Background The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the adjuvant treatment of non-small cell lung cancer (NSCLC) has not been well-established. Our ...meta-analysis aimed to determine whether the administration of EGFR-TKIs could improve the outcomes of patients with NSCLC undergoing complete resection. Methods We comprehensively searched databases and extracted data from eligible studies. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) as well as disease relapse with odds ratios (OR) were calculated using random and/or fixed-effects models. Meta-regression analysis and test for interaction between subgroups were also carried out. Results A total of 1,960 patients in five studies were included. Adjuvant EGFR-TKI treatment was associated with a significant benefit on DFS (HR, 0.63; 95% CI, 0.41-0.99), corresponding to an absolute benefit of 3.1% at 3 years, yet with significant heterogeneity ( I2 = 83.4%, P < .001). The survival benefit was superior ( Pinteraction = .03) in studies with more than an 18-month median treatment duration. EGFR mutation rate was also identified as a source of heterogeneity ( P = .017). In the population with EGFR mutations, HR for DFS was 0.48 (95% CI, 0.36-0.65), corresponding to an absolute benefit of 9.5% at 3 years, with a reduced risk of distant metastasis (OR, 0.71; 95% CI, 0.56-0.92). Adjuvant EGFR-TKI treatment resulted in a marginally statistically significant benefit on OS (HR, 0.72; 95% CI, 0.49-1.06). The rate of overall grade 3 or greater adverse events was 42.3% (95% CI, 39.1-45.6). Conclusions Adjuvant EGFR-TKI treatment may enhance disease-free survival and reduce the risk of distant metastasis in patients with EGFR-mutant NSCLC undergoing complete resection.
As a well-established technique for postoperative pain relief, the benefits of epidural analgesia (EDA) have been under debate recently. This study aimed to determine whether EDA could improve ...perioperative outcomes and survival in patients undergoing esophagectomy.
From January 2010 to December 2012, 587 consecutive cases undergoing McKeown-type esohpageactomy were retrospectively identified from a prospectively maintained database.
After propensity-matching, incorporating baseline characteristics, 178 cases were included in each group, and patients characteristics distributions were well-balanced between two groups. Compared with intravenous analgesia, the use of EDA significantly decreased the incidence of pneumonia from 32% to 19.7% (P = 0.008), and anastomotic leakage from 23.0% to 14.0% (P = 0.029). The change in CRP level of EDA group was significantly decreased (preoperative, 6.2 vs. 6.2; POD 1, 108.1 vs. 121.3; POD 3, 131.5 vs. 137.8; POD 7, 69.3 vs. 82.1 mg/L; P = 0.044). EDA patients had a significantly longer duration of indwelling urinary catheter (P<0.001), and lower levels in both systolic (P = 0.001) and diastolic blood pressure (P<0.001). There weren't significant differences in overall survival (log-rank P = 0.47) and recurrence (Gray-test P = 0.46) between two groups.
These findings revealed that EDA could attenuate inflammatory response and reduce the incidence of pneumonia and anastomotic leakage after esophagectomy, at the price of delayed urinary catheter removal and lower blood pressure. EDA remains an important component of multimodal perioperative management after esophagectomy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Microsporidia are fungal obligate intracellular pathogens, which infect most animals and cause microsporidiosis. Despite the serious threat that microsporidia pose to humans and agricultural animals, ...few drugs are available for the treatment and control of microsporidia. To identify novel inhibitors, we took advantage of the model organism Caenorhabditis elegans infected with its natural microsporidian Nematocida parisii. We used this system to screen the Pandemic Response Box, a collection of 400 diverse compounds with known antimicrobial activity. After testing these compounds in a 96-well format at high (100 μM) and low (40 μM) concentrations, we identified four inhibitors that restored the ability of C. elegans to produce progeny in the presence of N. parisii. All four compounds reduced the pathogen load of both N. parisii and Pancytospora epiphaga, a C. elegans-infecting microsporidia related to human-infecting species. One of these compounds, a known inhibitor of a viral protease, MMV1006203, inhibited invasion and prevented the firing of spores. A bis-indole derivative, MMV1593539, decreased spore viability. An albendazole analog, MMV1782387, inhibited proliferation of N. parisii. We tested albendazole as well as 5 other analogs and observed that MMV1782387 was amongst the strongest inhibitors of N. parisii and displayed the least host toxicity. Our study further demonstrates the effectiveness of the C. elegans-N. parisii system for discovering microsporidia inhibitors and the compounds we identified provide potential scaffolds for anti-microsporidia drug development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with
-mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant ...approaches that enhance adaptive immune responses-such as epigenetic modulation of antitumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an
CRISPR screen in a
/
LUAD model. Our data showed that loss of the histone chaperone
in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic
deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti-PD-1 immunotherapy. SIGNIFICANCE: Using an
epigenetic CRISPR screen, we identified
as a critical regulator of LUAD sensitivity to anti-PD-1 therapy.
deficiency synergized with anti-PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD.
.
.
Short-term exposure to major air pollutants (O
, CO, NO
, SO
, PM
, and PM
) has been associated with respiratory risk. However, evidence on the risk of chronic obstructive pulmonary disease (COPD) ...exacerbations is still limited. The present study aimed at evaluating the associations between short-term exposure to major air pollutants and the risk of COPD exacerbations.
After a systematic search up until March 30, 2016, in both English and Chinese electronic databases such as PubMed, EMBASE, and CNKI, the pooled relative risks and 95% confidence intervals were estimated by using the random-effects model. In addition, the population-attributable fractions (PAFs) were also calculated, and a subgroup analysis was conducted. Heterogeneity was assessed by
.
In total, 59 studies were included. In the single-pollutant model, the risks of COPD were calculated by each 10 μg/m
increase in pollutant concentrations, with the exception of CO (100 μg/m
). There was a significant association between short-term exposure and COPD exacerbation risk for all the gaseous and particulate pollutants. The associations were strongest at lag0 and lag3 for gaseous and particulate air pollutants, respectively. The subgroup analysis not only further confirmed the overall adverse effects but also reduced the heterogeneities obviously. When 100% exposure was assumed, PAFs ranged from 0.60% to 4.31%, depending on the pollutants. The adverse health effects of SO
and NO
exposure were more significant in low-/middle-income countries than in high-income countries: SO
, relative risk: 1.012 (95% confidence interval: 1.001, 1.023); and NO
, relative risk: 1.019 (95% confidence interval: 1.014, 1.024).
Short-term exposure to air pollutants increases the burden of risk of COPD acute exacerbations significantly. Controlling ambient air pollution would provide benefits to COPD patients.
Purpose: To investigate the impact of programmed death-ligand 1 (PD-L1) expression, oncogenic mutations, and clinical characteristics on survival after treatment with anti-PD-1/PD-L1 antibodies ...versus chemotherapy in non-small cell lung cancer (NSCLC).
Patients and Methods: This meta-analysis included randomized trials comparing anti-PD-1/PD-L1 antibodies with chemotherapy. Hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS) for the trial population and prespecified subgroups were extracted. We calculated pooled estimates of treatment efficacy using the fixed-effects or random-effects model when appropriate. All statistical tests were two sided.
Results: Seven trials involving 3871 patients were included. The pooled results showed that anti-PD-1/PD-L1 immunotherapy significantly prolonged OS (HR: 0.73; 95% CI, 0.63 to 0.84) and PFS (HR: 0.84; 95% CI, 0.71 to 0.99) compared to chemotherapy. OS benefit from immunotherapy were observed in all PD-L1 expression subgroups (negative: HR, 0.79; 95% CI, 0.67 to 0.93; weak-positive: HR, 0.80; 95% CI, 0.67 to 0.95; strong-positive: HR, 0.61; 95% CI, 0.47 to 0.78). Strong-positive PD-L1 expression showed a trend towards more benefit compared to weak-positive PD-L1 expression (interaction P = 0.08). KRAS mutant (HR: 0.60; 95% CI, 0.39 to 0.93), EGFR wild-type (HR: 0.73; 95% CI, 0.61 to 0.87) and smoker (HR: 0.70; 95% CI, 0.60 to 0.83) subgroups achieved significant OS benefit from immunotherapy compared to corresponding subgroups. Survival benefit to immunotherapy was not significantly associated with histology, CNS metastases, age, gender and performance status.
Conclusion: This study confirmed that treatment with anti-PD-1/PD-L1 improves overall survival compared with chemotherapy. Benefit was seen, regardless of PD-L1 expression levels; however, PD-L1 strong-positive patients trended to have greatest benefit. Patients with a KRAS mutant or EGFR wild-type tumor have improved survival benefit from immunotherapy compared with KRAS wild-type or EGFR mutant NSCLC, respectively.
IntroductionPrevious studies demonstrated that wedge resection is sufficient for ground glass-dominant lung adenocarcinoma (LUAD) with tumour diameter ≤2 cm, however, the optimal surgical type for ...ground glass-dominant LUAD with tumour diameter of 2–3 cm remains unclear. The purpose of this trial is to investigate the safety and efficacy of segmentectomy for ground glass-dominant invasive LUAD with tumour size of 2–3 cm.Methods and analysisWe initiated a phase III trial to investigate whether segmentectomy is suitable for ground glass-dominant invasive LUAD with tumour size of 2–3 cm. This trial plans to enrol 307 patients from multiple institutions including four general hospitals and two specialty cancer hospitals over a period of 5 years. The primary endpoint is 5 year disease-free survival. Secondary endpoints are lung function, 5 year overall survival, the site of tumour recurrence and metastasis, segmentectomy completion rate, radical segmentectomy (R0 resection) completion rate and surgery-related complications.Ethics and disseminationThis trial has been approved by the Ethics Committee of Fudan University Shanghai Cancer Centre (reference 2212267-18) and by the institutional review boards of each participating centre. Written informed consent is required from all participants. The study results will be published in a peer-reviewed international journal.Trial registration number NCT05717803.
Aberrant methylation of the global genome has been investigated as a prognostic indicator in various cancers, but the results are controversial and ambiguous.
This meta-analysis presents pooled ...estimates of the evidence to elucidate this issue. We searched the electronic databases: PubMed, Embase, ISI Web of Science and the Cochrane library (up to August 2013) to identify all of the relevant studies. The association between the level of surrogates' indexes of genome-wide hypomethylation (LINE-1, Alu and Sat-α) and the overall survival (OS) of cancer patients was examined. In addition, the pooled hazard ratios (HRs) with their 95% confidence interval (95%CI) were calculated to estimate the influences through fixed-effects and random-effects model. Finally, twenty studies with total population of 5447 met the inclusion criteria. The results indicate that the summary HRs for the studies employing LINE-1, Alu, and Sat-α repetitive elements also show that the global DNA hypomethylation have significant desirable effects on the tumour prognostic value. The pooled HRs (and CIs) of LINE-1, Alu and Sat-α were 1.83 (1.38-2.44), 2.00 (1.16-3.45), and 2.92 (1.04-8.25), with a heterogeneity measure index of I2 (and p-value) shows of 66.6% (p = 0.001), 57.1% (p = 0.053) and 68.2% (p = 0.076) respectively. The meta-regression and subgroup analysis indicated that the percentage of hypomethylated sample of cancer patients is one source of heterogeneity.
Our meta-analysis findings support the hypothesis that the global DNA hypomethylation is associated with a detrimental prognosis in tumour patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Uniportal video-assisted thoracoscopic surgery (U-VATS) has recently emerged as an alternative procedure for non-small cell lung cancer (NSCLC); however, whether U-VATS has advantages over ...multiportal VATS (M-VATS) remains unknown.
We performed a systematic review of two databases (Pubmed and Web of Science) to search comparative studies of U-VATS and M-VATS anatomical pulmonary resection for NSCLC. Operative time, blood loss, number of resected lymph nodes, drainage duration, length of postoperative stay, pain in postoperative day 1(POD1) and conversion rates were retrieved to estimate the comparison of outcomes. A subgroup analysis stratified by study type (propensity-matched analysis and randomized-controlled trial versus non-propensity matched analysis) was performed.
A total of 20 studies with 4142 patients were included in this meta-analysis. U-VATS was performed on 1869 patients, whereas the other 2173 patients underwent M-VATS. This meta-analysis showed that there was no significant difference in operative time (U-VATS: 146.48 ± 55.07 min versus M-VATS: 171.70 ± 79.40 min, P = 0.81), blood loss (74.49 ± 109.03 mL versus 95.48 ± 133.67 mL, P = 0.18), resected lymph nodes (17.28 ± 9.46 versus 18.31 ± 10.17, P = 0.62), conversion rate (6.18% versus 4.34%, P = 0.14), drainage duration (3.90 ± 2.94 days versus 4.44 ± 3.12 days, p = 0.09), length of postoperative stay (6.16 ± 4.40 days versus 6.45 ± 4.80 days, P = 0.22), and pain in POD1 (3.94 ± 1.68 versus 3.59 ± 2.76, p = 0.07). Subgroup analysis showed the value of PSM and RCT group consistency with overall value.
This up-to-date meta-analysis shows that the perioperative outcomes of U-VATS and M-VATS anatomical pulmonary resection are equivalent. In addition, the differences in long-term outcomes of these two approaches are still unclear. Thoracic surgeons should pay more emphasize on providing high-quality and personalized surgical care for patients, to improve the survival ultimately.
(
) causes severe pulmonary diseases, leading to high morbidity and mortality. It has been reported that inflammasomes such as NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 ...(AIM2) play an important role in the host defense against
infection. However, the role of NLRP6 in vivo and in vitro against
remains unclear. Therefore, we investigated the role of NLRP6 in regulating the
-induced inflammatory signaling pathway in vitro and the role of NLRP6 in the host defense against
in vivo by using NLRP6
mice. The results showed that the NLRP6 inflammasome regulated the maturation and secretion of IL-1β, but it did not affect the induction of IL-1β transcription in
-infected macrophages. Furthermore, the activation of caspase-1, caspase-11, and gasdermin D (GSDMD) as well as the oligomerization of apoptosis-associated speck-like protein (ASC) were also mediated by NLRP6 in
-infected macrophages. However, the activation of NLRP6 reduced the expression of NF-κB and ERK signaling pathways in
-infected macrophages. In vivo study showed that NLRP6
mice had a higher survival rate, lower number of bacteria, and milder inflammatory response in the lung compared with wild-type (WT) mice during
infection, indicating that NLRP6 plays a negative role in the host defense against
. Furthermore, increased bacterial clearance in NLRP6 deficient mice was modulated by the recruitment of macrophages and neutrophils. Our study provides a new insight on
-induced activation of NLRP6 and suggests that blocking NLRP6 could be considered as a potential therapeutic strategy to treat
infection.
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