There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have ...failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.
Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10mg/kg by intravenous infusion every 2weeks or physician’s choice of chemotherapy (paclitaxel 80mg/m2 on days 1, 8, and 15 or irinotecan 150mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0months; hazard ratio (HR)=1.1 95% confidence interval (CI) 0.9–1.4; P=0.81} or the secondary end points of PFS median, 1.4 versus 2.7months; HR=1.73 (95% CI 1.4–2.2); P>0.99 or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.
Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.
ClinicalTrials.gov: NCT02625623.
Summary
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse drug reaction. However, its histopathological features have not been well defined.
...Objectives
To identify the clinicohistopathological findings of DRESS, and analyse the cutaneous histopathological changes observed in DRESS compared with those observed in maculopapular exanthema (MPE).
Methods
In a retrospective study, conducted at Chang Gung Memorial Hospital (Taiwan) between 2001 and 2011, we compared the clinicohistopathological features of 32 patients with probable/definite DRESS (defined by the RegiSCAR scoring system) with those of 17 patients with MPE.
Results
The major pathological changes observed in patients with DRESS included dyskeratosis (97%), epidermal spongiosis (78%), interface vacuolization (91%), perivascular lymphocytic infiltration (97%) and eosinophilic infiltration (72%). Many pathological features were common to both MPE and DRESS. However, severe dyskeratosis, epidermal spongiosis and severe interface vacuolization were significantly more prominent in cases of DRESS (P < 0·05). The presence of severe dyskeratosis was significantly associated with the clinical severity of renal impairment (P = 0·01).
Conclusions
The severe dyskeratosis detected in patients with DRESS may correlate with a greater extent of systemic involvement compared with that noted in MPE. However, the histopathological changes associated with DRESS are not entirely specific.
What's already known about this topic?
Drug reaction with eosinophilia and systemic symptoms (DRESS) is characterized by severe skin rash, fever, haematological abnormalities and internal organ involvement.
What does this study add?
On histopathological examination, epidermal spongiosis, severe dyskeratosis and interface vacuolization were more commonly noted in DRESS than in maculopapular exanthema (MPE).
Severe dyskeratosis, observed in DRESS, may correlate with a greater extent of systemic involvement compared with that noted in MPE.
Summary
Aims: To investigate the diagnostic value of the International Prostate Symptom Score (IPSS) voiding‐to‐storage subscore ratio (IPSS‐V/S) in male lower urinary tract symptoms (LUTS).
...Methods: A total of 253 men with LUTS were enrolled from January 2005 to July 2010. The voiding (IPSS‐V) and storage IPSS (IPSS‐S) subscores were recorded separately by the patients themselves. The IPSS‐V/S was calculated and compared among various aetiologies based on videourodynamic studies. Receiver operating characteristics (ROC) curves were constructed for comparing the diagnostic value of various non‐invasive methods for predicting failure to voiding and storage lower urinary tract dysfunction (LUTD).
Results: Patients with failure to voiding LUTD, including benign prostatic obstruction (n = 72), bladder neck dysfunction (n = 19), urethral stricture (n = 3) and poor relaxation of the urethral sphincter (n = 32), had mean IPSS‐V/S scores > 1. In contrast, patients who were urodynamically normal (n = 2) or had failure to storage LUTD, including idiopathic detrusor overactivity (n = 84), increased bladder sensation (n = 37), and detrusor overactivity and impaired contractility (n = 4), had IPSS‐V/S scores ≤ 1. When IPSS‐V/S was used to differentiate male LUTS, failure to voiding LUTD was found in 81.2% of patients with IPSS scores > 1, while failure to storage LUTD was found in 75.7% of patients with IPSS‐V/S ≤ 1. The area under ROC curve of IPSS‐V/S was higher than for other non‐invasive methods for predicting failure to voiding and storage LUTD.
Conclusion: Measuring IPSS subscores and calculating IPSS‐V/S is a simple and useful method to differentiate failure to voiding and failure to storage LUTD in men with LUTS. IPSS‐V/S may provide a guide for the initial treatment, especially for primary care physicians without access to urological studies.
Linked Comment: Chapple. Int J Clin Pract 2011; 65: 519.
Summary
Current bibliometric analyses of the evolving trends in research scope category across different time periods using the H‐classics method in implantology are considerably limited. The purpose ...of this study was to identify the classic articles in implantology to analyse bibliometric characteristics and associated factors in implantology for the past four decades. H‐Classics in implantology were identified within four time periods between 1977 and 2016, based on the h‐index from the Scopus® database. For each article, the principal bibliometric parameters of authorship, geographic origin, country origin, and institute origin, collaboration, centralisation, article type, scope of study and other associated factors were analysed in four time periods. A significant increase in mean numbers of authors per H‐Classics was found across time. Both Europe and North America were the most productive region/country and steadily dominated this field in each time period. Collaborations of author, internationally and inter‐institutionally had significantly increased across time. A significant decentralisation in authorships, institutes and journals was noted in past four decades. The journal of Clinical Oral Implant Researches has raised its importance for almost 30 years (1987‐2016). Research on Complications, peri‐implant infection/pathology/therapy had been increasing in production throughout each period. This is the first study to evaluate research trends in implantology in the past 40 years using the H‐classics method, which through analysing via principle bibliometric characteristics reflected a historical perspective on evolutionary mainstream in the field. Prominence of research regarding complications may forecast innovative advancements in future.
Southeast Asia consists of several microcontinents that detached from the northeastern margin of Gondwanaland. The Song Ma belt in northern Vietnam consists of ophiolite, metabasite, metasedimentary ...rocks and eclogite, and it is thought to be a suture zone between the Indochina and South China blocks. However, the nature and boundaries of the Song Ma belt and the collision age of the two blocks have long been debated. In this article, petrological and geochemical studies on the Song Ma ophiolite and eclogite and first sensitive high‐resolution ion microprobe (SHRIMP) age dating of eclogite provide new light to resolve such debate. Eclogite consisting of garnet, omphacite, phengite, quartz, barroisite and rutile is closely associated with garnet–phengite–quartz schist in the ‘Nam Co antiform’, a northern subunit of the Song Ma belt. The eclogite experienced a three‐stage metamorphic evolution: (I) pre‐eclogite stage (amphibolite facies) defined by inclusions of taramite, barroisite, quartz, zoisite/epidote, mica, rutile & rare chlorite in garnet, (II) eclogite stage and (III) retrograde stage of amphibolite to greenschist facies. The P–T conditions of the three stages are of 14–16 kbar and 520–550 °C (I), 24–27 kbar and 650–750 °C (II), and 3–7 kbar and 430–510 °C (III), and show a clockwise P–T path based on their mineral assemblages and stability fields in the P–T pseudosection. Thermobarometric results yield similar peak pressure and temperature (26–28 kbar and 650–710 °C). These data suggest that the Song Ma eclogite underwent high‐pressure metamorphism in subduction zone with a low thermal gradient ∼8 °C km−1. The Song Ma ophiolite is composed of serpentinized peridotite, gabbro, basalt, mafic dyke and chert, and experienced ocean‐floor metamorphism. Metabasalt and gabbro of ophiolite suite and eclogite all have MORB‐type geochemical affinities. Zircon separates from eclogite have very low Th/U ratios of 0.01–0.05, indicating a metamorphic origin. SHRIMP U–Pb isotopic analyses of this zircon yield a 206Pb/238U weighted mean age of 230.5 ± 8.2 Ma. This age is interpreted as the closure age of the Paleotethys Ocean that separated the South China and Indochina blocks, and the subsequent collision of the two blocks that took place at the Middle Triassic corresponding to the major episode of the Indosinian Orogeny.
This study describes the development and validation of the Higher Education Student Engagement Scale (HESES). The psychometric evaluations of the scale included: (i) factor structure, (ii) internal ...consistency, and (iii) criterion validity. The HESES was developed based on our proposed five-factor model of student engagement, which was evolved from Finn and Zimmer's (In: Christenson SL, Reschly AL, Wylie C (eds) Handbook of research on student engagement. Springer, New York, 2012) student engagement model taken into account the distinctive characteristics in higher education. The five main facets of student engagement include: (1) academic engagement, (2) cognitive engagement, (3) social engagement with peers, (4) social engagement with teachers, and (5) affective engagement. The HESES was developed from the 61-item First Year Engagement Scales (FYES). For brevity, it was trimmed into a 28-item scale having regard to the content validity, factor loadings and error variances of the items. The CFA results supported the correlated five-dimensional model with all the dimensions showing high internal consistency based on Cronbach's alpha coefficients. A multi-group CFA also rendered the structure as gender invariant. Its criterion validity was evidenced by its correlations with different student learning outcomes and more importantly, its predictive power in explaining variances of GPA (15%) and satisfaction of the university experience (29%). Different from the dominant behavioral perspective of student engagement in higher education, the HESES is based on a psychological perspective, streamlining student engagement as students' level of involvement in the learning process and a multi-faceted construct with academic, cognitive, social and affective dimensions. The implications and merits of the HESES are discussed.
Aging is a biological process characterized by time-dependent functional declines that are influenced by changes in redox status and by oxidative stress-induced inflammatory reactions. An organism’s ...pro-inflammatory status may underlie the aging process and age-related diseases. In this review, we explore the molecular basis of low-grade, unresolved, subclinical inflammation as a major risk factor for exacerbating the aging process and age-related diseases. We focus on the redox-sensitive transcription factors, NF-κB and FOXO, which play essential roles in the expression of pro-inflammatory mediators and anti-oxidant enzymes, respectively. Major players in molecular inflammation are discussed with respect to the age-related up-regulation of pro-inflammatory cytokines and adhesion molecules, cyclo-oxygenase-2, lipoxygenase, and inducible nitric oxide synthase. The molecular inflammation hypothesis proposed by our laboratory is briefly described to give further molecular insights into the intricate interplay among redox balance, pro-inflammatory gene activation, and chronic age-related inflammatory diseases. The final section discusses calorie restriction as an aging-retarding intervention that also exhibits extraordinarily effective anti-inflammatory activity by modulating GSH redox, NF-κB, SIRT1, PPARs, and FOXOs.
Background
Exposure to environmental pollutants promotes Th2 cell responses. Aryl hydrocarbon receptor (AhR) activation aggravates allergic responses. Epithelium‐derived thymic stromal lymphopoietin ...(TSLP), interleukin (IL)‐25, and IL‐33 are implicated in the dysregulation of Th2 immune responses in severe allergic asthma.
Methods
Bronchial biopsies of 28 allergic severe asthma and 6 mild asthma subjects from highly polluted areas were analyzed for AhR nuclear translocation (NT), cytokine expression, and gene activation. Cultured primary epithelial cells were stimulated with diesel exhausted particles (DEP) to determine AhR‐mediated IL‐33, Il‐25, and TSLP synthesis and release.
Results
Primary bronchial epithelial cells exposed to DEP showed upregulation of IL‐33, IL‐25, and TSLP. These effects were abolished by knockdown of AhR by siRNA. Increased AhR/ARNT binding to promoters of IL‐33, IL‐25, and TSLP was found using chromatin immunoprecipitation (ChIP) assay. Allergic severe asthma with high AhR NT had higher bronchial gene and protein expression of IL‐33, IL‐25, and TSLP. These patients derived clinical benefit from anti‐IgE treatment.
Conclusion
Aryl hydrocarbon receptor activation by DEP mediates upregulation of IL‐33, IL‐25, and TSLP with Th2 activation, potentially linking environmental pollution and allergic severe asthma.
Environmental diesel exhaust particles (DEP) exposed to airway epithelium ligate cytoplasmic aryl hydrocarbon receptor (AhR), translocate to the nucleus with aryl hydrocarbon receptor nuclear translocator (ARNT), and then transactivate IL‐33, Il‐25, and TSLP gene expression. Patients with high AhR nucleus translocation overexpressed IL‐33, Il‐25, and TSLP cytokines compared to those with low. Patients with high AhR nucleus translocation are more response to anti‐IgE therapy compared to those with low.
Summary
Background and objectives
Podoplanin, a transmembrane sialoglycoprotein, is expressed by lymphatic endothelial cells and many tumor cells, and is involved in tumor cell‐induced platelet ...aggregation and tumor metastasis. A recent study found that C‐type lectin‐like receptor 2 (CLEC‐2) is a physiologic receptor for podoplanin. Previous studies showed that aggretin, a snake venom‐derived protein, activates platelets by targeting platelet CLEC‐2. We hypothesized that the C‐terminal fragment of aggretin may bind to platelet CLEC‐2 and displace podoplanin, in turn exerting antitumor metastatic effects.
Methods and results
Aggretin α‐chain C‐terminus (residues 106–136; AACT) prolonged the lag phase of platelet aggregation induced by aggretin in human washed platelets, indicating that AACT may target the binding site of CLEC‐2. HepG2 cells, which are podoplanin‐expressing hepatoma cells, induced platelet aggregation with a lag phase. Pretreatment with AACT inhibited platelet aggregation and prolonged the lag phase induced by HepG2 cells. This inhibitory effect was also found with another hepatocarcinoma cell line, HuH‐7. AACT inhibited the interaction between HuH‐7 cells and platelets, and a specific binding assay demonstrated that CLEC‐2 was the binding site for AACT on platelets. In addition, the invasive ability of HepG2 cells was abolished by AACT in a chick embryo chorioallantoic membrane model. Furthermore, formation of lung metastases after intravenous administration of HuH‐7 cells was significantly reduced when mice were treated with AACT.
Conclusions
AACT interacts with CLEC‐2 of platelets, leading to interference with platelet aggregation and the subsequent metastatic potential of tumor cells. These results suggest that aggretin AACT is a potential candidate for the treatment of tumor metastasis through CLEC‐2 blockade.
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