial Infarction Network Essen was initiated in order to establish a standardized procedure with immediate reopening of the infarcted vessel for patients with ST-elevation myocardial infarction (STEMI) in the city of Essen, Germany. The present study aims to evaluate gender-related differences in presentation of disease and clinical outcome. HYPOTHESIS: Gender is associated with differences in presentation and outcome of STEMI. METHODS: All patients with STEMI were included without exception. Parameters such as risk profile, mortality, and relevant time intervals were documented. The follow-up period was 1 year. RESULTS: For this study, 1365 patients (72.1% male) were recruited. Women were significantly older, with higher prevalence of diabetes (28.1% vs 20.3%, P = 0.004) and hypertension (76.5% vs 64.8%, P<0.0005). Analysis of time intervals between symptoms to actions showed no significant differences. However, women tended to wait longer before calling for medical assistance (358 vs 331 min, P = 0.091). In-hospital mortality was comparable with respect to gender, whereas women had higher 1-year mortality (18.6% vs 13.2%). Age and diabetes were associated with a higher mortality. Adjusted for age, gender is no longer an independent risk factor. In the follow-up period, significantly more women were readmitted to the hospital without a difference in the frequency of reangiography, surgery, or target-vessel revascularization. CONCLUSIONS: The present data display a successful implementation of a standardized procedure in patients with STEMI. Although differences between genders are not as obvious as expected, efforts should be taken to perform a gender-specific risk analysis as well as to promote education about proper behavior in case of new onset of angina.

[Comorbidity of internal inpatients in the german diagnosis related groups-system]. / Abbildung komorbider psychischer Störungen bei internistischen Patienten im G-DRG-System.

The representation of comorbid mental disorders within the German Diagnosis Related Groups-System was investigated. First the complication and complexity level CCL of diagnoses of mental disorders (ICD-10 category F) within the G-DRG-calculation handbooks 2004 and 2005 were checked. Second the revenue based on a fictitious base rate of 3000 with the G-DRG versions 2004/2005 respectively was calculated with and without inclusion of diagnosed comorbid mental disorders of 6610 cases of both medical departments of a hospital of tertiary care level (year 2004). Only F0-diagnoses could lead to a CCL of 3. In 28.2 % of the patients at least one comorbid diagnosis of the category F of the International Classification of Diseases (mental and substance induced disorders) had been coded. Renunciation of the diagnosed mental disorders would have been resulted in a fictitious reduction in revenues based on the G-DRG version 2004 of 93 600 and on the G-DRG version 2005 of 69 000 . The Patient Clinical Complexity Level PCCL was increased 0.15 by the comorbid mental disorders in each year. To achieve an adequate representation of comorbid mental disorders in the G-DRG-system and to ensure a financial survival of psychosomatic/psychiatric CL-services coordinated efforts of psychosomatic scientific societies and hospitals taking part in the G-DRG-calculation sample are necessary.

[Long-term outcome of intrapleural fibrinolytic therapy via small-bore catheter drainage in the management of complicated parapneumonic effusion and empyema-a case series]. / Langzeitergebnisse der intrapleuralen Fibrinolytikatherapie komplizierter parapneumonischer Pleuraergüsse und Empyeme über kleinlumige Katheter.

BACKGROUND AND PURPOSE: Complicated parapneumonic effusions (PPE) and pleural empyemas (PE) are associated with increased morbidity and mortality. Intrapleural fibrinolytic therapy (IFT) has been established, besides video-assisted thoracoscopy (VATS), in the management of PPE and PE. Combination of IFT and small-bore catheter drainage has previously not been investigated. PATIENTS AND METHODS: 15 patients consecutively referred for PPE and PE were managed with simultaneous IFT via small-bore catheter drainage (9, 12, 14 F). In addition to evaluation of primary outcome, lung function testing and radiologic studies were obtained after 3 months to predict potential pulmonary restrictive impairment and residual pleural thickening. RESULTS: Primary outcome of all 15 patients was positive. Only one patient showed a significant residual pleural thickening. None of the patients showed a restrictive lung function pattern. CONCLUSION: Proven applicability of IFT via small-bore catheter drainage seems to be effective in the face of long-term outcome. Further prospective and multicentric studies should be initiated to investigate the practicability of IFT via small-bore catheter drainage.

The value of magnetocardiography in the course of coronary intervention.

BACKGROUND: The noninvasive detection of restenosis after percutaneous coronary intervention (PCI) remains a clinical challenge. Previous studies have shown that magnetocardiograms reveal obvious changes in patients with coronary artery disease (CAD) and normal electrocardiogram (ECG) at rest. HYPOTHESIS: The present study aimed to evaluate the potential of magnetocardiography (MCG) for the detection of electrophysiological changes in the course of successful PCI. METHODS: Twelve-lead ECG and unshielded four-channel MCG (SQUID AG, Essen, Germany) were registered at nine prethoracic sites in 50 patients with CAD (62 +/- 10 years; EF = 76 +/- 11%; registration: before, 24 hours, and 1 month (n = 25) after PCI) and 57 normals (51 +/- 9 years). Current density vector (CDV) maps were reconstructed within the ST-T interval and classified from category 0 (normal) to category 4 (grossly abnormal). In both groups and at all registration times, the percentage of each category of maps was calculated and compared. RESULTS: Most CDV maps of normals were classified as category 0, 1, or 2 compared to CAD patients before PCI with most maps of category 3 and 4 (P < 0.0005). Twenty-four hours after PCI, more maps were classified as category 2 (P < 0.05) and less as category 4 (P < 0.005). One month after PCI the MCG results further improved: more maps were classified as category 1 (P < 0.05) and 2 (P < 0.005) and less maps as category 4 (P < 0.0001). The ECG remained unchanged in the course of PCI. CONCLUSION: Unshielded four-channel MCG reveals obvious changes in the course of successful PCI on the basis of CDV map reconstruction during repolarization. The method seems to be suitable for the follow-up of patients after PCI.

The value of magnetocardiography in patients with and without relevant stenoses of the coronary arteries using an unshielded system.

BACKGROUND: The diagnostic management of patients with chest pain remains a clinical challenge. Magnetocardiography (MCG) is a noninvasive method for the recording of cardiac electromagnetic signals at multiple sites above the chest cage. Contrary to electrocardiogram (ECG) the magnetic field is unaltered by surrounding tissues. The present study aimed to analyze the diagnostic value of an unshielded four-channel MCG for the detection of coronary artery disease (CAD) in patients with chest pain. METHODS: The study included 417 subjects: 177 patients with angiographically documented CAD (stenoses > or =50%), 123 symptomatic patients without hemodynamically relevant stenosis (nCAD) and 117 healthy subjects. Twelve-lead ECG was obtained in all subjects. The magnetocardiography recordings were taken from 36 positions at rest. From these current density vector maps were generated during the ST-T interval. Each map was classified using a classification system with a scale from 0 (normal) to 4 (grossly abnormal). RESULTS: While the ECG was normal in all subjects the MCG revealed typical differences. In normals most maps were classified as category 0, 1 or 2, in nCAD and more so in CAD patients the categories 3 and 4 prevailed. Using a cut-off value of 39.2% for the discrimination between normals and CAD patients sensitivity was 73.3%, specificity 70.1%. CONCLUSION: Contrary to ECG, unshielded MCG reveals significant differences between normals and symptomatic patients with and without relevant stenoses using current density reconstruction during repolarization at rest. This method might be a suitable noninvasive tool for the management of patients with chest pain.

Magnetocardiography in coronary artery disease with a new system in an unshielded setting.

BACKGROUND: The noninvasive detection of coronary artery disease (CAD) remains a clinical challenge. Magnetocardiography is a completely noninvasive method that permits the registration of cardiac electrical activity at multiple sites in a plane above the chest cage without the need for electrodes. In contrast to the electrocardiogram (ECG) which suffers from boundary effects and a variety of potential artifacts (electrode placement, etc.) the MCG is unaffected by such impediments as the magnetic field is unaltered by surrounding tissues. HYPOTHESIS: Magnetocardiography with a newly developed single-channel system in an unshielded setting should be a better qualitative diagnostic tool than the standard ECG for the detection and assessment of CAD. METHODS: In all, 52 patients with angiographically documented CAD and unimpaired ventricular function as well as 55 controls were included in this study. A standard 12-lead ECG was obtained in all subjects. The MCG recordings were taken from 36 positions under resting conditions. From these, current density vector maps were generated during the ST-T interval. Each map was then classified using a classification system with a scale from 0 (normal) to 4 (grossly abnormal). RESULTS: While the ECG was normal in all subjects, the MCG in the controls was classified as category 0, 1, or 2. However, in patients with abnormal coronary angiograms, mainly maps in categories 3 and 4 were seen (p < 0.05). CONCLUSION: A single-channel magnetometer in an unshielded setting reveals significant differences between normals and patients with CAD with normal ECG on the basis of current density reconstruction during the ST segment when measured under resting conditions. This method might be suitable for the noninvasive detection of CAD.

Simultaneous determination of spirapril and spiraprilat in plasma by capillary gas chromatography-mass spectrometry.

A specific, sensitive and precise method for the simultaneous determination of spirapril (CAS 94841-17-5) and spiraprilat (CAS 83602-05-5) in human plasma is described. The method involves the use of enalapril as internal standard, solid-phase extraction, derivatization and capillary gas chromatography with mass sensitive detection. The working range is from 2.5 to 500 micrograms/l for spirapril and spiraprilat, respectively. Data demonstrating the precision and accuracy of the analytical method are given. Moreover, data concerning freeze-thaw stability, long-term stability of frozen samples, short-term stability of thawed samples, and stability of the extracts in the autosampler are given.

Drug interaction of spirapril hydrochloride monohydrate and hydrochlorothiazide. A clinical study to compare the pharmacokinetics after administration of spirapril hydrochloride monohydrate tablets, hydrochlorothiazide tablets and fixed combination bi-layer tablets.

The potential influence of concomitantly administered hydrochlorothiazide (CAS 58-93-5) on the pharmacokinetics of spirapril (CAS 94841-17-5)/spiraprilat (CAS 83602-05-5) and of concomitantly administered spirapril on the pharmacokinetics of hydrochlorothiazide was investigated in an open, randomised, 3-way crossover study in 12 healthy male subjects. The test drug was a newly developed bi-layer tablet containing a fixed combination of spirapril hydrochloride monohydrate and hydrochlorothiazide (Quadroplus). The reference formulations were tablets containing solely spirapril hydrochloride monohydrate (Quadropril) or hydrochlorothiazide (produced exclusively for study medication). For spirapril, spiraprilat and hydrochlorothiazide the 90% confidence intervals of the AUC(0-infinity) as a measure for the extent of absorption were entirely included within the equivalence range of 0.8 to 1.25 and the 90% confidence intervals of the Cmax as a measure for the rate of absorption were entirely included within the extended equivalence range of 0.7 to 1.43. Therefore, bioequivalence was concluded for the test and reference formulations. The results suggest that hydrochlorothiazide does not interact in the fixed combination with the pharmacokinetics of spirapril and vice versa.