Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine

Cancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression but rather spatially separated and diversified. We hypothesize that precision medicine efforts are compromised when clinical decisions are based on a single-sample analysis, which ignores the mechanisms of cancer evolution and resulting intratumoral heterogeneity. Using multiregional whole-exome sequencing, we investigated the effect of somatic evolution on intratumoral heterogeneity aiming to shed light on the evolutionary biology of GC

Adverse events related to biologicals used for patients with multiple sclerosis: a comparison between information originating from regulators and information originating from the scientific community

Publisher's version (útgefin grein)Background and purpose: Clinical decision making is facilitated by healthcare professionals’ and patients’ adequate knowledge of the adverse events. This is especially important for biologicals used for treating multiple sclerosis (MS). So far, little is known about whether different information sources report adverse events consistently. Methods: Biologicals authorized by the European Medicines Agency for the treatment of MS were included in this study. Information on adverse events derived from phase 3 clinical trials from European Public Assessment Reports (EPARs) and from scientific publications was compared. Results: In the study, eight biologicals used for the treatment of MS were included for which the EPAR and/or scientific publication reported a total of 707 adverse events. Approximately one-third of the adverse events was reported in both the EPAR and scientific publication, one-third was only reported in the EPAR and one-third only in the scientific publication. Serious adverse events and adverse events that regulators classified as ‘important identified risk’ were significantly more often reported in both sources compared to adverse events not classified as such (respectively, 38% vs. 30% and 49% vs. 30%). Adverse events only reported in the EPAR or in the scientific publication were, in general, not described in the benefit–risk section or abstract, which were considered to be the most important sections of the documents. Conclusions: This study showed that there is substantial discordance in the reporting of adverse events on the same phase 3 trials between EPARs and scientific publications. To support optimal clinical decision making, both documents should be considered.It is confirmed that no specific funding was receivedfor this study.Peer Reviewe

Key factors underlying the willingness of patients with cancer to participate in medication redispensing

BACKGROUND: Redispensing medication unused by patients to other patients could reduce the environmental burden of medication waste. Simultaneously, associated financial loss could be reduced, particularly for expensive medication such as oral anticancer drugs. An important determinant for successful medication redispensing is patient participation. OBJECTIVE(S): To identify key factors underlying the willingness of patients with cancer to participate in the redispensing of unused oral anticancer drugs. METHODS: Semi-structured interviews via telephone or video call were conducted with adult patients diagnosed with cancer from two Dutch hospitals. The interview guide was framed using the COM-B model for behavioural change, to elicit patients' capability, opportunity and motivation to participate in medication redispensing. Questions were related to patients' willingness to accept redispensed medication, reasons thereof, perceived concerns and needs. Inductive thematic analysis was applied. RESULTS: Seventeen patients (aged 38-82 years, 71% female), with nine different types of cancer participated. The majority of participants supported medication redispensing. Four categories of key factors underlying the willingness of patients with cancer to participate in medication redispensing were identified. First, the driver for participation was having positive societal impact, relating to affordability and sustainability of healthcare. Second, having trust in product quality was a requirement, influenced by preconceived beliefs, quality assurance and patients' knowledge of this process. Third, a facilitator for participating in medication redispensing was adequate provision of information. This concerned awareness of medication waste, information about medication redispensing, support from healthcare providers and other patients, and insight into medication dispensing history. Last, a convenient process for returning unused medication to pharmacies would facilitate participation in medication redispensing. CONCLUSIONS: The willingness of patients with cancer to participate in medication redispensing relates to a drive for achieving positive societal impact, provided that medication is of high quality, there is adequate information provision and a convenient process

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Use of Dipeptidyl Peptidase-4 Inhibitors and the Reporting of Infections: A Disproportionality Analysis in the World Health Organization VigiBase

OBJECTIVE - Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. They inactivate incretin hormones but also have many other effects throughout the body, among which are effects on the immune system. This might result in an increased infection risk. This study assessed the association between use of DPP-4 inhibitors and the reporting of infections. RESEARCH DESIGN AND METHODS - A nested case-control was conducted using VigiBase, the World Health Organization-Adverse Drug Reactions (WHO-ADR) database. The base cohort consisted of ADRs for antidiabetic drugs (Anatomical Therapeutic Chemical code A10). Cases were defined as ADRs of infection according to the Medical Dictionary for Regulatory Activities (MedDRA) classification system. All other ADRs were considered controls. Reporting odds ratios (RORs) were calculated to estimate the strength of the association between different classes of antidiabetic drugs and the reporting of infections. RESULTS - We identified 305,415 suspected ADRs involving antidiabetic drugs in 106,469 case reports, of which 8,083 involved DPP-4 inhibitors monotherapy. Overall, the reporting of infections was higher for patients using DPP-4 inhibitors compared with users of biguanides (ROR 2.3 [95% CI 1.9-2.7]). Reporting of upper respiratory tract infections (ROR 12.3 [95% CI 8.6-17.5]) was significantly associated with use of DPP-4 inhibitors. CONCLUSIONS - This study indicates an increased reporting of infections, in particular upper respiratory tract infections, for users of DPP-4 inhibitors compared with users of other antidiabetic drugs. However, the limitations of spontaneous reporting systems (e.g., underreporting, the Weber-effect, reporting bias) should be taken into account. Therefore, further research is needed to evaluate this suspicion and the underlying mechanism

Quantifying antibiotic use in paediatrics: a proposal for neonatal DDDs

The defined daily dose (DDD) as defined by the World Health Organization (WHO) has been the most frequently used unit of measurement to measure antibiotic use. However, measuring antibiotic use in paediatrics is a problem as the WHO DDD methodology is not applicable in children (aged >1 month) due to the large variation in body weight within this population. Based on the narrow range of body weights in the neonatal population, we therefore aimed to develop a set of neonatal DDDs for antibiotics. Eight well-respected (inter)national sources for dosage recommendations of antibiotics in children and neonates were consulted for the assumed maintenance dose of the ten most frequently used antibiotics in neonatal intensive care units in its main indication for neonates. A set of neonatal DDDs for ten commonly used antibiotics in neonates based on an assumed neonatal weight of 2 kg was proposed. Primarily in children DDDs are not applicable to quantify antibiotic use since there is large variation in body weight. In the neonatal population, however, based on its narrow range of body weights and when access to patient level data is not available, neonatal DDDs can be used as a unit of measurement

First detection of a VHE gamma-ray spectral maximum from a Cosmic source: H.E.S.S. discovery of the Vela X nebula

The Vela supernova remnant (SNR) is a complex region containing a number of sources of non-thermal radiation. The inner section of this SNR, within 2 degrees of the pulsar PSR B0833-45, has been observed by the H.E.S.S. gamma-ray atmospheric Cherenkov detector in 2004 and 2005. A strong signal is seen from an extended region to the south of the pulsar, within an integration region of radius 0.8 deg. around the position (RA = 08h 35m 00s, dec = -45 deg. 36' J2000.0). The excess coincides with a region of hard X-ray emission seen by the ROSAT and ASCA satellites. The observed energy spectrum of the source between 550 GeV and 65 TeV is well fit by a power law function with photon index = 1.45 +/- 0.09(stat) +/- 0.2(sys) and an exponential cutoff at an energy of 13.8 +/- 2.3(stat) +/- 4.1(sys) TeV. The integral flux above 1 TeV is (1.28 +/- 0.17 (stat) +/- 0.38(sys)) x 10^{-11} cm^{-2} s^{-1}. This result is the first clear measurement of a peak in the spectral energy distribution from a VHE gamma-ray source, likely related to inverse Compton emission. A fit of an Inverse Compton model to the H.E.S.S. spectral energy distribution gives a total energy in non-thermal electrons of ~2 x 10^{45} erg between 5 TeV and 100 TeV, assuming a distance of 290 parsec to the pulsar. The best fit electron power law index is 2.0, with a spectral break at 67 TeV.Comment: 5 pages, 4 figures, accepted for publication in Astronomy and Astrophysics letter

H.E.S.S. observations of gamma-ray bursts in 2003-2007

Very-high-energy (VHE; >~100 GeV) gamma-rays are expected from gamma-ray bursts (GRBs) in some scenarios. Exploring this photon energy regime is necessary for understanding the energetics and properties of GRBs. GRBs have been one of the prime targets for the H.E.S.S. experiment, which makes use of four Imaging Atmospheric Cherenkov Telescopes (IACTs) to detect VHE gamma-rays. Dedicated observations of 32 GRB positions were made in the years 2003-2007 and a search for VHE gamma-ray counterparts of these GRBs was made. Depending on the visibility and observing conditions, the observations mostly start minutes to hours after the burst and typically last two hours. Results from observations of 22 GRB positions are presented and evidence of a VHE signal was found neither in observations of any individual GRBs, nor from stacking data from subsets of GRBs with higher expected VHE flux according to a model-independent ranking scheme. Upper limits for the VHE gamma-ray flux from the GRB positions were derived. For those GRBs with measured redshifts, differential upper limits at the energy threshold after correcting for absorption due to extra-galactic background light are also presented.Comment: 9 pages, 4 tables, 3 figure

Discovery of VHE gamma-rays from the high-frequency-peaked BL Lac object RGB J0152+017

Aims: The BL Lac object RGB J0152+017 (z=0.080) was predicted to be a very high-energy (VHE; > 100 GeV) gamma-ray source, due to its high X-ray and radio fluxes. Our aim is to understand the radiative processes by investigating the observed emission and its production mechanism using the High Energy Stereoscopic System (H.E.S.S.) experiment. Methods: We report recent observations of the BL Lac source RGB J0152+017 made in late October and November 2007 with the H.E.S.S. array consisting of four imaging atmospheric Cherenkov telescopes. Contemporaneous observations were made in X-rays by the Swift and RXTE satellites, in the optical band with the ATOM telescope, and in the radio band with the Nancay Radio Telescope. Results: A signal of 173 gamma-ray photons corresponding to a statistical significance of 6.6 sigma was found in the data. The energy spectrum of the source can be described by a powerlaw with a spectral index of 2.95+/-0.36stat+/-0.20syst. The integral flux above 300 GeV corresponds to ~2% of the flux of the Crab nebula. The source spectral energy distribution (SED) can be described using a two-component non-thermal synchrotron self-Compton (SSC) leptonic model, except in the optical band, which is dominated by a thermal host galaxy component. The parameters that are found are very close to those found in similar SSC studies in TeV blazars. Conclusions: RGB J0152+017 is discovered as a source of VHE gamma-rays by H.E.S.S. The location of its synchrotron peak, as derived from the SED in Swift data, allows clearly classification it as a high-frequency-peaked BL Lac (HBL).Comment: Accepted for publication in A&A Letters (5 pages, 4 figures