To explore the prognostic value of the plasma load of Epstein-Barr viral (EBV) DNA and the tumor response to neoadjuvant chemotherapy (NACT) in advanced-stage nasopharyngeal carcinoma (NPC).
In all, ...185 consecutive patients with stage III to IVb NPC treated with NACT followed by concurrent chemoradiation therapy (CCRT) were prospectively enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS).
EBV DNA was detected in 165 (89%) patients before treatment but was undetectable in 127 (69%) patients after NACT. Detectable EBV DNA levels after NACT were correlated with poor prognosis (3-year PFS 71.8% vs 85.2%, P=.008 and 3-year DMFS 82.5% vs 92.3%, P=.013). An unsatisfactory tumor response (stable disease or disease progression) after NACT was also correlated with poor clinical outcome (3-year PFS 71.1% vs 85.9%, P=.005 and 3-year LRFS 82.7% vs 93.5%, P=.012). Multivariate analysis showed that the EBV DNA level after NACT (hazard ratio HR 2.31, 95% CI 1.18-4.54, P=.015) and the tumor response to NACT (HR 2.84, 95% CI 1.42-5.67, P=.003) were both significant prognostic factors for PFS. Multivariate analysis also showed that EBV DNA after NACT was the only significant predictor of DMFS (HR 2.99, 95% CI 1.25-7.15, P=.014) and that tumor response to NACT was the only significant predictor of LRFS (HR 3.31, 95% CI 1.21-9.07, P=.020).
Detectable EBV DNA levels and an unsatisfactory tumor response (stable disease or disease progression) after NACT serve as predictors of poor prognosis for patients with advanced-stage NPC. These findings will facilitate further risk stratification, early treatment modification, or both before CCRT.
Background In patients with vitiligo, an increased reactive oxygen species (ROS) level has been proved to be a key player during disease initiation and progression in melanocytes. Nevertheless, ...little is known about the effects of ROS on other cells involved in the aberrant microenvironment, such as keratinocytes and the following immune events. CXCL16 is constitutively expressed in keratinocytes and was recently found to mediate homing of CD8+ T cells in human skin. Objective We sought to explicate the effect of oxidative stress on human keratinocytes and its capacity to drive CD8+ T-cell trafficking through CXCL16 regulation. Methods We first detected putative T-cell skin-homing chemokines and ROS in serum and lesions of patients with vitiligo. The production of candidate chemokines was detected by using quantitative real-time PCR and ELISA in keratinocytes exposed to H2 O2 . Furthermore, the involved mediators were analyzed by using quantitative real-time PCR, Western blotting, ELISA, and immunofluorescence. Next, we tested the chemotactic migration of CD8+ T cells from patients with vitiligo mediated by the CXCL16-CXCR6 pair using the transwell assay. Results CXCL16 expression increased and showed a positive correlation with oxidative stress levels in serum and lesions of patients with vitiligo. The H2 O2 -induced CXCL16 expression was due to the activation of 2 unfolded protein response pathways: kinase RNA (PKR)–like ER kinase–eukaryotic initiation factor 2α and inositol-requiring enzyme 1α–X-box binding protein 1. CXCL16 produced by stressed keratinocytes induced migration of CXCR6+ CD8+ T cells derived from patients with vitiligo. CXCR6+ CD8+ T-cell skin infiltration is accompanied by melanocyte loss in lesions of patients with vitiligo. Conclusion Our study demonstrated that CXCL16-CXCR6 mediates CD8+ T-cell skin trafficking under oxidative stress in patients with vitiligo. The CXCL16 expression in human keratinocytes induced by ROS is, at least in part, caused by unfolded protein response activation.
Abstract Background Pathogenesis and diagnostic biomarkers for diseases can be discovered by metabolomic profiling of human fluids. If the various types of coronary artery disease (CAD) can be ...accurately characterized by metabolomics, effective treatment may be targeted without using unnecessary therapies and resources. Objectives The authors studied disturbed metabolic pathways to assess the diagnostic value of metabolomics-based biomarkers in different types of CAD. Methods A cohort of 2,324 patients from 4 independent centers was studied. Patients underwent coronary angiography for suspected CAD. Groups were divided as follows: normal coronary artery (NCA), nonobstructive coronary atherosclerosis (NOCA), stable angina (SA), unstable angina (UA), and acute myocardial infarction (AMI). Plasma metabolomic profiles were determined by liquid chromatography–quadrupole time-of-flight mass spectrometry and were analyzed by multivariate statistics. Results We made 12 cross-comparisons to and within CAD to characterize metabolic disturbances. We focused on comparisons of NOCA versus NCA, SA versus NOCA, UA versus SA, and AMI versus UA. Other comparisons were made, including SA versus NCA, UA versus NCA, AMI versus NCA, UA versus NOCA, AMI versus NOCA, AMI versus SA, significant CAD (SA/UA/AMI) versus nonsignificant CAD (NCA/NOCA), and acute coronary syndrome (UA/AMI) versus SA. A total of 89 differential metabolites were identified. The altered metabolic pathways included reduced phospholipid catabolism, increased amino acid metabolism, increased short-chain acylcarnitines, decrease in tricarboxylic acid cycle, and less biosynthesis of primary bile acid. For differential diagnosis, 12 panels of specific metabolomics-based biomarkers provided areas under the curve of 0.938 to 0.996 in the discovery phase (n = 1,086), predictive values of 89.2% to 96.0% in the test phase (n = 933), and 85.3% to 96.4% in the 3-center external sets (n = 305). Conclusions Plasma metabolomics are powerful for characterizing metabolic disturbances. Differences in small-molecule metabolites may reflect underlying CAD and serve as biomarkers for CAD progression.
Background Obsessive–compulsive disorder (OCD) is a common, heritable neuropsychiatric disorder, hypothetically underpinned by dysfunction of brain cortical-striatal-thalamic-cortical (CSTC) ...circuits; however, the extent of brain functional abnormalities in individuals with OCD is unclear, and the genetic basis of this disorder is poorly understood. We determined the whole brain functional connectivity patterns in patients with OCD and their healthy first-degree relatives. Methods We used resting-state fMRI to measure functional connectivity strength in patients with OCD, their healthy first-degree relatives and healthy controls. Whole brain functional networks were constructed by measuring the temporal correlations of all brain voxel pairs and further analyzed using a graph theory approach. Results We enrolled 39 patients with OCD, 20 healthy first-degree relatives and 39 healthy controls in our study. Compared with healthy controls, patients with OCD showed increased functional connectivity primarily within the CSTC circuits and decreased functional connectivity in the occipital cortex, temporal cortex and cerebellum. Moreover, patients with OCD and their first-degree relatives exhibited overlapping increased functional connectivity strength in the bilateral caudate nucleus, left orbitofrontal cortex (OFC) and left middle temporal gyrus. Limitations Potential confounding factors, such as medication use, heterogeneity in symptom clusters and comorbid disorders, may have impacted our findings. Conclusion Our preliminary results suggest that patients with OCD have abnormal resting-state functional connectivity that is not limited to CSTC circuits and involves abnormalities in additional large-scale brain systems, especially the limbic system. Moreover, resting-state functional connectivity strength abnormalities in the left OFC, bilateral caudate nucleus and left middle temporal gyrus may be neuroimaging endophenotypes for OCD.
Objective To compare the differences of immunological characteristics between newborn and adults, we performed high-throughput sequencing to reveal the diversity of umbilical cord blood and adult ...peripheral blood at both T-cell receptor beta chain (TRB) and immunoglobulin heavy chain (IGH) levels. Study design High-throughput sequencing was performed to analyze the expression of TRB-CDR3 and IGH-CDR3 in circulating T and B cells isolated from 20 healthy adults, 56 pregnant women, and 40 newborns. Results Our results revealed different immunological characteristics between newborn and adults, such as distinctive complementarity determining region 3 (CDR3) lengths, usage bias of variable and joining segments, random nucleotide addition, a large number of unique CDR3 peptides, and a greater repertoire diversity. Moreover, each newborn had a distinctive TRB-/IGH-CDR3 repertoire that was independent of the maternal immune status. Conclusions This study presents comprehensive, unrestricted profiles of the TRB/IGH-CDR3 repertoire of newborns, pregnant women, and healthy adults at a sequence-level resolution. Our data may contribute to a better understanding of the immune system of newborns and benefit the efficient application of umbilical cord blood transplantation in future.
Background Previous studies have demonstrated that platelet activation occurs in patients with pulmonary arterial hypertension (PAH). Mean platelet volume (MPV) and platelet distribution width (PDW) ...are two markers of platelet activation, and have recently been recognised as risk predictors of cardiovascular diseases. This study aimed to investigate whether MPV and PDW would be useful to reflect disease severity and predict prognosis in idiopathic PAH (IPAH). Methods MPV and PDW levels were measured in 82 IPAH patients without antiplatelet or anticoagulant treatment on admission and 82 healthy controls. Concurrent collected data included clinical, haemodynamic and biochemical variables. All patients were followed-up from the date of blood testing. The endpoint was all-cause mortality. Results MPV and PDW were significantly higher in patients with IPAH than in age and sex-matched control subjects (11.4 ± 0.9fl vs. 10.3 ± 0.9fL and 14.3±2.9% vs. 11.9±1.9%, respectively; p = 0.000). Pearson's correlation analysis revealed that MPV and PDW correlated positively with right ventricular systolic pressure, mean pulmonary arterial pressure and pulmonary vascular resistance. After a mean follow-up of 14±8 months, 12 patients died of right heart failure. Receiver operating characteristic analysis showed that MPV and PDW could not predict all-cause mortality. Multivariate Cox regression analysis suggested that right/left ventricular end-diastolic diameter ratio and NT-proBNP were independent predictive parameters of all-cause mortality. Conclusions Our results suggest that MPV and PDW were elevated in patients with IPAH. They could partly reflect disease severity, but did not predict prognosis.
Background Treatment of cubitus varus deformity from a malunited fracture is a challenge. Anatomically accurate correction is the key to obtaining good functional outcomes after corrective osteotomy. ...The aim of this study was to attempt to increase the accuracy of treatment by use of 3-dimensional (3D) computer-aided design. We describe a novel method for ensuring an accurate osteotomy method in the treatment of cubitus varus deformity in teenagers by means of 3D reconstruction and reverse engineering. Materials and methods Between January 2006 and May 2008, 12 male and 6 female patients with cubitus varus deformities underwent scanning with spiral computed tomography (CT) preoperatively. The mean age was 15.7 years, ranging from 13 to 19 years. Three-dimensional CT image data of the affected and contralateral normal bones of cubitus were transferred to a computer workstation. Three-dimensional models of cubitus were reconstructed by use of MIMICS software. The 3D models were then processed by Imageware software. An osteotomy template that best fitted the angle and range of osteotomy was “reversely” built from the 3D model. These templates were manufactured by a rapid prototyping machine. The osteotomy templates guide the osteotomy of cubitus. Results An accurate angle of osteotomy was confirmed by postoperative radiography. After 12 to 24 months’ follow-up, the mean postoperative carrying angle in 18 patients with cubitus varus deformity was 7.3° (range, 5° to 11°), with a mean correction of 21.9° (range, 12° to 41°). Conclusions The patient-specific template technique is easy to use, can simplify the surgical act, and generates highly accurate osteotomy in cubitus varus deformity in teenagers.
To evaluate the effectiveness of deep brain stimulation (DBS) of the globus pallidus internus (GPi) on tic severity and common comorbidities in patients with severe Tourette syndrome that is ...refractory to pharmacological treatment and psychotherapy.
We retrospectively assessed the long-term clinical outcomes of 13 patients with treatment-refractory Tourette syndrome who underwent DBS targeting the GPi at the Beijing Tiantan Hospital from January 1, 2006, through May 31, 2013. The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale, and the secondary outcome was a change in associated behavioral disorders and mood as measured by the Gilles de la Tourette Syndrome-Quality of Life Scale assessment.
Compared with baseline, the mean reduction in the total Yale Global Tic Severity Scale scores at last follow-up (mean, 41.9 months; range, 13-80 months) was 52.1% (range, 4.3%-83.6%), and the mean improvement rates at 1 month, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 or more months were 11.8%, 20.0%, 26.8%, 36.7%, 44.7%, 49.0%, and 56.7%, respectively. A paired-sample t test revealed significant improvement of tic symptoms after 6 months of DBS programming (P<.05). The Gilles de la Tourette Syndrome-Quality of Life Scale score improved by a mean of 45.7% (range, 11.0%-77.2%).
This study is currently the largest reported GPi DBS case series of patients with treatment-refractory TS with the longest follow-up. Our results support the potential beneficial effect of GPi DBS on disabling tic reduction and improvement of quality of life.
Background Detection and differentiation of esophageal squamous neoplasia (ESN) are of value in improving patient outcomes. Probe-based confocal laser endomicroscopy (pCLE) can serve in targeted ...biopsies in the diagnosis of GI neoplasia. However, its performance in ESN has not yet been reported. Objective To investigate the diagnostic value of pCLE for early ESN screened by high-definition virtual chromoendoscopy (I-Scan) and verified by Lugol chromoendoscopy and histopathology. Design Prospective and noninferiority trial. Setting Single center in China. Patients Patients were enrolled who (1) previously had histologically verified early ESN or (2) were about to undergo screening endoscopy and were 50 to 80 years of age between February 2013 and February 2014. Interventions The esophagus was investigated sequentially by white-light endoscopy, I-Scan, then pCLE and iodine chromoendoscopy. The results were interpreted and compared with histopathologic results. Main Outcome Measurements Diagnostic characteristics of pCLE and I-Scan. Results In total, 356 patients were enrolled. In all, 42 patients were histologically proven to have 47 neoplasias. The diagnostic value of pCLE for ESN during ongoing endoscopy has a sensitivity, specificity, and accuracy of 94.6%, 90.7%, and 92.3%, respectively. The interobserver and intraobserver agreement was good and excellent, with κ values of 0.699 and 0.895, respectively. The detection rate by using I-Scan and Lugol chromoendoscopy was 10.4% and 12.9%, respectively ( P < .01 for noninferiority). Limitations Single center. Conclusions pCLE shows promise in diagnosing and differentiating ESN in vivo. The screening performance of I-Scan in the detection of ESN is noninferior to that of iodine chromoendoscopy.
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