To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.
Systematic review and network meta-analysis.
...Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.
Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.
36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.
Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.
PROSPERO CRD42017082553.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background： The prognostic values of staging parameters require continual re-assessment amid changes in diag-nostic and therapeutic methods. This study aimed to identify the prognostic factors and ...failure patterns of non-meta-static nasopharyngeal carcinoma（NPC） in the intensity-modulated radiotherapy（IMRT） era.Methods： We reviewed the data from 749 patients with newly diagnosed, biopsy-proven, non-metastatic NPC in our cancer center（South China, an NPC endemic area） between January 2003 and December 2007. All patients under-went magnetic resonance imaging（MRI） before receiving IMRT. The actuarial survival rates were estimated using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Multivariate analyses with the Cox proportional hazards model were used to test for the independent prognostic factors by backward eliminating insigniicant explanatory variables.Results： The 5-year occurrence rates of local failure, regional failure, locoregional failure, and distant failure were 5.4, 3.0, 7.4, and 17.4%, respectively. The 5-year survival rates were as follows： local relapse-free survival, 94.6%; nodal relapse-free survival, 97.0%; distant metastasis-free survival, 82.6%; disease-free survival, 75.1%; and overall survival, 82.0%. Multivariate Cox regression analysis revealed that orbit involvement was the only signiicant prognostic fac-tor for local failure（P = 0.011）. Parapharyngeal tumor extension, retropharyngeal lymph node involvement, and the laterality, longest diameter, and Ho＇s location of the cervical lymph nodes were signiicant prognostic factors for both distant failure and disease failure（all P 〈 0.05）. Intracranial extension had signiicant prognostic value for distant failure（P = 0.040）.Conclusions： The key failure pattern for NPC was distant metastasis in the IMRT era. With changes in diagnostic and therapeutic technologies as well as treatment modalities, the signiicant prognostic parameters for local control have also been altered substantially.
Scope
This study aims to investigate the underlying mechanism of a specific probiotic strain on suppression of adipogenesis and inflammatory response in white adipose tissue (WAT) of high‐fat diet ...(HFD)‐fed mice.
Methods and Results
Eight strains are screened in vitro for candidates of potential probiotics. Lactobacillus rhamnosus LRH05 (LRH05) and Lactobacillus reuteri LR47 (LR47) are screened out with lower triglyceride expression in vitro. The mice are fed a control diet (CD), HFD, or HFD supplemented with a dose of LRH05 or LR47 at 109 CFU per mouse per day for 10 weeks (n = 8), respectively. The results demonstrate that LRH05, but not LR47, significantly reduce body weight gain and the weight of WAT, as well as improve hepatic steatosis and glucose intolerance. LRH05 regulates the Mogat1, Igf‐1, Mcp‐1, and F4/80 mRNA expression and decreases macrophage infiltration in WAT. LRH05 shows an increase in butyric and propionic acid‐producing bacteria, including Lachnoclostridium, Romboutsia, and Fusobacterium that is coincident with the increased fecal propionic acid and butyric acid levels.
Conclusion
LRH05 shows a strain‐specific effect on ameliorating the pro‐inflammatory process by reducing inflammatory macrophage infiltration and the expression of inflammation‐related genes in mice. Thus, LRH05 can be considered a potential probiotic strain to prevent obesity.
This study aims to investigate the underlying mechanism of a Lactobacillus rhamnosus LRH05 on suppression of adipogenesis and inflammatory response in white adipose tissue (WAT) of high‐fat diet (HFD)‐fed mice. The results demonstrate that LRH05 significantly reduces body weight gain and the weight of WAT, as well as improves hepatic steatosis and glucose intolerance. Moreover, LRH05 regulates the Mogat1, Igf‐1, Mcp‐1, and F4/80 mRNA expression and decreases macrophage infiltration in WAT, as well as increases fecal propionic acid and butyric acid levels through manipulation of gut microbiota composition.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)-based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal ...carcinoma (NPC).
We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (
= 470), and then validated it on a test set (
= 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein-Barr virus (EBV) DNA.
A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (
< 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 95% confidence interval (95% CI), 0.709-0.800 in the training set and 0.722 (95% CI, 0.652-0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (
< 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC.
Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.
Low serum albumin is predictive of poor survival in nasopharyngeal carcinoma (NPC). We evaluated the ability of the pretreatment albumin/globulin ratio (AGR) to predict long-term mortality in ...patients with NPC.
This retrospective study examined an unselected cohort of 694 patients with NPC who had documented pretreatment total serum protein and serum albumin levels (ALB). AGR was calculated as AGR = ALB/(total serum protein--ALB). Survival analysis was used to evaluate the predictive value of AGR.
Multivariate analysis demonstrated that a low pretreatment serum AGR (<1.4) was an independent predictor of poor OS (P = 0.029) and DMFS (P = 0.033). A low AGR was significantly associated with advanced stage disease (P<0.001), high white blood cell count (P = 0.033), high neutrophil count (P = 0.047), high total serum protein (P<0.001) and low ALB (P<0.001).
The pretreatment AGR may represent a simple, potentially useful predictive biomarker for evaluating the long-term prognosis of patients with undifferentiated NPC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To identify the major infiltrating phagocytes during leptospirosis and examine the killing mechanism used by the host to eliminate Leptospira interrogans.
Major infiltrating phagocytes in ...Leptospira-infected C3H/HeJ mice were detected by immunohistochemistry. Chemokines and vascular endothelial cell adhesion molecules (VECAMs) of Leptospira-infected mice and leptospirosis patients were detected by microarray and immunohistochemistry. Leptospira-phagocytosing and -killing abilities of human or mouse macrophages and neutrophils, and the roles of intracellular ROS, NO and Ca2+i in Leptospira-killing process were evaluated by confocal microscopy and spectrofluorimetry.
Peripheral blood mononuclear-macrophages rather than neutrophils were the main infiltrating phagocytes in the lungs, liver and kidneys of infected mice. Levels of macrophage- but not neutrophil-specific chemokines and VECAMs were significantly increased in the samples from infected mice and patients. All macrophages tested had a higher ability than neutrophils to phagocytose and kill leptospires. Higher ROS and NO levels and Ca2+i in the macrophages were involved in killing leptospires. Human macrophages displayed more phagolysosome formation and a stronger leptospire-killing ability to than mouse macrophages.
Mononuclear-macrophages but not neutrophils represent the main infiltrating and anti-leptospiral phagocytes during leptospirosis. A lower level of phagosome-lysosome fusion may be responsible for the lower Leptospira-killing ability of human macrophages.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We analyzed the number of circulating tumor cells (CTCs) and Epstein–Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The ...levels of CTCs and EBV DNA were measured at baseline and after first‐line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non‐mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first‐line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first‐line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first‐line chemotherapy was associated with significantly longer progression‐free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first‐line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first‐line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
What's new?
Endemic nasopharyngeal carcinoma (NPC) is associated with latent infection of the oncogenic Epstein‐Barr virus (EBV) and frequently metastasizes to distant lymph nodes and organs. Metastatic NPC is treated by serial administration of cytotoxic or targeted therapies and treatment response is generally assessed with serial imaging, which often fails to detect changes in tumor burden. Here, the authors show that the number of circulating tumor cells (CTCs) and EBV DNA levels before, after, and during first‐line chemotherapy are strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Atosiban is administered to women undergoing in vitro fertilization-embryo transfer (IVF-ET) to improve pregnancy outcomes. However, the results of this treatment were controversial. We conducted ...this meta-analysis to investigate whether atosiban improves pregnancy outcomes in the women undergoing in vitro fertilization (IVF).
Databases of PubMed, EMBASE, Web of Science, China BioMedicine, and Google Scholar were systematically searched. Meta-analyses were performed to investigate whether atosiban improves pregnancy outcomes in the women undergoing IVF.
Our results showed that atosiban was associated with higher implantation (OR = 1.63, 95% CI: 1.17-2.27; P = 0.004) and clinical pregnancy (OR = 1.84, 95% CI: 1.31-2.57; P < 0.001) rates. However, atosiban showed no significant association with the miscarriage, live birth, multiple pregnancy or ectopic pregnancy rates. When a further subgroup analysis was performed in the women undergoing repeated implantation failure (RIF), implantation (OR = 1.93, 95% CI: 1.45-2.57; P < 0.001), clinical pregnancy (OR = 2.48, 95% CI: 1.70-3.64; P <0.001) and the live birth (OR = 2.89, 95% CI: 1.78-4.67; P < 0.001) rates were significantly higher in the case group. Nevertheless, no significant difference was detected in the miscarriage and multiple pregnancy rates between the case and control groups.
Atosiban may be more appropriate for women undergoing RIF and play only a limited role in improving pregnancy outcomes in the general population of women undergoing IVF. These conclusions should be verified in large and well-designed studies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human telomerase reverse transcriptase (hTERT) plays a crucial role in ovarian cancer (OC) progression. However, the mechanisms underlying hTERT upregulation in OC, and the specific microRNAs ...(miRNAs) involved in the regulation of hTERT in OC cells, remains unclear. We performed a bioinformatics search to identify potential miRNAs that bind to the 3'-untranslated region (3'-UTR) region of the hTERT mRNA. We examined the expression levels of miR-532/miR-3064 in OC tissues and normal ovarian tissues, and analyzed the correlation between miRNA expression and OC patient outcomes. The impacts of miR-532/miR-3064 on hTERT expression were evaluated by western blot analysis and hTERT 3'-UTR reporter assays. We investigated the effects of miR-532/miR-3064 on proliferation and invasion in OC cells. We found that miR-532 and miR-3064 are down-regulated in OC specimens. We observed a significant association between reduced miR-532/miR-3064 expression and poorer survival of patients with OC. We confirmed that in OC cells, these two miRNAs downregulate hTERT levels by directly targeting its 3'-UTR region, and inhibited proliferation, EMT and invasion of OC cells. In addition, the overexpression of the hTERT cDNA lacking the 3'-UTR partially restored miR-532/miR-3064-inhibited OC cell proliferation and invasion. The silencing of hTERT by siRNA oligonucleotides abolished these malignant features, and phenocopied the effects of miR-532/miR-3064 overexpression. Furthermore, overexpression of miR-532/miR-3064 inhibits the growth of OC cells in vivo. Our findings demonstrate a miR-532/miR-3064-mediated mechanism responsible for hTERT upregulation in OC cells, and reveal a possibility of targeting miR-532/miR-3064 for future treatment of OC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pollution of greenhouse soils and crops by heavy metals as a result of annual application of large amounts of pesticides and fertilizers is of great concerns. We investigated the effect of biochar ...(BC) as a potential immobilizing medium for cadmium (Cd) by assessing Cd bioavailability, fractions, and uptake of metals by lettuce plants in metal-contaminated greenhouse soils. Experiments were conducted in two typical vegetable greenhouses displaying different levels of heavy metal pollution (GH1, lightly heavy-metal-polluted greenhouse; GH2, heavily heavy-metal-polluted greenhouse), in Wuhan City suburbs, Hubei Province, China. For each greenhouse site three replicates of each of three levels of BC (B0, 0tha−1; B10, 10tha−1; B20, 20tha−1) were arranged in a randomized complete block design. The application of BC increased soil pH and soil organic matter and changed Cd fractions in the soil. The exchangeable Cd fraction decreased and there was an increase in the oxide- and organic-bound and residual fractions with the application of BC, implying that BC application could immobilize the Cd in greenhouse soil. The rates of Cd immobilization in soil increased with the amount of BC applied. The exchangeable Cd fractions in soils amended with B10 decreased by 45–62% and in soils amended with B20 by 66–89% compared to the control. The addition of BC reduced the concentration of Cd in lettuce shoots in the lightly heavy-metal-polluted soils, but in the heavily heavy-metal-contaminated soils it had either no effect, or promoted Cd absorption by lettuce shoots. Total Cd measured in lettuce tissues did not decrease with the addition of BC when compared to the control, as there was increased accumulations of lettuce biomass with biochar application.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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