Summary Background Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre ...randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia. Methods This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14–59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m2 per day on days 1–7, cytarabine 100 mg/m2 per day on days 1–7, and aclarubicin 20 mg/day on days 1–7 (HAA); homoharringtonine 2 mg/m2 per day on days 1–7, cytarabine 100 mg/m2 per day on days 1–7, and daunorubicin 40 mg/m2 per day on days 1–3 (HAD); or daunorubicin 40–45 mg/m2 per day on days 1–3 and cytarabine 100 mg/m2 per day on days 1–7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m2 every 12 h on days 1–3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention-to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. Findings We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0·0108); 3-year event-free survival was 35·4% (95% CI 28·6–42·2) versus 23·1% (95% CI 17·4–29·3; p=0·0023). 133 of 198 patients (67%) in the HAD group had complete remission ( vs DA, p=0·20) and 3-year event-free survival was 32·7% (95% CI 26·1–39·5; vs DA, p=0·08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 5·8%) and HAD (13 of 198 6·6%) groups died within 30 days than in the DA group (two of 205 1%; p=0·0067 vs HAA; p=0·0030 vs HAD). Interpretation A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia. Funding Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project.
Summary Background Major adjuvant treatments for pancreatic adenocarcinoma include fluorouracil, gemcitabine, chemoradiation, and chemoradiation plus fluorouracil or gemcitabine. Since the optimum ...regimen remains inconclusive, we aimed to compare these treatments in terms of overall survival after tumour resection and in terms of grade 3–4 toxic effects with a systematic review and random-effects Bayesian network meta-analysis. Methods We searched PubMed, trial registries, and related reviews and abstracts for randomised controlled trials comparing the above five treatments with each other or observation alone before April 30, 2013. We estimated relative hazard ratios (HRs) for death and relative odds ratios (ORs) for toxic effects among different therapies by combining HRs for death and survival durations and ORs for toxic effects of included trials. We assessed the effects of prognostic factors on survival benefits of adjuvant therapies with meta-regression. Findings Ten eligible articles reporting nine trials were included. Compared with observation, the HRs for death were 0·62 (95% credible interval 0·42–0·88) for fluorouracil, 0·68 (0·44–1·07) for gemcitabine, 0·91 (0·55–1·46) for chemoradiation, 0·54 (0·15–1·80) for chemoradiation plus fluorouracil, and 0·44 (0·10–1·81) for chemoradiation plus gemcitabine. The proportion of patients with positive lymph nodes was inversely associated with the survival benefit of adjuvant treatments. After adjustment for this factor, fluorouracil (HR 0·65, 0·49–0·84) and gemcitabine (0·59, 0·41–0·83) improved survival compared with observation, whereas chemoradiation resulted in worse survival than fluorouracil (1·69, 1·12–2·54) or gemcitabine (1·86, 1·04–3·23). Chemoradiation plus gemcitabine was ranked the most toxic, with significantly higher haematological toxic effects than second-ranked chemoradiation plus fluorouracil (OR 13·33, 1·01–169·36). Interpretation Chemotherapy with fluorouracil or gemcitabine is the optimum adjuvant treatment for pancreatic adenocarcinoma and reduces mortality after surgery by about a third. Chemoradiation plus chemotherapy is less effective in prolonging survival and is more toxic than chemotherapy. Funding None.
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.
Metformin is recommended as a first-line treatment for patients with type 2 diabetes. However, use of this drug has been contraindicated in individuals with impaired kidney function because of the ...perceived risk of lactic acidosis. Evidence now supports cautious use of metformin in people with mild-to-moderate chronic kidney disease. However, studies examining the use of metformin in patients with advanced chronic kidney disease are lacking. We aimed to assess the safety of metformin in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease.
We did a retrospective, observational, cohort study of patients with type 2 diabetes who were enrolled prospectively in Taiwan's national health insurance research database between Jan 1, 2000, and June 30, 2009, and had follow-up data until Dec 31, 2009. We included individuals with a serum creatinine concentration greater than 530 μmol/L, which is approximately equivalent to stage 5 chronic kidney disease. From a consecutive sample of 12 350 patients with type 2 diabetes and chronic kidney disease, 1005 used metformin and 11 345 were non-users. We matched users and non-users of metformin by propensity score in a 1:3 ratio. Our primary outcome was all-cause mortality.
813 metformin users were matched by propensity score to 2439 non-users. The two groups of patients did not differ significantly by 30 baseline clinical and socioeconomic variables. Median follow-up in the matched cohort was 2·1 years (range 0·3-9·8). All-cause mortality was reported in 434 (53%) of 813 metformin users and in 1012 (41%) of 2439 non-users. After multivariate adjustment, metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20-1·51; p<0·0001). The increased mortality risk was dose-dependent and was consistent across all subgroup analyses. However, metformin use compared with no use was associated with a higher but non-significant risk of metabolic acidosis (1·6 vs 1·3 events per 100 patient-years; adjusted hazard ratio 1·30, 95% CI 0·88-1·93; p=0·19).
Use of metformin in people with type 2 diabetes and a serum creatinine concentration greater than 530 μmol/L is associated with a significantly increased risk of all-cause mortality compared with non-users. Metformin use should not be encouraged in this patient group.
Taipei Tzu Chi Hospital, Taipei Veterans General Hospital, Foundation for Poison Control, National Health Research Institutes, Ministry of Science and Technology of Taiwan.
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