Background and aim
Sepsis-induced acute lung injury (ALI) is a complex and life-threatening condition lacking specific and efficient clinical treatments. Extracellular histones, identified as a novel ...type of damage-associated molecular patterns, have been implicated in the inflammatory process of ALI. However, further elucidation is needed regarding the precise mechanism through which extracellular histones induce inflammation. The aim of this study was to investigate whether extracellular histones can activate NLRP3 inflammasome-mediated inflammation in alveolar macrophages (AMs) by affecting TWIK2-dependent potassium efflux.
Methods and results
We conducted experiments using cecal ligation and puncture (CLP) C57BL/6 mice and extracellular histone-stimulated LPS-primed MH-S cells. The results demonstrated a significant increase in the levels of extracellular histones in the plasma and bronchoalveolar lavage fluid (BALF) of CLP mice. Furthermore, neutralizing extracellular histone mitigated lung injury and inflammation in CLP-induced ALI mice. In vitro studies confirmed that extracellular histones upregulated the expression of NLRP3 inflammasome activation-related proteins in MH-S cells, and this effect was dependent on increased potassium efflux mediated by the TWIK2 channel on the plasma membrane. Moreover, extracellular histones directly triggered a substantial influx of calcium, leading to increased Rab11 activity and facilitating the trafficking and location of TWIK2 to the plasma membrane.
Conclusion
These findings underscore the critical role of extracellular histone-induced upregulation of TWIK2 expression on the plasma membrane of alveolar macrophages (AMs). This upregulation leads to potassium efflux and subsequent activation of the NLRP3 inflammasome, ultimately exacerbating lung inflammation and injury during sepsis.
Background Colorectal cancer is one of the most common cancers in the world. Several studies suggest using the Asia-Pacific colorectal screening (APCS) score and its modified versions to select ...high-risk populations for early colonoscopy, but external validation remains rare, and which score should be selected for CRC screening in China is unclear. Validation of multiple scores in the same population might help to choose the best performing score. Methods We conducted a cross-sectional study under the framework of Cancer Screening Program in Urban China, data from asymptomatic colorectal cancer screening in Xuzhou was used to validate the APCS score, the colorectal neoplasia predict (CNP) score, the Korean colorectal screening (KCS) score, the Modified APCS score and the 8-point risk score in predicting colorectal advanced neoplasia (CAN). Results 1804 subjects were included in the analysis and 112 CAN (6.21%) was detected. In each score, the detection rate of CAN was higher in the high-risk group than in the non-high-risk group (P < 0.05), and the RR (95%C.I.) ranged 2.20 (1.50-3.22) 8-point risk to 4.00 (2.41-6.65) Modified APCS. The c-statistics (95%C.I.) of the scoring systems ranged from 0.58 (0.53-0.62) 8-point risk to 0.65 (0.61-0.69) KCS. The sensitivity (95%C.I.) of these systems ranged from 31.25 (22.83-40.70) 8-point risk to 84.82 (76.81-90.90) Modified APCS, while the specificity (95%C.I.) ranged from 43.50 (41.12-45.90) Modified APCS to 83.81 (81.96-85.53) 8-point risk. Using the APCS scoring system as a comparator, the net reclassification improvement (NRI) of each modified version ranged from - 10.34% (95%C.I.: - 22.63 to 1.95%) 8-point risk to 4.79% (95%C.I.: - 1.50% to 11.08) KCS. The colonoscopy resource load (95%C.I.) ranged from 9 1-3 8-point risk to 11 3-5 APCS and Modified APCS. Conclusions The APCS score and its modified versions have certain ability to predict the risk of advanced neoplasia and reduce the resource load. The modified APCS score and the KCS score seemed the preferable systems to classify high risk subjects based on its high RR, sensitivity and predictive ability in the selected population. Future research could focus on adding risk factors or combining with laboratory test results to improve the predictive power of the scoring system. Keywords: Colorectal neoplasia, Mass screening, Early detection of cancer, Risk assessment, Validation studies as topic
Background:
A reliable model is needed to estimate the risk of postoperative recurrence and the benefits of postoperative radiotherapy (PORT) in patients with thoracic esophageal squamous cell cancer ...(TESCC).
Methods:
The study retrospectively reviewed 3652 TESCC patients in stage IB-IVA after radical esophagectomy, with or without PORT. In one institution as the training cohort (n = 1620), independent risk factors associated with locoregional recurrence (LRR), identified by the competing-risks regression, were used to establish a predicting nomogram, which was validated in an external cohort (n = 1048). Area under curve (AUC) values of receiver operating characteristic curves were calculated to evaluate discrimination. Risk stratification was conducted using a decision tree analysis based on the cumulative point score of the LRR nomogram. After balancing the baseline of characteristics between treatment groups by inverse probability of treatment weighting, the effect of PORT was evaluated in each risk group.
Results:
Sex, age, tumor location, tumor grade, and N category were identified as independent risk factors for LRR and added into the nomogram. The AUC values were 0.638 and 0.706 in the training and validation cohorts, respectively. Three risk groups were established. For patients in the intermediate- and high-risk groups, PORT significantly improved the 5-year overall survival by 10.2% and 9.4%, respectively (p < 0.05). Although PORT was significantly associated with reduced LRR in the low-risk group, overall survival was not improved.
Conclusion:
The nomogram can effectively estimate the individual risk of LRR, and patients in the intermediate- and high-risk groups are highly recommended to undergo PORT.
The role of conformal radiotherapy (cRT) in thoracic esophageal squamous cell carcinoma (TESCC) has not been addressed in adjuvant settings. The aim of this study was to investigate whether ...postoperative radiotherapy using cRT after an R0 resection improves outcomes in pT3N0M0 TESCC compared with resection alone.
This study included 678 patients with pT3N0M0 TESCC who were treated at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2004 to December 2011. The patients were divided into two groups: a surgery plus cRT group (S+cRT group) comprising patients who underwent cRT after an R0 resection and a surgery group (S group), comprising a control group of patients who underwent an R0 resection alone. Propensity score matching was used to create patient groups that were balanced across several covariates (n = 83 in each group). Outcome measures included overall survival (OS), disease-free survival (DFS), and recurrence.
In the overall study cohort, 5-year OS (75.2% versus 58.5%, p = 0.004) and DFS (71.8% versus 49.2%, p = 0.001) rates were significantly higher in the S+cRT group than in the S group. These data were confirmed in the matched samples (5-year OS, 75.7% versus 58.8% p = 0.017; DFS, 71.7% versus 50.3% p = 0.009). The overall (p = 0.001) and locoregional (p = 0.004) recurrence rates in the S+cRT group were significantly lower than in the S group. Multivariate Cox analyses in the matched samples revealed that surgery and postoperative cRT were independently associated with longer OS (hazard ratio = 0.505, 95% confidence interval: 0.291–0.876, p = 0.015) and longer DFS (hazard ratio = 0.513, 95% confidence interval: 0.309–0.854, p = 0.010) than resection alone.
Postoperative radiotherapy using cRT is strongly associated with improved OS and DFS in patients with pT3N0M0 TESCC. A multicenter, randomized phase III clinical trial is warranted to confirm these findings.
There were few reports of postoperative radiotherapy (PORT) in stage pIII-N2 Non-small-cell Lung Cancer (NSCLC) patients receiving pneumonectomy followed by adjuvant chemotherapy. This study aims to ...evaluate safety and efficacy of PORT among these patients.
Between Jan. 2004 and Dec. 2015, stage pIII-N2 NSCLC patients receiving pneumonectomy and adjuvant chemotherapy with or without PORT in our institution were retrospectively reviewed.
Totally 119 patients were included, 32 patients receiving adjuvant chemotherapy and PORT (PORT group) and 87 receiving adjuvant chemotherapy alone (Control group). There were more patients with non-R0 resection in PORT group than Control group (25% vs. 8%, p = 0.031). In PORT group, ≥Grade 2 radiation-induced pneumonitis was 2/32. No severe radiation-related heart injury was observed. There was no PORT-related death. Of all patients, median follow-up time was 25 months. Median overall survival time (mOS) and median disease-free survival time (mDFS) were 46 months and 15 months, respectively. The PORT group had significantly better OS (not reached vs. 34 months, p = 0.003), DFS (19 months vs. 13 months, p = 0.024), local recurrence free survival (LRFS, p = 0.012), and distant metastasis free survival (DMFS, p = 0.047) than the Control group. As for failure pattern, PORT significantly reduced local regional failure rate (39.1% vs. 15.6%, p = 0.016). In subgroup analysis, patients with R0 resection (n = 104), OS and LRFS in PORT group were significantly longer, and PORT tended to increase DFS and DMFS.
For patients with stage pIII-N2 NSCLC after pneumonectomy and adjuvant chemotherapy, PORT can improve OS, DFS, LRFS and DMFS with tolerable toxicity.
Currently, adjuvant therapy is not recommended for patients with thoracic esophageal squamous cell cancer (TESCC) after radical surgery, and a proportion of these patients go on to develop ...locoregional recurrence (LRR) within 2 years. Besides, there is no evidence for salvage chemoradiation therapy (CRT) in patients with residual tumor after esophagectomy (R1/R2 resection). In addition, factors like different failure patterns and relationship with normal organs influence the decision for salvage strategy. Here, we aimed to design a modularized salvage CRT strategy for patients without a chance of salvage surgery according to different failure patterns (including R1/R2 resection), and further evaluated its efficacy and safety.
Our study was designed as a one arm, multicenter, prospective clinical trial. All enrolled patients were stratified in a stepwise manner based on the nature of surgery (R0 or R1/2), recurrent lesion diameter, involved regions, and time-to-recurrence, and were further assigned to undergo either elective nodal irradiation or involved field irradiation. Then, radiation technique and dose prescription were modified according to the distance from the recurrent lesion to the thoracic stomach or intestine. Ultimately, four treatment plans were established.
This prospective study provided high-level evidence for clinical salvage management in patients with TESCC who developed LRR after radical surgery or those who underwent R1/R2 resection.
Prospectively Registered. ClinicalTrials.gov NCT03731442 , Registered November 6, 2018.
Since the development of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT), no prospective study has investigated whether concurrent chemoradiotherapy (SIB-IMRT ...with 60 Gy) remains superior to radiotherapy (SIB-IMRT) alone for unresectable esophageal cancer (EC). Furthermore, the optimal therapeutic regimen for patients who cannot tolerate concurrent chemoradiotherapy is unclear. We recently completed a phase I/II radiation dose-escalation trial using simultaneous integrated boost (SIB), elective nodal irradiation, and concurrent chemotherapy for unresectable EC. We now intend to conduct a prospective, phase III, randomized study of SIB-IMRT with or without concurrent chemotherapy. We aim to find a safe, practical, and effective therapeutic regimen to replace the conventional segmentation (1.8-2.0 Gy) treatment mode (radiotherapy ± chemotherapy) for unresectable EC.
This two-arm, open, randomized, multicenter, phase III trial will recruit esophageal squamous cell carcinoma patients (stage IIA-IVB UICC 2002; IVB only with metastasis to the supraclavicular or celiac lymph nodes). In all, 164 patients will be randomized using a 1:1 allocation ratio, and stratified by study site and disease stage, especially the extent of lymph node metastasis. Patients in the SIB arm will receive definitive SIB radiotherapy (95% planning target volume/planning gross tumor volume, 50.4 Gy/59.92 Gy/28 f, equivalent dose in 2-Gy fractions = 60.62 Gy). Patients in the SIB + concurrent chemotherapy arm will receive definitive SIB radiotherapy with weekly paclitaxel and a platinum-based drug (5-6 weeks). Four cycles of consolidated chemoradiotherapy will also be recommended. The primary objective is to compare the 1-year, 2-year, and 3-year overall survival of the SIB + chemotherapy group and SIB groups. Secondary objectives include progression-free survival, local recurrence-free rate, completion rate, and adverse events. Detailed radiotherapy protocol and quality-assurance procedures have been incorporated into this trial.
In unresectable, locally advanced EC, a safe and effective total radiotherapy dose and reasonable segmentation doses are required for the clinical application of SIB-IMRT + two-drug chemotherapy. Whether this protocol will replace the standard treatment regimen will be prospectively investigated. The effects of SIB-IMRT in patients with poor physical condition who cannot tolerate definitive chemoradiotherapy will also be investigated.
clinicaltrials.gov ( NCT03308552 , November 1, 2017).
Background
The role of postoperative radiotherapy in pathological T2–3N0M0 esophageal squamous cell carcinoma is unknown. We aimed to evaluate the efficacy and safety of postoperative radiotherapy in ...patients with pathological T2–3N0M0 thoracic esophageal squamous cell carcinoma.
Materials and Methods
Patients aged 18–72 years with pathological stage T2–3N0M0 esophageal squamous cell carcinoma after radical surgery and without neoadjuvant therapy were eligible. Patients were randomly assigned to surgery alone or to receive postoperative radiotherapy of 50.4 Gy in supraclavicular field and 56 Gy in mediastinal field in 28 fractions over 6 weeks. The primary endpoint was disease‐free survival. The secondary endpoints were local‐regional recurrence rate, overall survival, and radiation‐related toxicities.
Results
From October 2012 to February 2018, 167 patients were enrolled in this study. We analyzed 157 patients whose follow‐up time was more than 1 year or who had died. The median follow‐up time was 45.6 months. The 3‐year disease‐free survival rates were 75.1% (95% confidence interval CI 65.9–85.5) in the postoperative radiotherapy group and 58.7% (95% CI 48.2–71.5) in the surgery group (hazard ratio 0.53, 95% CI 0.30–0.94, p = .030). Local‐regional recurrence rate decreased significantly in the radiotherapy group (10.0% vs. 32.5% in the surgery group, p = .001). The overall survival and distant metastasis rates were not significantly different between two groups. Grade 3 toxicity rate related to radiotherapy was 12.5%.
Conclusion
Postoperative radiotherapy significantly increased disease‐free survival and decreased local regional recurrence rate in patients with pathological T2–3N0M0 thoracic esophageal squamous cell carcinoma with acceptable toxicities in this interim analysis. Further enrollment and follow‐up are warranted to validate these findings in this ongoing trial.
Implications for Practice
The value of adjuvant radiotherapy for patients with node‐negative esophageal cancer is not clear. The interim results of this phase III study indicated that postoperative radiotherapy significantly improved disease‐free survival and decreased local‐regional recurrence rate in patients with pathological T2–3N0M0 thoracic esophageal squamous cell carcinoma compared with surgery alone with acceptable toxicities. The distant metastasis rates and overall survival rates were not different between the two groups. Adjuvant radiotherapy should be considered for pathologic T2–3N0M0 thoracic esophageal squamous cell carcinoma. Prospective trials to identify high‐risk subgroups are needed.
This phase III randomized controlled study compared surgery alone with surgery followed by postoperative radiotherapy in patients with pathological T2‐3N0M0 esophageal squamous cell carcinoma. Interim results are reported.
Abstract The serine protease inhibitor (SERPIN) B1 is expressed in numerous human tumors, but little is known regarding its role in the pathophysiology of glioma. In this paper, we report that ...SERPINB1 expression was down-regulated in high-grade human glioma tissue samples and glioblastoma cell lines. To investigate the role of SERPINB1 in glioma migration and invasion, we generated human glioma cell lines in which SERPINB1 was either overexpressed or depleted. Overexpression of SERPINB1 suppressed, while elimination of SERPINB1 promoted, the migration and invasion of glioma cells. SERPINB1 inhibited glioma migration and invasion probably by dampening the expression of matrix metalloproteinase-2 (MMP-2). Molecular data showed that the effect of SERPINB1 in glioma cells might be mediated via sustained inactivation of the phosphorylation of focal adhesion kinase (FAK) involved in the downregulation of the expressions of MMP-2. In a multivariate analysis, high SERPINB1 expression was showed to be associated with good prognosis in glioma. In conclusion, our data suggest that SERPINB1 negatively regulates glioma cell migration and invasion probably by abrogating the expression of MMP-2 and the activation of FAK. We suggest that SERPINB1 may offer the application in clinical medicine.
Objective:
This study aimed to determine the long-term survival of patients with cT4 esophageal cancer (EC) and whether neoadjuvant chemoradiotherapy/radiotherapy plus surgery (nCRT/RT + S) is ...superior to definitive CRT(dCRT)/RT in terms of survival in cT4 EC downstaged after nCRT/RT.
Summary background data:
Treatment options for cT4 EC include dCRT/RT and nCRT/RT + S, but it is not clear whether the latter provides survival benefit in patients downstaged after nCRT/RT.
Methods:
From 2002 to 2017, 726 patients with cT4 esophageal squamous cell carcinoma (ESCC) were retrospectively analyzed. Patients achieving clinical complete response (cCR) or partial response (PR) after 4-week RT (median dose, 40.7 Gy) and considered fit for surgery were offered esophagectomy. Of the 726 patients, 308 (42.4%) achieved cCR/PR, while 74 patients received subsequent surgery (nCRT/RT + S group), 234 patients received dCRT/RT.
Results:
Median follow-up was 58 months. The 3-year overall survival (OS) and progression-free survival (PFS) rates for all patients were 33.3% and 35.6%, respectively. The corresponding OS and PFS rates were 54.8% and 48.5% in the nCRT/RT + S group versus 30.0% and 22.1% in the dCRT/RT group (both p < 0.0001). After adjusting the confounding variables with inverse probability of treatment weighting, the adjusted 3-year OS rates were 50.4% in the nCRT/RT + S group versus 50.8% in the dCRT/RT group (p = 0.15). However, the adjusted 3-year PFS rates were significantly different between the two groups (49.0% and versus 38.3%, p = 0.004). Postoperative complications occurred in 18 (24.3%) patients.
Conclusion:
The long-term survival of cT4 ESCC was improved after the use of three-dimensional CRT. In cT4, EC responded to nCRT/RT, surgery improves PFS but not OS.
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