Summary Background Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide ...improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. Methods The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4–12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00409188. Findings From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5–29·2) with tecemotide versus 22·3 months (19·6–25·5) with placebo (adjusted HR 0·88, 0·75–1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6–36·8) compared with 20·6 months (17·4–23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64–0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months 95% CI 17·6–23·1 vs 24·6 months 18·8–33·0, respectively; adjusted HR 1·12, 0·87–1·44; p=0·38). Grade 3–4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 5% of 1024 patients in the tecemotide group vs 21 4% of 477 patients in the placebo group), metastases to central nervous system (29 3% vs 6 1%), and pneumonia (23 2% vs 12 3%). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 3% in the tecemotide group vs 14 3% in the placebo group), dyspnoea (29 3% vs 13 3%), and metastases to central nervous system (32 3% vs 9 2%). Serious immune-related adverse events did not differ between groups. Interpretation We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Funding Merck KGaA (Darmstadt, Germany).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective To analyze the effectiveness of psychological treatments on symptom load and associated disability in children with functional somatic symptoms, and to explore potential moderators of ...effects. Study design Cochrane, PubMed, PsycINFO, EMBASE, and CINAHL were searched for randomized controlled trials published in peer-reviewed journals. Randomized controlled trials studying the effect of a psychological treatment on symptom load and disability in children with functional somatic symptoms were selected. Data on symptom load, disability, and school absence directly post-treatment and at follow-up were extracted by 2 assessors. Studies were appraised with the Cochrane risk of bias tool. Standardized mean differences were pooled in a random-effects model. Heterogeneity in effect-sizes was explored by use of meta-regressions. PROSPERO Registration ID: CRD42015029667. Results Out of 4098 identified records, 27 studies were included in this review of which 21 were included in meta-analyses. Psychological treatments reduced symptom load (Hedges g = −0.61), disability (Hedges g = −0.42), and school absence (Hedges g = −0.51) post-treatment in children suffering from various functional somatic symptoms. Effects were maintained at follow-up. Type and duration of symptoms, age, and treatment dose did not explain heterogeneity in effect-sizes between studies. Effect-sizes should be interpreted with caution because of the variety in outcome measures, unexplained heterogeneity in found effects and potential publication bias. Conclusions Psychological interventions reduce symptom load, disability, and school absence in children with functional somatic symptoms. Future research should clarify which patient and treatment characteristics modify outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The effects of acute excessive alcohol ingestion on echocardiographic parameters of left ventricular (LV) function are unclear.
One hundred ninety-nine healthy subjects (44 ± 5 years, 71% male) were ...prospectively examined within 6 hours after excessive alcohol ingestion as well as after 4 weeks with strict alcohol abstinence. Echocardiography was performed at baseline and follow-up for conventional parameters (left ventricular ejection fraction LVEF, transmitral E and A Doppler flow velocities, E/A ratio, tissue Doppler velocity lateral and septal (é), E/é ratio, deceleration time of E, and isovolumic relaxation time) and myocardial deformation data (such as global radial and global and layer-specific circumferential endo and epi global CS and longitudinal endo and epi global LS strain). Multivariate regression was used to assess the impact of independent variables on echocardiographic parameters.
Alcohol levels were 1.2 ± 0.3 g/L at the time of drinking cessation. After alcohol ingestion endo CS (30% ± 2% vs 37% ± 3%, P = .008) and endo LS (27% ± 4% vs 33% ± 3%, P = .002) were significantly lower at baseline versus follow-up. Blood pressure, LVEF and heart rate, and other echocardiographic parameters did not differ between the two examinations. Alcohol levels were modestly, negatively associated with change in endo CS and endo LS (r = -0.54, 95% CI, -0.63 to -0.43, P < .001; and r = -0.26, 95% CI, -0.39 to -0.14; P < .003, respectively). Alcohol levels were the strongest predictor for endo CS (β = -4.84; 95% CI, -6.31 to -3.37) and endo LS (β = -2.50; 95% CI, -4.32 to -0.68).
Acute alcohol ingestion effects endocardial CS and LS, suggesting an acute and transient toxic effect on myocardial deformation, an effect that remains undetected by conventional echocardiographic parameters. The current findings may help clinicians to gain more understanding into the mechanism of developing an alcohol cardiomyopathy and to detect early persistent alcohol-induced myocardial disturbances for an effective therapy in time to prevent harm.
Abstract Background/Objectives Molecular mechanisms of congestive heart failure as reflected by alterations of protein expression patterns are still incompletely analyzed. We therefore investigated ...intraventricular (ie, left ventricular congestive heart failure LV-CHF vs. LV-control CTRL, and right ventricular RV-CHF vs. RV-CTRL) and interventricular (ie, LV-CHF vs. RV-CHF, and LV-CTRL vs. RV-CTRL) protein expression differences in an animal model. Methods The model of rapid ventricular pacing in rabbits was combined with a proteomic approach using 2-dimensional gel electrophoresis. Identification of proteins was done by matrix-assisted laser desorption/ionization-tandem mass spectrometry (MALDI-MS/MS). Results Rapid ventricular pacing-induced heart failure was characterized by LV dilatation, dysfunction, and hypotension as well as by increased BNP gene expression. By comparing LV-CHF vs. LV-CTRL, proteins were found to be underexpressed at 3 crucial points of cellular energy metabolism. In RV-CHF vs. RV-CTRL, proteins belonging to respiratory chain complexes were underexpressed, but additionally a disturbance in the nitric oxide–generating enzymatic apparatus was seen. Regarding the interventricular analyses, a stronger expression of energetic pathways was accompanied by an underexpression of contractile and stress response proteins in failing left vs. right ventricles. Finally, significant protein expression differences were found in LV-CTRL vs. RV-CTRL reflecting a higher expression of contractile, stress response, and respiratory chain proteins in LV tissue. Conclusions In tachycardia-induced heart failure, significant inter- and intraventricular protein expression patterns were found with a predominance of proteins, which are involved in cellular energy metabolism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The present case report describes a 37-year-old man who presented to the emergency room with symptoms of a myocardial infarction but no high-grade stenosis on conventional catheter angiography. ...Consecutive multidetector row computed tomography of the coronary arteries showed an intimal flap along a fibrous plaque formation in the left anterior descending artery. This finding was found to represent a plaque rupture, and the lesion was treated with an 18 mm stent. Multidetector row computed tomography helped to correctly position the stent by identifying the exact location of the rupture along the long plaque formation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but ...screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. Methods ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55–69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50–74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years’ follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. Findings With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83–1·99) after 9 years (1·64 1·58–1·69 including France), 1·66 (1·60–1·73) after 11 years, and 1·57 (1·51–1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70–1·03) after 9 years, 0·78 (0·66–0·91) after 11 years, and 0·79 (0·69–0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490–1929) men invited for screening or one per 27 (17–66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61–0·88). Interpretation In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. Funding Each centre had its own funding responsibility.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 210 000 deaths worldwide. However, little is known about the causes of death and the virus's ...pathologic features.
To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests.
Prospective cohort study.
Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction-confirmed diagnosis of COVID-19.
The first 12 consecutive COVID-19-positive deaths.
Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed. Clinical data and medical course were evaluated.
Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (
= 10) or outpatient sector (
= 2). Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively). Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients. Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients. In all patients, SARS-CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart.
Limited sample size.
The high incidence of thromboembolic events suggests an important role of COVID-19-induced coagulopathy. Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19-related death, as well as possible therapeutic interventions to reduce it.
University Medical Center Hamburg-Eppendorf.
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