Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain ...metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.
We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0–2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001).
Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64–88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4–20·2). Median duration of response was 24·6 months (95% CI 11·4–34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten 8%) and neutropenia (five 4%). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four 3%) and cardiac disorders (three 2%). No treatment-related deaths occurred.
Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC.
Ignyta/F Hoffmann-La Roche.
Self-efficacy has been consistently found to be a protective factor against psychological distress and disorders in the literature. However, little research is done on the moderating effect of ...self-efficacy on depressive symptoms in the context of chronic pain. This cross-sectional study aimed to examine if pain self-efficacy attenuated the direct relationship between pain intensity and depressive symptoms, as well as their indirect relationship through reducing the extent of catastrophizing when feeling pain (moderated mediation). 664 community-dwelling Chinese older adults aged 60-95 years who reported chronic pain for at least three months were recruited from social centers. They completed a battery of questionnaires on chronic pain, pain self-efficacy, catastrophizing, and depressive symptoms in individual face-to-face interviews. Controlling for age, gender, education, self-rated health, number of chronic diseases, pain disability, and pain self-efficacy, pain catastrophizing was found to partially mediate the connection between pain intensity and depressive symptoms. Furthermore, the relationship between pain intensity and depressive symptoms was moderated by pain self-efficacy. Self-efficacy was also found to moderate the relationship between pain intensity and catastrophizing and the moderated mediation effect was confirmed using bootstrap analysis. The results suggested that with increasing levels of self-efficacy, pain intensity's direct effect on depressive symptoms and its indirect effect on depressive symptoms via catastrophizing were both reduced in a dose-dependent manner. Our findings suggest that pain self-efficacy is a significant protective factor that contributes to psychological resilience in chronic pain patients by attenuating the relationship of pain intensity to both catastrophizing and depressive symptoms.
Sphingomyelin (SM) levels in the circulation correlate positively with atherosclerosis burden. SM is a ubiquitous component of human diets, but it is unclear if dietary SM increases circulating SM ...levels. Dietary choline increases atherosclerosis by raising circulating trimethylamine N-oxide (TMAO) levels in mice and humans. As SM has a choline head group, we ask in this study if dietary SM accelerates atherosclerotic lesion development by increasing circulating SM and TMAO levels. Three studies were performed: (Study 1) C57BL/6 mice were maintained on a high fat diet with or without SM supplementation for 4 weeks prior to quantification of serum TMAO and SM levels; (Study 2) atherosclerosis was studied in apoE-/- mice after 16 weeks of a high fat diet without or with SM supplementation and (Study 3) apoE-/- mice were maintained on a chow diet for 19 weeks without or with SM supplementation and antibiotic treatment prior to quantification of atherosclerotic lesions and serum TMAO and SM levels. SM consumption did not increase circulating SM levels or atherosclerosis in high fat-fed apoE-/- mice. Serum TMAO levels in C57BL/6 mice were low and had no effect atherosclerosis lesion development. Dietary SM supplementation significantly reduced atherosclerotic lesion area in the aortic arch of chow-fed apoE-/- mice. This study establishes that dietary SM does not affect circulating SM levels or increase atherosclerosis in high fat-fed apoE-/- mice, but it is anti-atherogenic in chow-fed apoE-/- mice.
The COVID-19 pandemic has resulted in massive disruptions within health care, both directly as a result of the infectious disease outbreak, and indirectly because of public health measures to ...mitigate against transmission. This disruption has caused rapid dynamic fluctuations in demand, capacity, and even contextual aspects of health care. Therefore, the traditional face-to-face patient–physician care model has had to be re-examined in many countries, with digital technology and new models of care being rapidly deployed to meet the various challenges of the pandemic. This Viewpoint highlights new models in ophthalmology that have adapted to incorporate digital health solutions such as telehealth, artificial intelligence decision support for triaging and clinical care, and home monitoring. These models can be operationalised for different clinical applications based on the technology, clinical need, demand from patients, and manpower availability, ranging from out-of-hospital models including the hub-and-spoke pre-hospital model, to front-line models such as the inflow funnel model and monitoring models such as the so-called lighthouse model for provider-led monitoring. Lessons learnt from operationalising these models for ophthalmology in the context of COVID-19 are discussed, along with their relevance for other specialty domains.
Summary Objectives Osteoarthritis (OA) is related to carotid atherosclerosis. Few studies have investigated the incidence of cerebrovascular diseases in patients with OA. Therefore, we conducted a ...population-based cohort study to determine the incidence and risk of stroke in patients with OA. Methods We used data from Taiwan's Longitudinal Health Insurance Database 2000 (LHID2000) to investigate the incidence of stroke in 43,635 patients with OA newly diagnosed between 2002 and 2003. The non-osteoarthritis (non-OA) cohort comprised 43,635 people from the general population. The follow-up period was from the index date of OA to the date of censoring date or stroke diagnosis, or to the end of 2010. Results The overall incidence of stroke was 36% higher in the OA cohort than in the non-OA cohort, with an adjusted hazard ratio (aHR) of 1.10 (95% confidence interval CI = 1.06–1.14) after adjustment for covariates. Men, age, comorbidity, non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), and Cox-2 selective NSAIDs are independent risk factors of stroke. The OA adults with mild to moderate OA (aHR = 1.97, 95% CI = 1.70–2.28 for young adults; aHR = 1.33, 95% CI = 1.25–1.42 for middle-aged adults; aHR = 1.16, 95% CI = 1.12–1.21 for older adults) and severe OA (aHR = 3.78, 95% CI = 2.50–5.70 for young adults; aHR = 1.34, 95% CI = 1.16–1.56 for middle-aged adults; and aHR = 1.01, 95% CI = 0.92–1.10 for older adults) exhibited increased risks of stroke compared with their counterparts without OA. Conclusion OA may be associated with a slightly increased risk of stroke.
A metasurface (MS) used to convert the linearly polarized (LP) signal from a source antenna into a circularly polarized (CP) signal is proposed and studied. The MS consists of 16 unit cells arranged ...in a 4 × 4 layout. Each unit cell is a rectangular loop with a diagonal microstrip. By placing close to a source antenna, the MS converts the LP signal generated from the source antenna into a CP signal. Two source antennas (patch and slot antennas) are used for studies. The source antenna together with the MS is here called a MS antenna. A total of four low-profile MS antennas operating at the frequency of about 2.45 GHz are designed using computer simulation. For verification of simulation results, the MS antennas are fabricated and measured. Simulated and measured results show good agreements. Results show that the MS antennas have substantially better performances, in terms of gain, return-loss bandwidth (RLBW), axial-ratio bandwidth (ARBW) and radiation pattern, than the source antennas. Moreover, the ARBW of the MS antennas is mainly determined by the MS.
Accurate diagnosis of Helicobacter pylori(H. pylori) infection is a crucial part in the effective management of many gastroduodenal diseases. Several invasive and non-invasive diagnostic tests are ...available for the detection of H. pylori and each test has its usefulness and limitations in different clinical situations. Although none can be considered as a single gold standard in clinical practice,several techniques have been developed to give the more reliable results. Invasive tests are performed via endoscopic biopsy specimens and these tests include histology,culture,rapid urease test as well as molecular methods. Developments of endoscopic equipment also contribute to the real-time diagnosis of H. pylori during endoscopy. Urea breathingtest and stool antigen test are most widely used noninvasive tests,whereas serology is useful in screening and epidemiological studies. Molecular methods have been used in variable specimens other than gastric mucosa. More than detection of H. pylori infection,several tests are introduced into the evaluation of virulence factors and antibiotic sensitivity of H. pylori,as well as screening precancerous lesions and gastric cancer. The aim of this article is to review the current options and novel developments of diagnostic tests and their applications in different clinical conditions or for specific purposes.
Abstract Background and aims Many coronary artery disease (CAD) patients exhibit chronic low-grade inflammation. Carotenoids are anti-oxidants with potential anti-inflammatory properties. Here, we ...first assessed relationships between interleukin (IL)-6 and individual carotenoids in plasma from CAD patients. Based on the results, we proceeded to assess anti-inflammatory effects of one carotenoid, lutein, in peripheral blood mononuclear cells (PBMCs) from CAD patients. Methods Lutein + zeaxanthin (isomers with lutein being dominant), β-cryptoxanthin, lycopene, α- and β-carotene and IL-6 were measured in plasma from 134 patients with stable angina (SA) and 59 patients with acute coronary syndrome. In 42 patients, plasma measurements were also performed 3 months after coronary intervention. PBMCs from SA patients were pre-treated with lutein (1, 5 and 25 μM) for 24 h followed by 24 h incubation ± lipopolysaccharide (LPS). Cell pellets were collected for IL-6 , IL-1β and TNF mRNA and intracellular lutein. Cytokine secretion was measured in cell media. Results Only lutein + zeaxanthin were inversely correlated with IL-6 in SA patients at baseline ( r = −0.366, p < 0.001) and follow-up ( r = −0.546, p < 0.001). Ex vivo , lutein was taken up by PBMCs from SA patients in a dose- and time-dependent manner. Pre-treatment with lutein dose-dependently lowered LPS-induced secretion of IL-6, IL-1β ( p < 0.01) and TNF ( p < 0.05), and also reduced IL-6 , IL-1β and TNF mRNA expression ( p < 0.05). Conclusions Clinical findings highlighted the inverse association between lutein and IL-6 in CAD patients. Anti-inflammatory effects of lutein in PBMCs from CAD patients were consolidated in ex vivo experiments. Taken together, these results show that lutein has the potential to play a role in resolution of chronic inflammation in CAD patients.
We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with ...Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinib-based chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n=33), late molecular responders (LMRs, n=35), intermediate molecular responders (IMRs, n=9) and poor molecular responders (PMRs, n=18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.
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