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ObjectiveTo provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.DesignSystematic review and network meta-analysis.Data sourcesElectronic 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.Review methodsOnly 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.Results36 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.ConclusionsCompared 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.Systematic review registrationPROSPERO CRD42017082553.

Atrophic vaginitis (AV) is common in postmenopausal women, but its causes are not well understood. The symptoms, which include vaginal itching, burning, dryness, irritation, and dyspareunia, can usually be alleviated by low doses of estrogen given orally or locally. Regrettably, the composition of vaginal bacterial communities in women with AV have not been fully characterized and little is known as to how these communities change over time in response to hormonal therapy. In the present intervention study we determined the response of vaginal bacterial communities in postmenopausal women with AV to low-dose estrogen therapy. The changes in community composition in response to hormonal therapy were rapid and typified by significant increases in the relative abundance of Lactobacillus spp. that were mirrored by a decreased relative abundance of Gardnerella. These changes were paralleled by a significant four-fold increase in serum estradiol levels and decreased vaginal pH, as well as nearly a two-fold increase in the Vaginal Maturation Index (VMI). The results suggest that after menopause a vaginal microbiota dominated by species of Lactobacillus may have a beneficial role in the maintenance of health and these findings that could lead to new strategies to protect postmenopausal women from AV.

Background Gallbladder cancer (GBC) is an extremely malignant tumor with a high mortality rate. Little is known about its invasion and metastasis mechanism so far. Methods To identify the driver genes in GBC metastasis, we performed a mRNA microarray of metastatic GBC and paired non-tumor samples, and found PLEK2 was markedly upregulated in GBC tissues. Next, the expression of PLEK2 in GBC were examined in a larger cohort of patients by qRT-PCR, western blot and IHC staining. The clinicopathologic correlation of PLEK2 was determined by statistical analyses. The biological involvement of PLEK2 in GBC metastasis and the underlying mechanisms were investigated. Results In this study, we found that PLEK2 had higher expression in GBC tumor tissues compared to non-cancerous adjacent tissues and cholecystolithiasis tissues. The clinicopathologic analyses showed PLEK2 expression was positively correlated with tumor TNM stage, distant metastasis and PLEK2 was an independent predictor of overall survival (OS) in GBC patients. The cellular function assays showed PLEK2 promoted GBC cells migration, invasion and liver metastasis in mouse model via the regulation of epithelial-mesenchymal transition (EMT) process. Our mass spectrum and co-immunoprecipitation (co-IP) assays demonstrated that PLEK2 could interact with the kinase domain of EGFR and suppress EGFR ubiquitination mediated by c-CBL, leading to constitutive activation of EGFR signaling. Furthermore, RNA-sequencing and qRT-PCR results demonstrated chemokine (C-C motif) ligand 2 (CCL2), a target gene downstream of PLEK2/EGFR signaling, mediated the motility-promoting function of PLEK2. Conclusions On the basis of these collective data, we propose that PLEK2 promotes the invasion and metastasis of GBC by EGFR/CCL2 pathway and PLEK2 can serve as a potential therapeutic target for GBC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1250-8) contains supplementary material, which is available to authorized users.

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Background: To explore the value of chemoradiotherapy (CRT) in stage II nasopharyngeal carcinoma (NPC) compared to radiotherapy (RT) alone which includes two-dimensional radiotherapy (2D-RT) and intensity-modulated radiotherapy (IMRT).Methods:All topic-related comparative articles were identified by a comprehensive search of public databases (MEDLINE, EMBASE, Cochrane Library and CBMdisc). The primary outcomes were overall survival (OS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS). Secondary outcomes were grade 3-4 acute toxicity events. We performed subgroup analysis of CRT versus 2D-RT/IMRT alone to investigate the optimal modality. Sensitivity analysis focused on CRT versus IMRT alone was used to assess stability of the study results.Results:Eleven comparative studies (2138 patients) were eligible. CRT had significantly higher OS (HR = 0.67, 95% CI = 0.45-0.98, P = 0.04) and LRRFS (HR = 0.61, 95% CI = 0.46-0.80, P = 0.0003) than RT alone, but no significant difference was observed in DMFS (HR = 0.83, 95% CI = 0.52-1.31, P = 0.41). Meanwhile, CRT was associated with higher frequencies of grade 3-4 leukopenia, mucositis and nausea (P = 0.005, 0.03, < 0.0001, respectively). Subgroup analysis showed that IMRT alone could achieve equivalent OS, LRRFS and DMFS compared to CRT (P = 0.14, 0.06, 0.89, respectively). Significant value was only observed in LRRFS for CRT compared to 2D-RT alone (P = 0.01). Sensitivity analysis for the comparison of CRT and IMRT alone demonstrated generally stable outcomes, in support of the final conclusions.Conclusions:In the treatment of patients with stage II NPC, CRT was better than 2D-RT alone with significant benefit in LRRFS. IMRT alone was superior to CRT with equivalent survival outcomes and fewer grade 3-4 acute toxicities.

♦ Background: Icodextrin is widely used in peritoneal dialysis (PD); however, the safety and efficacy of icodextrin are unclear. In the present study, we performed a systematic review of randomized controlled trials (RCTs) that compared icodextrin and glucose for the once-daily long dwell in PD. ♦ Methods: Electronic searches were performed in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to select all eligible studies. Eligible studies, as determined by consensus using predefined criteria, were reviewed, and data were extracted onto a standard form. ♦ Results: In the 9 RCTs that were identified, patients using icodextrin were found to have much greater net ultrafiltration (UF) and a lower incidence of negative net UF compared to patients using 1.5%, 2.5%, and 4.25% glucose solutions. Additionally, icodextrin has a markedly increased UF efficiency ratio and peritoneal clearance of creatinine and urea nitrogen, but residual renal function was not different from patients using glucose solutions for PD. No significant differences were observed between icodextrin and glucose groups with respect to risk of mortality, peritonitis, and total adverse events. Although rashes occurred significantly more often in icodextrin groups, few differences were noted between icodextrin and glucose groups when withdrawal rates secondary to adverse events were compared. ♦ Conclusions: This meta-analysis suggests that icodextrin provides patients with greater fluid removal and small solute clearance and does not cause any damage to residual renal function. Icodextrin is particularly appropriate for use in patients with high peritoneal transport status.

The occurrence pattern of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) in cancer treatment remains unclear. Materials and Methods Phase II-III clinical trials that evaluated ICI-based treatments in cancer and were published between January 2007 and December 2019 were retrieved from public electronic databases. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were generated using the metamedian package of R software. Results Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. The PMT-O of all-grade irAEs ranged from 2.2 to 14.8 weeks, with the longest in renal events. The PMT-O of grade ≥ 3 irAEs was significantly longer than that of all-grade irAEs induced by programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) inhibitors (27.5 vs. 8.4 weeks; p < 0.001) and treatment of nivolumab (NIV) plus ipilimumab (IPI) (7.9 vs. 6.0 weeks; p < 0.001). The PMT-R of all-grade irAEs ranged from 0.1 to 54.3 weeks, with the shortest and longest in hypersensitivity/infusion reaction and endocrine events, respectively. The PMT-IMR of grade ≥ 3 irAEs was significantly shorter than that of all-grade irAEs caused by PD-1/PD-L1 blockade (6.9 vs. 40.6 weeks; p = 0.002) and NIV+IPI treatment (3.1 vs. 5.9 weeks; p = 0.031). Conclusion This study revealed the general and specific occurrence pattern of ICI-induced irAEs in pancancers, which was deemed to aid the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.