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  • Article  (5)
  • 2018  (5)
  • Medicine
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  • Article  (5)
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  • 2018  (5)
  • 1
    Language: English
    In: Critical Reviews in Oncology / Hematology, October 2018, Vol.130, pp.13-26
    Description: The use of immune checkpoint inhibitors constitutes an emerging therapeutic field for the therapy of gastrointestinal (GI) malignancies following the recent FDA approvals of PD-1 inhibitors for esophago-gastric adenocarcinoma, hepatocellular carcinoma and for microsatellite-instable tumors, which are mainly colorectal cancers. This paper reviews the clinical evidence end of 2017 and discusses the clinical development programs of atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab in GI-tract cancers. Since 2014, these antagonists of the PD-1/PD-L1 axis have gained approval for use in numerous other tumors. Phase II trials and phase I expansion cohorts demonstrate clinical activity in patients with oesophageal, gastric, colorectal, anal and hepatic cancer. Signals of outstanding efficacy are particularly observed in biomarker selected populations and for certain combination regimen. Comprehensive phase III development programs have been initiated in oesophageal and gastric cancer, with randomized trials ongoing in hepatocellular and colorectal cancer as well.
    Keywords: Medicine
    ISSN: 1040-8428
    E-ISSN: 1879-0461
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  • 2
    Language: English
    In: The Journal of Urology, April 2018, Vol.199(4), pp.e366-e366
    Keywords: Medicine
    ISSN: 0022-5347
    E-ISSN: 1527-3792
    Source: ScienceDirect Journals (Elsevier)
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  • 3
    Language: English
    In: European Journal of Applied Physiology, 2018, Vol.118(1), pp.195-203
    Description: Purpose Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. Methods Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO2) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP). Results The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 ± 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 ± 3.2 mmHg, p 〈 0.0001). Both, sildenafil (− 6.8 ± 4.4 mmHg) and ANP (− 6.4 ± 3.8 mmHg) significantly (p 〈 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified. Conclusions By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.
    Keywords: Pulmonary hypertension ; Atrial natriuretic peptide ; Drug development ; Sildenafil ; Dog ; Animal model
    ISSN: 1439-6319
    E-ISSN: 1439-6327
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  • 4
    Language: English
    In: BMC Medical Education, 01 June 2018, Vol.18(1), pp.1-10
    Description: Abstract Background The German quality assurance programme for evaluating work capacity is based on peer review that evaluates the quality of medical experts’ reports. Low reliability is thought to be due to systematic differences among peers. For this purpose, we developed a curriculum for a standardized peer-training (SPT). This study investigates, whether the SPT increases the inter-rater reliability of social medical physicians participating in a cross-institutional peer review. Methods Forty physicians from 16 regional German Pension Insurances were subjected to SPT. The three-day training course consist of nine educational objectives recorded in a training manual. The SPT is split into a basic module providing basic information about the peer review and an advanced module for small groups of up to 12 peers training peer review using medical reports. Feasibility was tested by assessing selection, comprehensibility and subjective use of contents delivered, the trainers’ delivery and design of training materials. The effectiveness of SPT was determined by evaluating peer concordance using three anonymised medical reports assessed by each peer. Percentage agreement and Fleiss’ kappa (κm) were calculated. Concordance was compared with review results from a previous unstructured, non-standardized peer-training programme (control condition) performed by 19 peers from 12 German Pension Insurances departments. The control condition focused exclusively on the application of peer review in small groups. No specifically training materials, methods and trainer instructions were used. Results Peer-training was shown to be feasible. The level of subjective confidence in handling the peer review instrument varied between 70 and 90%. Average percentage agreement for the main outcome criterion was 60.2%, resulting in a κm of 0.39. By comparison, the average percentage concordance was 40.2% and the κm was 0.12 for the control condition. Conclusion Concordance with the main criterion was relevant but not significant (p = 0.2) higher for SPT than for the control condition. Fleiss’ kappa coefficient showed that peer concordance was higher for SPT than randomly expected. Nevertheless, a score of 0.39 for the main criterion indicated only fair inter-rater reliability, considerably lower than the conventional standard of 0.7 for adequate reliability.
    Keywords: Training Curriculum ; Peer Review ; Quality Assurance ; Work Capacity Evaluation ; Inter-Rater Reliability ; Medicine
    E-ISSN: 1472-6920
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  • 5
    Language: English
    In: The Lancet Oncology, July 2018, Vol.19(7), pp.940-952
    Description: Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with number . Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Merck & Co, Inc.
    Keywords: Medicine
    ISSN: 1470-2045
    E-ISSN: 1474-5488
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