Treatment with trametinib, a MEK inhibitor, resulted in significantly improved progression-free and overall survival, as compared with chemotherapy, in patients with advanced melanoma and activating ...BRAF mutations.
About 160,000 new cases of melanoma are diagnosed and 48,000 melanoma-related deaths occur worldwide each year.
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Among cancers in patients under 40 years of age, the incidence of melanoma is second only to that of breast cancer for women and leukemia for men.
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Before 2010, no systemic therapy had been shown to improve overall survival among patients with metastatic melanoma, and only modest improvements were observed with interferon as an adjuvant drug.
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Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), and vemurafenib, a selective BRAF inhibitor, have both been shown to improve survival among patients with metastatic melanoma . . .
Summary Background The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no ...continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. Methods In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov , number NCT00973609. Findings Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5–25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1–8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3–7·4) for the bevacizumab alone group, and 6·4 months (4·8–7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio HR 1·08 95% CI 0·85–1·37; p=0·53; upper limit of the one-sided 98·8% CI 1·42), whereas no treatment was not (HR 1·26 0·99–1·60; p=0·056; upper limit of the one-sided 98·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 19% patients in the fluoropyrimidine plus bevacizumab group, 67 43% in the bevacizumab monotherapy group, and 73 46% in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 13% of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 14% of 156 patients in the bevacizumab alone group, and 12 8% of 158 patients in the no treatment group). Interpretation Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies. Funding RochePharma AG and AIO Studien gGmbH.
Overuse of short-acting beta-2 agonists (SABA), which do not treat the underlying inflammation of asthma, is linked to poor clinical outcomes such as increased exacerbation risk. This study, as part ...of the SABINA program, estimated the prevalence of SABA overuse and associated variables in outpatients in Germany.
This retrospective study used anonymized electronic healthcare data from the Disease Analyzer database (IQVIA). A total of 15,640 patients aged ≥ 12 years with asthma who received ≥ 1 SABA prescription(s) between July 2017 and June 2018 in 924 general physician and 22 pneumologist (PN) practices were included. SABA overuse was defined as ≥ 3 prescribed inhalers (~ 200 puffs each) during the study period. The associations between SABA overuse and physician specialty, Global Initiative for Asthma (GINA) steps (based on asthma medications), age, sex, and inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) use were estimated using multivariable regression for patients with probable moderate (GINA step 2) and probable severe (GINA steps 3-5) asthma.
Annually, 36% of all patients (GINA steps 1-5) in general and 38% in PN practices received ≥ 3 SABA inhalers. The risk of SABA overuse was 14% higher in patients treated by a general practitioner vs. a PN; 34% and 85% higher in GINA steps 4 and 5, respectively, vs. GINA step 3; and 40% higher in male vs. female patients.
SABA overuse is prevalent among patients with asthma across all GINA steps in Germany, which may indicate suboptimal asthma control. Further studies are needed to investigate the reasons behind SABA overuse.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In order to gain a deeper insight into the phylogenetic background and diversity of methicillin-resistant
S. pseudintermedius (MRSP) of animal origin, genetic relationships and clonal distribution ...among 146 European MRSP were examined using different molecular and phenotypical typing approaches. MRSP strains were derived from clinical microbiological specimens (mainly of small animal origin) sent in for diagnostic purposes from various veterinary facilities between 2005 and 2008. Pulsed-field gel electrophoresis (PFGE) of SmaI-macrorestriction fragments allowed differentiation of five PFGE-clusters that were subdivided into further distinct subtypes. Representatives of each PFGE subtype were analyzed by multilocus sequence typing (MLST) for assignment of sequence types (ST). With one exception (ST5), all these MRSP strains belonged to ST71. Furthermore, assessment of
spa-typing results revealed that the majority of all strains harboured
spa type t02. Further sporadically detected
spa types t05 and t06 as well as two new types (t15 and t23), were found to be closely related to t02. According to PCR-based SCC
mec-typing, SCC
mecIII was the most prevalent type (
n
=
138), and solely one non-typeable variant was identified in several strains (
n
=
8). In addition, all strains were tested positive by PCR for the leukotoxin encoding operon LukI and the
Staphylococcus intermedius-exfoliative toxin (SIET), respectively.
Our cumulative data indicate a recent emergence of a certain multidrug-resistant MRSP-lineage (ST71) in central and southern European countries during the last few years.
This randomized trial compared preoperative with postoperative chemoradiotherapy for locally advanced rectal cancer. Overall survival was similar in the two groups, but patients assigned to ...preoperative chemoradiotherapy had lower rates of local recurrence and fewer long-term toxic effects than patients in the postoperative group.
In this trial of nearly 800 patients, those assigned to preoperative chemoradiotherapy had lower rates of local recurrence and fewer toxic effects.
Adjuvant radiotherapy with or without chemotherapy has been used widely to improve outcomes in patients with rectal cancer. For locally advanced disease, postoperative chemoradiotherapy significantly improves both local control and overall survival as compared with surgery alone or surgery plus irradiation.
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This information prompted a National Institutes of Health consensus conference, convened in 1990, to recommend postoperative adjuvant chemoradiotherapy as standard treatment for patients with rectal cancer classified as tumor–node–metastasis (TNM) stage II (i.e., a tumor penetrating the rectal wall, without regional lymph-node involvement) or stage III (i.e., any tumor with regional lymph-node involvement).
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Several randomized studies have found . . .
Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced—ie, unresectable or metastatic—melanoma. This criterion, however, ...excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population.
We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18–80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1–12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing.
Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7–36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3–33·3) in the nivolumab group and 6·4 months (3·3–9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12–0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33–0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0–84·9) and at 2 years was 70% (55·1–81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1–63·9) and at 2 years was 42% (28·6–54·5); and in the placebo group, this rate was 32% (19·8–45·3) at 1 year and 14% (5·9–25·7) at 2 years. Treatment-related grade 3–4 adverse events were reported in 71% (95% CI 57–82) of patients in the nivolumab plus ipilimumab group and in 27% (16–40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment.
Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3–4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease.
Bristol-Myers Squibb.
Despite the increasing importance of methicillin-resistant Staphylococcus aureus (MRSA) in veterinary medicine, knowledge about the epidemiology of the pathogen in horses is still poor. The ...phylogenetic relationship of strains of human and equine origins has been addressed before, usually by analyzing results of common standard classification methods for MRSA. This work intends to go beyond the baseline of typing procedures in order to comparatively characterize equine and human MRSA strains with similar phylogenetic backgrounds. In addition to multilocus sequence typing, pulsed-field gel electrophoresis, spa typing, staphylococcal cassette chromosome mec typing, and a PCR for Panton-Valentine leukocidin gene detection, a microarray analysis of a total of 185 structural, virulence-associated, and resistance loci was applied. The results showed that clonal complex 8 (CC8) was absolutely predominant (16 strains) in 19 investigated equine MSRA strains. Of the CC8 strains, 13 belonged to sequence type 254 (ST254) and the other 3 to ST8. This genotype has been isolated from different equine patients in various regions over several years, substantiating the apparent predominance of CC8 STs in MRSA strains of horses worldwide. Furthermore, comparatively investigated human strains of ST254 displayed molecular-typing results indistinguishable from those for strains of equine origin. Two further equine strains (ST22 and ST1117) showed similarity to ST22 human strains (CC22). One equine strain belonged to ST398, a genotype recently described as being frequently isolated from specimens from pigs and pig farmers. These data provide evidence for the adaptation of certain MRSA genotypes to more than one mammalian species, reflecting their extended host spectra.
Atmospheric‐pressure dielectric barrier discharges (DBDs) in argon with admixtures of small amounts of hexamethyldisiloxane (HMDSO) have been analysed by means of numerical modelling. A ...time‐dependent, spatially one‐dimensional fluid‐Poisson model has been used, which takes into account the spatial variation of the discharge plasma between the plane‐parallel dielectrics covering the electrodes. Main features of the model, including the reaction kinetics for HMDSO, are given. Good agreement with related experimental studies of the ignition voltage for HMDSO amounts of up to 200 ppm and the temporal course of the discharge current for conditions typical of deposition experiments is obtained by the model calculations when assuming that 30% of the reactions of HMDSO with excited argon atoms, with a rate coefficient of 5.0 × 10−10 cm3/s, lead to the production of electrons due to Penning ionization. The modelling results for constant frequency f = 86.2 kHz and applied voltage Ua = 4 kV show that the electrical energy dissipated in the DBD decreases with an increasing amount of HMDSO and enable the determination of the energy absorbed per HMDSO molecule on the basis of their energy balance. The analysis of the plasma–chemical processes also makes clear that collision processes of HMDSO with excited argon atoms and molecules leading to neutral reaction products are essential for the formation of thin polymer films.
Quantum sensors based on coherent matter-waves are precise measurement devices whose ultimate accuracy is achieved with Bose-Einstein condensates (BECs) in extended free fall. This is ideally ...realized in microgravity environments such as drop towers, ballistic rockets and space platforms. However, the transition from lab-based BEC machines to robust and mobile sources with comparable performance is a challenging endeavor. Here we report on the realization of a miniaturized setup, generating a flux of quantum degenerate 87Rb atoms every 1.6 s. Ensembles of atoms can be produced at a 1 Hz rate. This is achieved by loading a cold atomic beam directly into a multi-layer atom chip that is designed for efficient transfer from laser-cooled to magnetically trapped clouds. The attained flux of degenerate atoms is on par with current lab-based BEC experiments while offering significantly higher repetition rates. Additionally, the flux is approaching those of current interferometers employing Raman-type velocity selection of laser-cooled atoms. The compact and robust design allows for mobile operation in a variety of demanding environments and paves the way for transportable high-precision quantum sensors.
Antibiotic-resistant Klebsiella pneumoniae are a major cause of hospital- and community-acquired infections, including sepsis, liver abscess, and pneumonia, driven mainly by the emergence of ...successful high-risk clonal lineages. The K. pneumoniae sequence type (ST) 307 lineage has appeared in several different parts of the world after first being described in Europe in 2008. From June to October 2019, we recorded an outbreak of an extensively drug-resistant ST307 lineage in four medical facilities in north-eastern Germany.
Here, we investigated these isolates and those from subsequent cases in the same facilities. We performed whole-genome sequencing to study phylogenetics, microevolution, and plasmid transmission, as well as phenotypic experiments including growth curves, hypermucoviscosity, siderophore secretion, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance for an in-depth characterization of this outbreak clone.
Phylogenetics suggest a homogenous phylogram with several sub-clades containing either isolates from only one patient or isolates originating from different patients, suggesting inter-patient transmission. We identified three large resistance plasmids, carrying either NDM-1, CTX-M-15, or OXA-48, which K. pneumoniae ST307 likely donated to other K. pneumoniae isolates of different STs and even other bacterial species (e.g., Enterobacter cloacae) within the clinical settings. Several chromosomally and plasmid-encoded, hypervirulence-associated virulence factors (e.g., yersiniabactin, metabolite transporter, aerobactin, and heavy metal resistance genes) were identified in addition. While growth, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance were comparable to several control strains, results from siderophore secretion and hypermucoviscosity experiments revealed superiority of the ST307 clone, similar to an archetypical, hypervirulent K. pneumoniae strain (hvKP1).
The combination of extensive drug resistance and virulence, partly conferred through a "mosaic" plasmid carrying both antibiotic resistance and hypervirulence-associated features, demonstrates serious public health implications.
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