Summary Background The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is ...unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial. Methods We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III–IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18–59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2 on day 1), intravenous cisplatin (60 mg/m2 on day 1), and continuous intravenous fluorouracil (600 mg/m2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov , number NCT01245959. Findings Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38–49), 3-year failure-free survival was 80% (95% CI 75–85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66–78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48–0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 42% vs 17 7%), leucopenia (98 41% vs 41 17%), and stomatitis (98 41% vs 84 35%). Interpretation Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities. Funding Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).
Background Capsule endoscopy (CE) has been widely used in clinical practice. Objective To provide systematically pooled results on the indications and detection, completion, and retention rates of ...small-bowel CE. Design A systematic review. Main Outcome Measurements We searched the PubMed database (2000-2008) for original articles relevant to small-bowel CE for the evaluation of patients with small-bowel signs and symptoms. Data on the total number of capsule procedures, the distribution of different indications for the procedures, the percentages of procedures with positive detection (detection rate), complete examination (completion rate), or capsule retention (retention rate) were extracted and/or calculated, respectively. In addition, the detection, completion, and retention rates were also extracted and/or calculated in relation to indications such as obscure GI bleeding (OGIB), definite or suspected Crohn's disease (CD), and neoplastic lesions. Results A total of 227 English-language original articles involving 22,840 procedures were included. OGIB was the most common indication (66.0%), followed by the indication of only clinical symptoms reported (10.6%), and definite or suspected CD (10.4%). The pooled detection rates were 59.4%; 60.5%, 55.3%, and 55.9%, respectively, for overall, OGIB, CD, and neoplastic lesions. Angiodysplasia was the most common reason (50.0%) for OGIB. The pooled completion rate was 83.5%, with the rates being 83.6%, 85.4%, and 84.2%, respectively, for the 3 indications. The pooled retention rates were 1.4%, 1.2%, 2.6%, and 2.1%, respectively, for overall and the 3 indications. Limitations Inclusion and exclusion criteria were loosely defined. Conclusions The pooled detection, completion, and retention rates are acceptable for total procedures. OGIB is the most common indication for small-bowel CE, with a high detection rate and low retention rate. In addition, angiodysplasia is the most common finding in patients with OGIB. A relatively high retention rate is associated with definite or suspected CD and neoplasms.
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 Objective This study was conducted to explore the role of microRNA (miR)-30a in the development of aortic dissection. Methods Human aortic specimens of aortic dissections and aneurysms were ...harvested. Aortic specimens from donors for heart transplantation were used as control. Rat aortic vascular smooth muscle cells (VSMCs) were transfected with agomiR-30a or antagomiR-30a and control cells were incubated with empty vectors. Rats were pretreated with agomiR-30a or antagomiR-30a (5×107 TU/every 3days, for 4 weeks), while empty vectors were infused to controls. Acute aortic dissection was induced by subcutaneous infusion of angiotensin II (1μg·kg-1 ·min-1 for 24h). Protein expressions of lysyl oxidase (LOX), elastin and gene expression of miR-30a were measured in VSMCs, human and rat aortic specimens by western blot and qRT-PCR. Results Gene expression of miR-30a in patients with aortic dissections was much higher, while protein abundances of LOX and elastin were significantly lower ( P <0.05, vs control, respectively). Transfection of agomiR-30a markedly decreased the luciferase activity of LOX in VSMCs of wild type but not of LOX-3’UTR mutant ( P =0.002). In cultured VSMCs, transfection of agomiR-30a dramatically enhanced the gene expression of miR-30a and down-regulated the protein abundances of LOX and elastin ( P <0.05, vs controls, respectively). Pretreatment with agomiR-30a in vivo enhanced the miR-30a expression and down-regulated protein abundances of LOX and elastin in rat aortas ( P <0.05, vs controls, respectively). The ratio of dissection in rats pretreated with agomiR-30a was much higher ( P =0.003, vs control). Conclusions Overexpression of miR-30a contributes to the development of aortic dissection, possibly by targeting LOX.
Abstract Animal and imaging study evidence favors early reperfusion for acute myocardial infarction (AMI). However, in clinical trials the effect of symptom-onset-to-balloon (S2B) time on clinical ...outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) has been inconsistent. Moreover, there is few data regarding the ischemic time in China. A total of 3877 consecutive STEMI patients with available S2B time undergoing pPCI from January 2013 to September 2014 at 108 hospitals that participated in the China Acute Myocardial Infarction (CAMI) registry were included and stratified into three S2B groups: <6 h, 6-12 h, >12 h. S2B time was tested in multivariate logistic regression analyses as an independent risk factor of mortality (primary outcome), major adverse cardiovascular and cerebrovascular events (MACCE) and impaired myocardial perfusion (secondary outcomes). The median S2B time was 5.5 (3.75-8.50) hours. Longer S2B time was associated with higher in-hospital mortality (<6 h: 2.7%; 6-12 h: 3.4%; >12 h: 4.9%; P=0.047) and ST-segment resolution <50% (<6 h: 16.7%; 6-12 h: 19.2%; >12 h: 24.3%; P=0.002) but not MACCE. In multivariate adjusted analysis, S2B>12 h remained associated with ST-segment resolution<50% (OR=1.53, 95% CI 1.16-2.01, P=0.002), but not with in-hospital mortality (1.673 0.95-2.94, P=0.073). In conclusion, median S2B time in STEMI patients undergoing pPCI was longer than that in registry studies from other countries. Longer S2B time was associated with impaired myocardial perfusion but not with in-hospital mortality or MACCE.
Abstract Background context Pedicle subtraction osteotomy (PSO) is the most commonly recommended technique for the correction of local post-traumatic thoracolumbar deformity; however, the surgical ...results are not always satisfactory because the possibly damaged upper disc is preserved, and all the posterior elements are resected. Purpose The aim was to compare the results of standard PSO and modified PSO in the treatment of post-traumatic thoracolumbar kyphosis. Study design This was a retrospective multicenter comparative clinical study. Patient sample A total of 86 patients were included in the final analysis. Outcome measures The outcome measures included local Cobb angle of the kyphosis, visual analog scale (VAS) score, and Oswestry disability index (ODI) score. Methods The upper disc was resected, and the inferior wall of the index pedicle and the lower facet joint were preserved in the modified PSO. Patients with focal kyphosis greater than 30° who were treated with one-level osteotomy, without the presence of spine neoplasm, infection, or previous surgery, were included. The measurements included the VAS score, ODI score, and preoperative and postoperative Cobb angles. Results Forty-two patients in the modified PSO group and 44 in the standard PSO group were included in the final analysis. The mean surgical time and blood loss were similar between the two groups. Both the VAS and ODI scores had improved significantly at the final follow-up in the two groups. The mean Cobb angle significantly improved from 39.6° to 5.6° in the modified PSO group and from 39.1° to 4.8° in the standard PSO group, with no significant difference between the two groups preoperatively or at the final follow-up. Conclusions The modified PSO provides an alternative method with which to correct kyphotic deformity in patients with post-traumatic thoracolumbar kyphosis.
Abstract Background context Thoracic myelopathy caused by multilevel (three or more levels) ossification of the ligamentum flavum (OLF) is rare. Little is known about its clinical features, and the ...surgical outcomes along with its related factors are also unclear. Purpose To describe the clinical features, assess the safety and effectiveness of surgical decompression, and determine the prognostic factors relevant for patients with thoracic myelopathy caused by multilevel OLF. Study design/setting A retrospective clinical study. Patient sample Seventy-five consecutive multilevel OLF patients who underwent surgical decompression were analyzed. Outcome measures Modified Japanese Orthopedic Association (JOA) scale and the recovery rate. Methods Patients who underwent surgical decompression for symptomatic multilevel OLF during January 1996 to June 2010 were all included. Clinical data were collected from medical and operative records; patients were evaluated by using the JOA scale preoperatively and during the follow-up. Correlations between the surgical outcome and various factors were also analyzed. Results Forty-three men and 32 women with a mean age of 54.7 years (range 36–78 years) were included. The mean number of involved levels is 4.6 and contiguous OLF presented in 73.3% of these patients. The most common involved levels were T10/T11 (15.4%), T9/T10 (13.3%), and T11/T12 (12.5%). Coexisting spinal disorders were found in 41 patients (54.7%). Preoperative evaluation showed the mean JOA score was 5.8±1.7; 37.3% of these patients had mild myelopathy, 53.3% had moderate myelopathy, and 9.3% had severe myelopathy. All patients received posterior laminectomy. The JOA score (mean 8.2±2.1) significantly increased postoperatively (p<.05), and multiple regression analysis showed that preoperative duration of symptoms and preoperative JOA score were important predictors of surgical outcome. Conclusions Laminectomy with partially internal fixation is safe and effective in treatment of patients with symptomatic multilevel OLF. The results of our study show that preoperative JOA score and preoperative duration of symptoms were important predictors for the clinical outcome.
Abstract Background Late gadolinium enhancement (LGE) is a standard method to evaluate myocardial fibrosis, but restricted due to contrast agent contraindications. Non-contrast T1rho can generate ...endogenous contrast, and detect fibrosis in chronic myocardial infarction. However, T1rho for hypertrophic cardiomyopathy (HCM) patients is still unreported. The present study aimed to investigate T1rho for fibrotic assessment and the clinical implication in HCM patients. Methods 18 HCM patients and 8 controls underwent T1rho, cine, and LGE cardiac magnetic resonance (CMR). T1rho relaxation time maps were created. Left ventricular (LV) parameters assessed included wall thickness, wall thickening, chamber volumes, ejection function, and fibrotic size. New York Heart Association (NYHA) functional classification was conducted. Results Hyper-T1rho value was identified in 12 HCM patients, consistent with LGE. The mean T1rho values of controls, LGE-negative patients, and remote myocardium of LGE-positive patients were 42.2 ± 1.6 ms, 43.9 ± 2.5 ms, and 42.5 ± 1.2 ms respectively, and these values showed no significant difference (all p > 0.05). T1rho-3-SD and T1rho-4-SD fibrotic sizes (32.5 ± 14.0% and 25.1 ± 11.5%) did not differ from LGE fibrotic size (28.1 ± 11.2%) (both p > 0.05). For the fibrotic size, T1rho-3-SD method obtained the strongest correlation with LGE ( r = 0.88, p < 0.001), and T1rho-4-SD obtained the minimal mean difference with LGE (−3.1%; −15.2 to 9.1%), compared with other SDs. All the fibrotic sizes assessed by both methods correlated directly with LV maximal end-diastolic thickness (all p < 0.05). Negative correlation was found between T1rho-4-SD fibrotic size and LV ejection fraction ( r = −0.49, p = 0.11). T1rho-4-SD fibrotic size showed positive correlation with NYHA class ( r = 0.46, p = 0.13). Conclusions T1rho CMR has potential to detect fibrosis in HCM patients. 4-SD may be the appropriate threshold for assessment.
Summary Background The combination of stent insertion and single high-dose brachytherapy is a feasible and safe palliative treatment regimen in patients with unresectable oesophageal cancer. We aimed ...to further assess the efficacy of this treatment strategy compared to a conventional covered stent in patients with dysphagia caused by unresectable oesophageal cancer. Methods In this multicentre, single-blind, randomised, phase 3 trial, we enrolled patients with unresectable oesophageal cancer from 16 hospitals in China. We included adult patients (aged ≥20 years) with progressive dysphagia, unresectable tumours due to extensive lesions, metastases, or poor medical condition, and with clear consciousness, cooperation, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–3. Eligible patients were randomly assigned (in 1:1 ratio, no stratification) to receive either a stent loaded with125 iodine radioactive seeds (irradiation group) or a conventional oesophageal stent (control group). The primary endpoint was overall survival. Survival analyses were done in a modified intention-to-treat group. This study is registered with ClinicalTrials.gov , number NCT01054274. Findings Between Nov 1, 2009, and Oct 31, 2012, 160 patients were randomly assigned to receive treatment with either an irradiation stent (n=80) or a conventional stent (n=80). During a median follow-up of 138 days (IQR 72–207), 148 stents (73 in the irradiation group and 75 in the control group) were successfully placed into the diseased oesophagus in 148 participants. Median overall survival was 177 days (95% CI 153–201) in the irradiation group versus 147 days (124–170) in the control group (p=0·0046). Major complications and side-effects of the treatment were severe chest pain (17 23% of 73 patients in the irradiation group vs 15 20% of 75 patents in the control group), fistula formation (six 8% vs five 7%), aspiration pneumonia (11 15% vs 14 19%), haemorrhage (five 7% vs five 7%), and recurrent dysphagia (21 28% vs 20 27%). Interpretation In patients with unresectable oesophageal cancer, the insertion of an oesophageal stent loaded with125 iodine seeds prolonged survival when compared with the insertion of a conventional covered self-expandable metallic stent. Funding National High-tech Research Foundation of China, National Basic Research Program of China, Jiangsu Provincial Special Program of Medical Science, National Scientific and Technical Achievement Translation Foundation, and National Natural Science Foundation of China.
Background and Aims Image quality can be guaranteed with the conventional dosage of fluorescein sodium in probe-based confocal laser endomicroscopy (pCLE). However, yellow discoloration of the skin ...seriously affects daily life and simultaneously increases the risk of adverse events such as allergic reactions. The aim of this study was to test whether a lower dosage of fluorescein sodium can provide satisfactory image quality and to compare the diagnostic accuracy of gastric intestinal metaplasia (GIM) through a randomized blind controlled trial. Methods Consecutive patients were randomly assigned to different doses of fluorescein sodium. Image quality was determined by the endoscopists’ subjective assessments and signal-to-noise ratio (SNR) assessment systems. Skin discoloration was tested using a neonatal transcutaneous jaundice detector. In addition, consecutive patients with a known or suspected diagnosis of GIM were examined by pCLE with the lower dose and the traditional dose. Results Only 0.01 mL/kg dose of 10% fluorescein sodium led to a significant decrease in image quality ( P < .05), and a dose of 0.02 mL/kg had the highest SNR value ( P < .05). There were no significant differences in skin discoloration between the 0.01 mL/kg and 0.02 mL/kg doses ( P = .148) and no statistical difference in the diagnostic accuracy of pCLE for GIM between the 0.02 mL/kg and 0.10 mL/kg doses ( P > .05). The kappa values for the correlation between pCLE and histopathology were 0.867 (95% confidence interval, 0.782–0.952) and 0.891 (95% confidence interval, 0.811–0.971). Conclusions The 0.02 mL/kg dose of 10% fluorescein sodium seems to be the best dose for pCLE in the upper GI tract, with comparable image quality with the conventional dose and insignificant skin discoloration. This dose is also very efficient for the diagnosis of GIM.
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