Summary Background Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to ...assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). Methods We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov , number NCT00412061. Findings 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7–21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4–14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59–1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62% vs 14%), rash (37% vs 12%), fatigue (31% vs 23%), and diarrhoea (27% vs 16%). Interpretation Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. Funding Novartis Pharmaceuticals.
Background Double balloon endoscopy (DBE) and videocapsule endoscopy (VCE) have been useful in managing obscure GI bleeding (OGIB). Objective This study evaluated the usefulness of DBE for diagnosis, ...treatment, and prognosis of OGIB and compared diagnostic yield between DBE and VCE in Japan. Methods Detection rates of abnormalities and diagnostic yields between VCE and DBE were compared in 74 patients at 5 centers. Of 244 patients who underwent DBE at Nagoya University Hospital, 130 (53%) with OGIB were enrolled for investigation of therapeutic procedures. Setting Seven Japanese medical centers. Patients Of 1034 patients who underwent DBE between September 2000 and December 2005 at 7 medical centers, 479 (46%) with OGIB were enrolled. Results Overall diagnostic yield of DBE for OGIB was 277 of 479 (58%). In patients with overt-ongoing bleeding, overt-previous bleeding of sporadic type, overt-previous bleeding of first attack only, occult bleeding with continuous positive fecal occult blood test (FOBT), or occult bleeding with 1 positive FOBT with iron deficiency anemia, diagnostic yield was 24 of 31 (77%), 179 of 310 (58%), 34 of 72 (47%), 24 of 35 (71%), and 56 of 93 (60%), respectively. Regarding positive findings in 277 patients, ulcers or erosions (53%) were the most frequent, followed by angiodysplasia (23%), tumors or polyps (22%), and diverticula (4%). Diagnoses in these patients were as follows: chronic inflammatory diseases (24%), vascular diseases (24%), tumor or polyps (21%), drug or radiation injury (7%), other small-bowel diseases (7%), upper GI diseases (9%), colorectal diseases (9%), and biliary disease (0.4%). Small-bowel diseases were confirmed in 226 patients (47%). Comparison of overall detection rate of abnormalities in the small bowel between VCE (65%) and DBE (53%) was not significantly different, nor was that of overall diagnostic yield between VCE (50%) and DBE (53%). Eight acute pancreatitis and 4 perforation episodes occurred with no mortalities at DBE. Of 130 patients at Nagoya University Hospital, 78 (60%) were diagnosed with small-bowel diseases and underwent treatments as follows: medication or observation only (n = 30), enteroscopic therapies (electrocoagulation in 21, clipping in 4, and polypectomy in 3), and surgery (n = 22). Small-bowel vascular diseases were more prone to rebleeding than small-bowel nonvascular diseases in patients without surgical treatment at a median follow-up of 423 days. Conclusions DBE was relatively safe and useful for diagnosis and treatment of OGIB. A spectrum of small-bowel diseases presenting with OGIB in Japan may be distinct from that in the Western world.
Summary Background Human infection with avian influenza A H7N9 virus emerged in eastern China in February, 2013, and has been associated with exposure to poultry. We report the clinical and ...microbiological features of patients infected with influenza A H7N9 virus and compare genomic features of the human virus with those of the virus in market poultry in Zhejiang, China. Methods Between March 7 and April 8, 2013, we included hospital inpatients if they had new-onset respiratory symptoms, unexplained radiographic infiltrate, and laboratory-confirmed H7N9 virus infection. We recorded histories and results of haematological, biochemical, radiological, and microbiological investigations. We took throat and sputum samples, used RT-PCR to detect M, H7, and N9 genes, and cultured samples in Madin-Darby canine kidney cells. We tested for co-infections and monitored serum concentrations of six cytokines and chemokines. We collected cloacal swabs from 86 birds from epidemiologically linked wet markets and inoculated embryonated chicken eggs with the samples. We identified and subtyped isolates by RT-PCR sequencing. RNA extraction, complementary DNA synthesis, and PCR sequencing were done for one human and one chicken isolate. We characterised and phylogenetically analysed the eight gene segments of the viruses in the patient's and the chicken's isolates, and constructed phylogenetic trees of H, N, PB2, and NS genes. Findings We identified four patients (mean age 56 years), all of whom had contact with poultry 3–8 days before disease onset. They presented with fever and rapidly progressive pneumonia that did not respond to antibiotics. Patients were leucopenic and lymphopenic, and had impaired liver or renal function, substantially increased serum cytokine or chemokine concentrations, and disseminated intravascular coagulation with disease progression. Two patients died. Sputum specimens were more likely to test positive for the H7N9 virus than were samples from throat swabs. The viral isolate from the patient was closely similar to that from an epidemiologically linked market chicken. All viral gene segments were of avian origin. The H7 of the isolated viruses was closest to that of the H7N3 virus from domestic ducks in Zhejiang, whereas the N9 was closest to that of the wild bird H7N9 virus in South Korea. We noted Gln226Leu and Gly186Val substitutions in human virus H7 (associated with increased affinity for α-2,6-linked sialic acid receptors) and the PB2 Asp701Asn mutation (associated with mammalian adaptation). Ser31Asn mutation, which is associated with adamantane resistance, was noted in viral M2. Interpretation Cross species poultry-to-person transmission of this new reassortant H7N9 virus is associated with severe pneumonia and multiorgan dysfunction in human beings. Monitoring of the viral evolution and further study of disease pathogenesis will improve disease management, epidemic control, and pandemic preparedness. Funding Larry Chi-Kin Yung, National Key Program for Infectious Diseases of China.
To evaluate candidate fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging biomarkers for head-and-neck chemoradiotherapy outcomes in the cooperative group trial ...setting.
Radiation Therapy Oncology Group (RTOG) protocol 0522 patients consenting to a secondary FDG-PET/CT substudy were serially imaged at baseline and 8 weeks after radiation. Maximum standardized uptake value (SUVmax), SUV peak (mean SUV within a 1-cm sphere centered on SUVmax), and metabolic tumor volume (MTV) using 40% of SUVmax as threshold were obtained from primary tumor and involved nodes.
Of 940 patients entered onto RTOG 0522, 74 were analyzable for this substudy. Neither high baseline SUVmax nor SUVpeak from primary or nodal disease were associated with poor treatment outcomes. However, primary tumor MTV above the cohort median was associated with worse local-regional control (hazard ratio 4.01, 95% confidence interval 1.28-12.52, P=.02) and progression-free survival (hazard ratio 2.34, 95% confidence interval 1.02-5.37, P=.05). Although MTV and T stage seemed to correlate (mean MTV 6.4, 13.2, and 26.8 for T2, T3, and T4 tumors, respectively), MTV remained a strong independent prognostic factor for progression-free survival in bivariate analysis that included T stage. Primary MTV remained prognostic in p16-associated oropharyngeal cancer cases, although sample size was limited.
High baseline primary tumor MTV was associated with worse treatment outcomes in this limited patient subset of RTOG 0522. Additional confirmatory work will be required to validate primary tumor MTV as a prognostic imaging biomarker for patient stratification in future trials.
Sensitive probing of temperature variations on nanometre scales is an outstanding challenge in many areas of modern science and technology. In particular, a thermometer capable of subdegree ...temperature resolution over a large range of temperatures as well as integration within a living system could provide a powerful new tool in many areas of biological, physical and chemical research. Possibilities range from the temperature-induced control of gene expression and tumour metabolism to the cell-selective treatment of disease and the study of heat dissipation in integrated circuits. By combining local light-induced heat sources with sensitive nanoscale thermometry, it may also be possible to engineer biological processes at the subcellular level. Here we demonstrate a new approach to nanoscale thermometry that uses coherent manipulation of the electronic spin associated with nitrogen-vacancy colour centres in diamond. Our technique makes it possible to detect temperature variations as small as 1.8 mK (a sensitivity of 9 mK Hz(-1/2)) in an ultrapure bulk diamond sample. Using nitrogen-vacancy centres in diamond nanocrystals (nanodiamonds), we directly measure the local thermal environment on length scales as short as 200 nanometres. Finally, by introducing both nanodiamonds and gold nanoparticles into a single human embryonic fibroblast, we demonstrate temperature-gradient control and mapping at the subcellular level, enabling unique potential applications in life sciences.
Statistical mechanics underlies our understanding of macroscopic quantum systems. It is based on the assumption that out-of-equilibrium systems rapidly approach their equilibrium states, forgetting ...any information about their microscopic initial conditions. This fundamental paradigm is challenged by disordered systems, in which a slowdown or even absence of thermalization is expected. We report the observation of critical thermalization in a three dimensional ensemble of ∼10^{6} electronic spins coupled via dipolar interactions. By controlling the spin states of nitrogen vacancy color centers in diamond, we observe slow, subexponential relaxation dynamics and identify a regime of power-law decay with disorder-dependent exponents; this behavior is modified at late times owing to many-body interactions. These observations are quantitatively explained by a resonance counting theory that incorporates the effects of both disorder and interactions.
A quantum spin liquid is an exotic quantum state of matter in which spins are highly entangled and remain disordered down to zero temperature. Such a state of matter is potentially relevant to ...high-temperature superconductivity and quantum-information applications, and experimental identification of a quantum spin liquid state is of fundamental importance for our understanding of quantum matter. Theoretical studies have proposed various quantum-spin-liquid ground states, most of which are characterized by exotic spin excitations with fractional quantum numbers (termed 'spinons'). Here we report neutron scattering measurements of the triangular-lattice antiferromagnet YbMgGaO
that reveal broad spin excitations covering a wide region of the Brillouin zone. The observed diffusive spin excitation persists at the lowest measured energy and shows a clear upper excitation edge, consistent with the particle-hole excitation of a spinon Fermi surface. Our results therefore point to the existence of a quantum spin liquid state with a spinon Fermi surface in YbMgGaO
, which has a perfect spin-1/2 triangular lattice as in the original proposal of quantum spin liquids.
Abstract Objectives The purpose of this study was to investigate diffuse myocardial fibrosis in patients with systolic heart failure (SHF) and in patients with heart failure with preserved ejection ...fraction (HFpEF) and the association with diastolic dysfunction of the left ventricle (LV). Background Increased diffuse myocardial fibrosis may impair LV diastolic function. However, no study has verified the association between the degree of diffuse myocardial fibrosis and the severity of impaired diastolic function in SHF and HFpEF. Methods Forty patients with SHF, 62 patients with HFpEF, and 22 patients without HF underwent cardiac magnetic resonance (CMR), including T1 mapping and cine CMR on a 3-T system. Extracellular volume fraction (ECV), a measure of diffuse myocardial fibrosis, was quantified from T1 mapping. Systolic and diastolic functions of the LV were assessed by cine CMR. The ECV values and LV functional indexes were compared among the 3 groups. Associations between ECV and LV diastolic function were also investigated. Results Compared with patients without HF, significantly higher ECV was found in patients with SHF (31.2% interquartile range (IQR): 29.0% to 34.1% vs. 27.9% IQR: 26.2% to 29.4%, p < 0.001) and HFpEF (28.9% IQR: 27.8% to 31.3% vs. 27.9% IQR: 26.2% to 29.4%, p = 0.006). Peak filling rate, a diastolic functional index assessed by cine CMR, was significantly decreased in patients with SHF (1.00 s−1 IQR: 0.79 to 1.49 s−1 vs. 3.86 s−1 IQR: 3.34 to 4.48 s−1 , p < 0.001) and HFpEF (2.89 s−1 IQR: 2.13 to 3.50 s−1 vs. 3.86 s−1 IQR: 3.34 to 4.48 s−1 , p < 0.001). Myocardial ECV was significantly correlated with peak filling rate in the HFpEF group (r = −0.385, p = 0.002), but no correlation was found in the SHF and non-HF groups (r = 0.030, p = 0.856 and r = −0.238, p = 0.285, respectively). Conclusions In patients with HF, only those with HFpEF show a significant correlation between increased diffuse myocardial fibrosis and impaired diastolic function. Diffuse myocardial fibrosis plays a unique role in the pathogenesis of HFpEF.
Objectives To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. Methods We performed PubMed ...database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. Results The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. Conclusion Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions.
Background We previously reported that magnifying narrow-band imaging (M-NBI) is a high-performance diagnostic tool for small, depressed gastric cancer. However, an efficient diagnostic strategy ...using endoscopic findings has not been fully elucidated. Objective To identify the endoscopic findings that contribute to accurate diagnosis of small, depressed gastric cancer and to propose the ideal diagnostic approach to such lesions. Design Post-hoc analysis of a prospective, randomized, controlled trial. Setting Nine hospitals. Patients Three hundred fifty-three patients with small, depressed gastric lesions. Interventions In the M-NBI group (n = 177), cancer diagnosis was made with diagnostic criteria including a demarcation line (DL) and an irregular microvascular pattern (IMVP). In the conventional white-light imaging (C-WLI) group (n = 176), diagnostic criteria were both an irregular margin and a spiny depressed area. In the C-WLI group, M-NBI was performed after C-WLI diagnosis. Main Outcome Measurements The diagnostic performance of each criterion in M-NBI alone, C-WLI, and M-NBI after C-WLI was investigated. Results M-NBI after C-WLI ultimately showed the best diagnostic performance in each diagnostic criterion. In M-NBI after C-WLI, evaluation of DL is technically easier than that of IMVP, and DL alone had a high sensitivity (95%) and negative predictive value (99%). The IMVP in M-NBI after C-WLI had a high sensitivity and specificity (95% and 96%, respectively) for diagnosis of cancer. Limitations Lesions were limited to the small, depressed type. Conclusions For a diagnosis using M-NBI after C-WLI, identification of DL is the first step, and subsequent inspection of IMVP diagnosed by DL is an efficient strategy.
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