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).
Summary Background The avian influenza A H7N9 virus has caused infections in human beings in China since 2013. A large epidemic in 2016–17 prompted concerns that the epidemiology of the virus might ...have changed, increasing the threat of a pandemic. We aimed to describe the epidemiological characteristics, clinical severity, and time-to-event distributions of patients infected with A H7N9 in the 2016–17 epidemic compared with previous epidemics. Methods In this epidemiological study, we obtained information about all laboratory-confirmed human cases of A H7N9 virus infection reported in mainland China as of Feb 23, 2017, from an integrated electronic database managed by the China Center for Disease Control and Prevention (CDC) and provincial CDCs. Every identified human case of A H7N9 virus infection was required to be reported to China CDC within 24 h via a national surveillance system for notifiable infectious diseases. We described the epidemiological characteristics across epidemics, and estimated the risk of death, mechanical ventilation, and admission to the intensive care unit for patients admitted to hospital for routine clinical practice rather than for isolation purpose. We estimated the incubation periods, and time delays from illness onset to hospital admission, illness onset to initiation of antiviral treatment, and hospital admission to death or discharge using survival analysis techniques. Findings Between Feb 19, 2013, and Feb 23, 2017, 1220 laboratory-confirmed human infections with A H7N9 virus were reported in mainland China, with 134 cases reported in the spring of 2013, 306 in 2013–14, 219 in 2014–15, 114 in 2015–16, and 447 in 2016–17. The 2016–17 A H7N9 epidemic began earlier, spread to more districts and counties in affected provinces, and had more confirmed cases than previous epidemics. The proportion of cases in middle-aged adults increased steadily from 41% (55 of 134) to 57% (254 of 447) from the first epidemic to the 2016–17 epidemic. Proportions of cases in semi-urban and rural residents in the 2015–16 and 2016–17 epidemics (63% 72 of 114 and 61% 274 of 447, respectively) were higher than those in the first three epidemics (39% 52 of 134, 55% 169 of 306, and 56% 122 of 219, respectively). The clinical severity of individuals admitted to hospital in the 2016–17 epidemic was similar to that in the previous epidemics. Interpretation Age distribution and case sources have changed gradually across epidemics since 2013, while clinical severity has not changed substantially. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection with A H7N9 virus. Funding The National Science Fund for Distinguished Young Scholars.
Objectives: To analyze the progression manifestations and characteristics of pulmonary lesions in patients with COVID-19 by bed-side pulmonary ultrasonography. Methods: A total of 20 COVID-19 ...patients admitted to the hospital from January to March in 2020 were retrospectively recruited. All cases were diagnosed according to the "Novel Coronavirus Pneumonia Treatment Protocol (Trial 7th edition)". The imaging characteristics of bed-side pulmonary ultrasonography were analyzed and summarized during the different disease stages. Results: The average course of disease was 21.2 days, including 10.5 days of the progression period and 10.7 days of the recovery period. The ultrasound images of the patients were mainly presented as unsmoothed or interrupted pleural line, and B-line distribution was observed in all cases (20/20,100%). The "inflatable signs" in the consolidation lesion were visualized in 16 cases (16/20, 75.00%). In progressive stage, the ultrasound image changed from B-line sign to sieve-like consolidation, then the consolidation aggravated from patchy to chunk-like gradually, with the decreasing air bronchogram sign within the consolidation lesion. While the imaging characteristics of the ultrasound in the recovery stage were opposite to the progress stage, Color mode showed that the perfusion in the lesions of consolidation gradually increased as well. Conclusion: The ultrasonic manifestations of COVID-19 patients had certain characteristics in the different disease stages. The application of ultrasound in these patients could provide imaging evidence in evaluation of the disease courses and therapeutic efficacy.
Summary Background The effect of the addition of adjuvant chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to assess the ...contribution of adjuvant chemotherapy to concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone. Methods We did an open-label phase 3 multicentre randomised controlled trial at seven institutions in China. Randomisation was by a computer-generated random number code. Patients were stratified by treatment centre and randomly assigned in blocks of four. Treatment allocation was not masked. We randomly assigned patients with non-metastatic stage III or IV (except T3–4N0) nasopharyngeal carcinoma to receive concurrent chemoradiotherapy plus adjuvant chemotherapy or concurrent chemoradiotherapy alone. Patients in both groups received 40 mg/m2 cisplatin weekly up to 7 weeks, concurrently with radiotherapy. Radiotherapy was given as 2·0–2·27 Gy per fraction with five daily fractions per week for 6–7 weeks to a total dose of 66 Gy or greater to the primary tumour and 60–66 Gy to the involved neck area. The concurrent chemoradiotherapy plus adjuvant chemotherapy group subsequently received 80 mg/m2 adjuvant cisplatin and 800 mg/m2 per day fluorouracil for 120 h every 4 weeks for three cycles. Our primary endpoint was failure-free survival. We did efficacy analyses in our intention-to-treat population. Our trial is ongoing; in this report we present the 2 year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov , number NCT00677118. Findings 251 patients were assigned to the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 257 to the concurrent chemoradiotherapy alone group. After a median follow-up of 37·8 months (range 1·3–61·0), the estimated 2 year failure-free survival rate was 86% (95% CI 81–90) in the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 84% (78–88) in concurrent chemoradiotherapy only group (hazard ratio 0·74, 95% CI 0·49–1·10; p=0·13). Stomatitis was the most commonly reported grade 3 or 4 adverse event during both radiotherapy (76 of 249 patients in the concurrent chemoradiotherapy plus adjuvant chemotherapy group and 82 of 254 in the concurrent chemoradiotherapy alone group) and adjuvant chemotherapy (43 21% of 205 patients treated with adjuvant chemotherapy). Interpretation Adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve failure-free survival after concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma. Longer follow-up is needed to fully assess survival and late toxic effects, but such regimens should not, at present, be used outside well-designed clinical trials. Funding Sun Yat-sen University Clinical Research 5010 Programme (No 2007037), Science Foundation of Key Hospital Clinical Programme of Ministry of Health PR China (No 2010–178), and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2010).
Summary Background Seroprevalence data suggest that a third of the world's population has been infected with the hepatitis E virus. Our aim was to assess efficacy and safety of a recombinant ...hepatitis E vaccine, HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China) in a randomised, double-blind, placebo-controlled, phase 3 trial. Methods Healthy adults aged 16–65 years in, Jiangsu Province, China were randomly assigned in a 1:1 ratio to receive three doses of HEV 239 (30 μg of purified recombinant hepatitis E antigen adsorbed to 0·8 mg aluminium hydroxide suspended in 0·5 mL buffered saline) or placebo (hepatitis B vaccine) given intramuscularly at 0, 1, and 6 months. Randomisation was done by computer-generated permuted blocks and stratified by age and sex. Participants were followed up for 19 months. The primary endpoint was prevention of hepatitis E during 12 months from the 31st day after the third dose. Analysis was based on participants who received all three doses per protocol. Study participants, care givers, and investigators were all masked to group and vaccine assignments. This trial is registered with ClinicalTrials.gov , number NCT01014845. Findings 11 165 of the trial participants were tested for hepatitis E virus IgG, of which 5285 (47%) were seropositive for hepatitis E virus. Participants were randomly assigned to vaccine (n=56 302) or placebo (n=56 302). 48 693 (86%) participants in the vaccine group and 48 663 participants (86%) in the placebo group received three vaccine doses and were included in the primary efficacy analysis. During the 12 months after 30 days from receipt of the third dose 15 per-protocol participants in the placebo group developed hepatitis E compared with none in the vaccine group. Vaccine efficacy after three doses was 100·0% (95% CI 72·1–100·0). Adverse effects attributable to the vaccine were few and mild. No vaccination-related serious adverse event was noted. Interpretation HEV 239 is well tolerated and effective in the prevention of hepatitis E in the general population in China, including both men and women age 16–65 years. Funding Chinese National High-tech R&D Programme (863 programme), Chinese National Key Technologies R&D Programme, Chinese National Science Fund for Distinguished Young Scholars, Fujian Provincial Department of Sciences and Technology, Xiamen Science and Technology Bureau, and Fujian Provincial Science Fund for Distinguished Young Scholars.
Background Distinguishing pancreatic adenocarcinomas from other pancreatic masses remains challenging with current imaging techniques. Contrast-enhanced EUS further improved the efficacy of EUS to ...characterize pancreatic lesions. Objective To assess the accuracy of contrast-enhanced EUS for diagnosing adenocarcinoma in patients with pancreatic masses by pooling data of existing trials. Design We systematically searched the Medline, PubMed, Web of Science, Embase, and Cochrane Central Trials databases for relevant studies published. Meta-analysis was performed. Pooling was conducted in a fixed-effect model or a random-effects model. Patients Twelve studies involving 1139 patients were included. Intervention Contrast-enhanced EUS. Main Outcome Measurements Meta-analysis and meta-regression analysis. Results The pooled sensitivity of contrast-enhanced EUS for the differential diagnosis of pancreatic adenocarcinomas was 94% (95% CI, 0.91-0.95), and the specificity was 89% (95% CI, 0.85-0.92). The area under the curve under summary receiver operating characteristic was 0.9732. The pooled positive likelihood ratio was 8.09 (95% CI, 4.47-14.64), and the negative likelihood ratio was 0.08 (95% CI, 0.06-0.10). The subgroup analysis by exclusion of the outliers provided a sensitivity of 93% (95% CI, 0.91-0.95) and a specificity of 93% (95% CI, 0.89-0.95) for the differential diagnosis of pancreatic adenocarcinomas. The area under the curve under summary receiver operating characteristic was 0.9745. Limitations A small number of studies met the inclusion criteria. Conclusion Contrast-enhanced EUS is a promising, reliable modality for the differential diagnosis of pancreatic adenocarcinoma in patients with pancreatic mass lesions. The finding of a hypoenhanced lesion was a sensitive and accurate predictor of pancreatic adenocarcinomas. It seems to be a useful tool in clinical practice.
Objectives To investigate the frequency of constitutional Wilms tumor 1 gene ( WT1 ) abnormalities in children with bilateral Wilms tumor (WT) and the age of tumor onset in patients with a mutation. ...Study design Eight patients with bilateral WT were studied. High-resolution melting and direct sequencing were used to screen for the WT1 gene. Western blotting was performed to determine whether the identified mutations were associated with expressed truncated WT1 protein. Results The median age of tumor onset in patients with a mutation in the WT1 was lower (10 months) than in those without a mutation (39 months). Three novel heterozygous nonsense mutations were identified in exon 8 in peripheral blood from 3 individuals, whereas all 3 tumor tissues lacked the wild-type allele. All mutations led to a premature stop codon with truncation of the WT1 protein. In 1 patient, a truncated form of WT1 protein was identified, suggesting that development of the WT may have resulted from expression of an abnormal protein. Four distinct silent single-nucleotide polymorphisms (SNPs) were detected. All 3 patients with a pathogenic WT1 mutation had 2 synonymous SNPs, whereas only 1 of the remaining 5 patients had a single synonymous SNP ( P < .05). Conclusions Bilateral WT are associated with early presentation in pediatric patients and a high frequency of WT1 nonsense mutations in exon 8. Silent SNPs may also be involved in the development of WT.
Background Esophagectomy is the conventional treatment for Barrett's esophagus with high-grade dysplasia and intramucosal cancer. Endotherapy is an alternative treatment. Objective To compare the ...efficacy and safety of these 2 treatments. Design PubMed, Web of Science, EMBASE, Cochrane Library and momentous meeting abstracts were searched. Studies comparing endotherapy with esophagectomy were included in the meta-analysis. Pooling was conducted in a random-effects model. Setting Tertiary-care facility. Patients Seven studies involving 870 patients were included. Intervention Endotherapy and esophagectomy. Main Outcome Measurements Neoplasia remission rate, neoplasia recurrence rate, overall survival rate, neoplasia-related death, and major adverse events. Results Meta-analysis showed that there was no significant difference between endotherapy and esophagectomy in the neoplasia remission rate (relative risk RR 0.96; 95% CI, 0.91-1.01); overall survival rate at 1 year (RR 0.99; 95% CI, 0.94-1.03), 3 years (RR 1.03; 95% CI, 0.96-1.10), and 5 years (RR 1.00; 95% CI, 0.93-1.06); and neoplasia-related mortality (risk difference RD 0; 95% CI, -0.02 to 0.01). Endotherapy was associated with a higher neoplasia recurrence rate (RR 9.50; 95% CI, 3.26-27.75) and fewer major adverse events (RR 0.38; 95% CI, 0.20-0.73). Limitations Relatively small number of retrospective studies available, different types of endoscopic treatments were used. Conclusion Endotherapy and esophagectomy show similar efficacy except in the neoplasia recurrence rate, which is higher after endotherapy. Prospective, randomized, controlled trials are needed to confirm these results.
Objective Our objective was to determine if antegrade cerebral perfusion (ACP) and retrograde cerebral perfusion (RCP) combined with deep hypothermia circulatory arrest in aortic arch surgery results ...in different mortality and neurologic outcomes. Methods The Cochrane Library, Medline, EMBASE, CINAHL, Web of Science, and the Chinese Biomedical Database were searched for studies reporting on postoperative strokes, permanent neurologic dysfunction, temporary neurologic dysfunction, and all causes mortality within 30 days postoperation in aortic arch surgery. Meta-analysis for effect size, t test, and I2 for detecting heterogeneity and sensitivity analysis for assessing the relative influence of each study was performed. Results Fifteen included studies encompassed a total of 5060 patients of whom 2855 were treated with deep hypothermic circulatory arrest plus ACP and 1897 were treated with deep hypothermic circulatory arrest plus RCP. Pooled analysis showed no significant statistical difference ( P > .01) of 30-day mortality, permanent neurologic dysfunction, and transient neurologic dysfunction in the 2 groups. Before sensitivity analysis, postoperative stroke incidence in the ACP group was higher than in the RCP group (7.2% vs 4.7%; P < .01). After a study that included a different percentage of patients with a history of central neurologic events in the 2 groups was ruled out, postoperative stroke incidence in the 2 groups also showed no significant statistical difference ( P > .01). Conclusions ACP and RCP provide similar cerebral protective effectiveness combined with deep hypothermia circulatory arrest and could be selected according to the actual condition in aortic arch surgery. A high-quality randomized controlled trial is urgently needed to confirm this conclusion, especially for stroke morbidity following ACP or RCP.
Background Observational studies suggest that patients with immunoglobulin A nephropathy (IgAN) with active proliferative lesions show a good response to immunosuppressive treatment. Study Design ...Multicenter, prospective, randomized, controlled trial. Setting & Participants 176 patients with IgAN with active proliferative lesions (cellular and fibrocellular crescents, endocapillary hypercellularity, or necrosis), proteinuria with protein excretion ≥ 1.0 g/24 h, and estimated glomerular filtration rate > 30 mL/min/1.73 m2. Intervention Mycophenolate mofetil (MMF) group: MMF, 1.5 g/d, for 6 months and prednisone, 0.4 to 0.6 mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months; prednisone group: prednisone, 0.8 to 1.0 mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months. All patients were followed up for another 6 months. Outcomes The primary end point was complete remission rate at 6 and 12 months. Results At baseline, median estimated glomerular filtration rates were 90.2 and 94.3 mL/min/1.73 m2 and mean proteinuria was protein excretion of 2.37 and 2.47 g/24 h in the MMF and prednisone groups, respectively. At 6 months, complete remission rates were 37% (32 of 86 patients) and 38% (33 of 88 patients); the between-group difference was not statistically significant ( P = 0.9). At 12 months, complete remission rates were 48% (35 of 73 patients) and 53% (38 of 72 patients) in the MMF and prednisone groups, respectively; the between-group difference was not statistically significant ( P = 0.6). Incidences of Cushing syndrome and newly diagnosed diabetes mellitus were lower in the MMF group than in the prednisone group. Limitations Not all participants were treated with renin-angiotensin system blockers, relatively short follow-up. Conclusions MMF plus prednisone versus full-dose prednisone did not differ in reducing proteinuria, but patients treated with the former had fewer adverse events in patients with IgAN with active proliferative lesions.
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