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).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective The study goal was to determine the diagnostic accuracy of a specific cytokine pattern including interferon-gamma (IFN-γ), interleukin (IL)-10, and IL-6 for hemophagocytic ...lymphohistiocytosis (HLH) in febrile children. Study design In this prospective study, 756 patients with fever admitted to a hematology-oncology unit were enrolled. The causes of fever were documented and the serum cytokines, including IFN-γ, tumor necrosis factor-alpha (TNF-α), IL-10, IL-6, IL-4, and IL-2, were determined using cytometric bead array techniques. Results Of 1474 episodes of fever that were analyzed, 71 episodes of HLH manifested a specific cytokine pattern of highly increased levels of IFN-γ (median level: 1088.5 pg/mL) and IL-10 (623.5 pg/mL) but a moderately increased level of IL-6 (51.1 pg/mL). IL-6 was predominantly increased to varied extents in patients in the sepsis group (244.6 pg/mL) and the nonsepsis infection group (34.7 pg/mL). The diagnostic accuracy of IFN-γ and IL-10 for HLH was 99.5% and 92.8%, respectively. By applying the cutoff point of 100 pg/mL, IFN-γ had a sensitivity of 94.4% and a specificity of 97.2% for HLH. When using the criteria of IFN-γ >75 pg/mL and IL-10 >60 pg/mL, the specificity reached 98.9% and the sensitivity was 93.0%. Conclusions The specific cytokine pattern of markedly elevated levels of IFN-γ and IL-10 with only modestly elevated IL-6 levels has high diagnostic accuracy for HLH and may be a useful approach to differentiate HLH from infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To propose a lymph node (N) staging system for nasopharyngeal carcinoma (NPC) based on the International Consensus Guidelines for lymph node (LN) levels and MRI-determined nodal variables.
The MRI ...scans and medical records of 749 NPC patients receiving intensity modulated radiation therapy with or without chemotherapy were retrospectively reviewed. The prognostic significance of nodal level, laterality, maximal axial diameter, extracapsular spread, necrosis, and Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) size criteria were analyzed.
Nodal level and laterality were the only independent prognostic factors for distant failure and disease failure in multivariate analysis. Compared with unilateral levels Ib, II, III, and/or Va involvement (hazard ratio HR 1), retropharyngeal lymph node involvement alone had a similar prognostic value (HR 0.71; 95% confidence interval CI 0.43-1.17; P=.17), whereas bilateral levels Ib, II, III, and/or Va involvement (HR 1.65; 95% CI 1.06-2.58; P=.03) and levels IV, Vb, and/or supraclavicular fossa involvement (HR 3.47; 95% CI 1.92-6.29; P<.01) both significantly increased the HR for distant failure. Thus we propose that the N category criteria could be revised as follows: N0, no regional LN metastasis; N1, retropharyngeal lymph node involvement, and/or unilateral levels Ib, II, III, and/or Va involvement; N2, bilateral levels Ib, II, III, and/or Va involvement; N3, levels IV, Vb, and/or supraclavicular fossa involvement. Compared with the 7th edition of the UICC/AJCC criteria, the proposed N staging system provides a more satisfactory distinction between the HRs for regional failure, distant failure, and disease failure in each N category.
The proposed N staging system defined by the International Consensus Guidelines and laterality is predictive and practical. However, because of no measurements of the maximal nodal diameter on MRI slices, the prognostic significance of LN size needs further evaluation.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Background:
Traditional Chinese medicine (TCM) is widely integrated into cancer care in China. An overview in 2011 identified 2384 randomized and non-randomized controlled trials (RCTs, non-RCTs) on ...TCM for cancer published in the Chinese literature. This article summarizes updated evidence of RCTs on TCM for cancer care.
Methods:
We searched 4 main Chinese databases: China National Knowledge Infrastructure, Chinese Scientific Journal Database, SinoMed, and Wanfang. RCTs on TCM used in cancer care were analyzed in this bibliometric study.
Results:
Of 5834 RCTs (477 157 cancer patients), only 62 RCTs were indexed in MEDLINE. The top 3 cancers treated were lung, stomach, and breast cancer. About 4752 RCTs (81.45%) tested TCM combined with conventional treatment, and 1082 RCTs (18.55%) used TCM alone for treating symptoms and side-effects. Herbal medicine was the most frequently used TCM modality (5087 RCTs; 87.20%). The most frequently reported outcome was symptom improvement (3712 RCTs; 63.63%) followed by quality of life (2725 RCTs; 46.71%), and biomarkers (2384 RCTs; 40.86%). The majority of RCTs (4051; 69.44%) concluded there were beneficial effects using either TCM alone or TCM plus conventional treatment compared with conventional treatment.
Conclusion:
Substantial randomized trials demonstrated different types/stages of cancer were treated by various TCM modalities, alone or in combination with conventional medicine. Further evaluation on the effects and safety of TCM modalities focusing on outcomes such as quality of life is required.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Sepsis is the commonest cause of acute kidney injury in critically ill patients. Its pathophysiology is complex and not well understood. Until recently, it was believed that kidney ...hypoperfusion is the major contributor of septic acute kidney injury. However, recent publications have improved our understanding on this topic. We now know that its mechanisms included the following: (1) renal macrocirculatory and microcirculatory disturbance, (2) surge of inflammatory markers and oxidative stress, (3) coagulation cascade activation, and (4) bioenergetics adaptive response with controlled cell-cycle arrest aiming to prevent cell death. Uncovering these complicated mechanisms may facilitate the development of more appropriate therapeutic measures in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Background On the basis of the results of the randomised clinical trial HPTN 052 and observational studies, WHO has recommended that antiretroviral therapy be offered to all HIV-infected ...individuals with uninfected partners of the opposite sex (serodiscordant couples) to reduce the risk of transmission. Whether or not such a public health approach is feasible and the outcomes are sustainable at a large scale and in a developing country setting has not previously been assessed. Methods In this retrospective observational cohort study, we included treated and treatment-naive HIV-positive individuals with HIV-negative partners of the opposite sex who had been added to the national HIV epidemiology and treatment databases between Jan 1, 2003 and Dec 31, 2011. We analysed the annual rate of HIV infection in HIV-negative partners during follow-up, stratified by treatment status of the index partner. Cox proportional hazards analyses were done to examine factors related to HIV transmission. Findings Based on data from 38 862 serodiscordant couples, with 101 295·1 person-years of follow-up for the seronegative partners, rates of HIV infection were 2·6 per 100 person-years (95% CI 2·4–2·8) among the 14 805 couples in the treatment-naive cohort (median baseline CD4 count for HIV-positive partners 441 cells per μl IQR 314–590) and 1·3 per 100 person-years (1·2–1·3) among the 24 057 couples in the treated cohort (median baseline CD4 count for HIV-positive partners 168 cells per μl 62–269). We calculated a 26% relative reduction in HIV transmission (adjusted hazard ratio 0·74, 95% CI 0·65–0·84) in the treated cohort. The reduction in transmission was seen across almost all demographic subgroups and was significant in the first year (0·64, 0·54–0·76), and among couples in which the HIV-positive partner had been infected by blood or plasma transfusion (0·76, 0·59–0·99) or heterosexual intercourse (0·69, 0·56–0·84), but not among couples in which the HIV-positive partner was infected by injecting drugs (0·98, 0·71–1·36). Interpretation Antiretroviral therapy for HIV-positive individuals in serodiscordant couples reduced HIV transmission across China, which suggests that the treatment-as-prevention approach is a feasible public health prevention strategy on a national scale in a developing country context. The durability and generalisability of such protection, however, needs to be further studied. Funding Chinese Government's 12th Five-Year Plan, the National Natural Science Foundation of China, and the Canadian International Development Research Centre.
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