Analysis of Immune and Prognostic-Related lncRNA PRKCQ-AS1 for Predicting Prognosis and Regulating Effect in Sepsis.

Background: Sepsis was a high mortality and great harm systemic inflammatory response syndrome caused by infection. lncRNAs were potential prognostic marker and therapeutic target. Therefore, we expect to screen and analyze lncRNAs with potential prognostic markers in sepsis. Methods: Transcriptome sequencing and limma was used to screen dysregulated RNAs. Key RNAs were screened by correlation analysis, lncRNA-mRNA co-expression and weighted gene co-expression network analysis. Immune infiltration, gene set enrichment analysis and gene set variation analysis were used to analyze the immune correlation. Kaplan-Meier curve, receiver operator characteristic curve, Cox regression analysis and nomogram were used to analyze the correlation between key RNAs and prognosis. Sepsis model was established by lipopolysaccharide-induced HUVECs injury, and then cell viability and migration ability were detected by cell counting kit-8 and wound healing assay. The levels of apoptosis-related proteins and inflammatory cytokines were detected by RT-qPCR and Western blot. Reactive Oxygen Species and superoxide dismutase were detected by commercial kit. Results: Fourteen key differentially expressed lncRNAs and 663 key differentially expressed genes were obtained. And these lncRNAs were closely related to immune cells, especially T cell activation, immune response and inflammation. Subsequently, Subsequently, lncRNA PRKCQ-AS1 was identified as the regulator for further investigation in sepsis. RT-qPCR results showed that PRKCQ-AS1 expression was up-regulated in clinical samples and sepsis model cells, which was an independent prognostic factor in sepsis patients. Immune correlation analysis showed that PRKCQ-AS1 was involved in the immune response and inflammatory process of sepsis. Cell function tests confirmed that PRKCQ-AS1 could inhibit sepsis model cells viability and promote cell apoptosis, inflammatory damage and oxidative stress. Conclusion: We constructed immune-related lncRNA-mRNA regulatory networks in the progression of sepsis and confirmed that PRKCQ-AS1 is an important prognostic factor affecting the progression of sepsis and is involved in immune response.

Association of Systemic Immune-Inflammation Index with Non-Alcoholic Fatty Liver Disease: A Population-Based Cross-Sectional Study.

Background: The aim of this study was to explore the relationship between systemic immune-inflammation (SII) index with non-alcoholic fatty liver disease (NAFLD) in the general population of the United States (U.S.). Methods: We conducted a cross-sectional study of subjects in the National Health and Nutrition Examination Survey 2017-2018. For the analysis of the association between SII index and risk of NAFLD, the restricted cubic spline (RCS) plot, we performed multivariable logistic regression models and subgroup analysis. In addition, generalized additive models with smooth functions were conducted for the relationship between the SII index and the ZJU index, the BARD score, and the NAFLD fibrosis score. Results: There were a total of 1197 individuals in our study. Taking into account known confounding variables, compared with the lowest quartiles, the odds ratios with 95% confidence intervals for NAFLD across the quartiles were 0.923 (0.585, 1.455), 0.563 (0.351, 0.901), and 1.061 (0.669, 1.682), respectively. As shown by the RCS plot, the SII index was linked with NAFLD risk in a U-shaped pattern. Based on the results of subgroup analysis, SII index and NAFLD risk were U-curve correlated among participants in all age groups, male or female, with or without hypertension, with diabetes mellitus, and with a BMI of <30 or >30 kg/m2. The SII index was linearly positive with the ZJU index but negative with the NAFLD fibrosis score. However, the SII index and BARD score showed a trend of first decreasing, then increasing, and then decreasing. Conclusion: The U-shaped relationships exist between SII index and risk of NAFLD, which highlighted that we should focus on the dynamic change of SII index.

Screening and Biological Function Analysis of miRNA and mRNA Related to Lung Adenocarcinoma Based on Bioinformatics Technology.

Objective: To screen the differentially expressed miRNAs (DEMs) and the differentially expressed gene mRNAs (DEGs) in lung adenocarcinoma (LUAD) from the TCGA database and to explore the relationship between miRNAs and the prognosis of lung adenocarcinoma and their biological functions. Methods: The RNA-seq and miRNA-seq data of lung adenocarcinoma samples were downloaded from the TCGA database for analysis, and the R program was used to screen for differentially expressed miRNAs and mRNAs. Then, the molecular functions, biological processes, cellular components, and signaling pathways involved in the occurrence and development of LUAD were analyzed using the functional accumulation analysis software of GSEA. The relationship between the integrated differentially expressed RNAs was analyzed by miRcode, TargetScan, and miRTarbase databases, and the miRNA-mRNA network was constructed. Result: A total of 516 differentially expressed miRNAs and 5464 differentially expressed mRNAs were identified in LUAD. The GSEA enrichment analysis showed that miRNAs and mRNAs were mainly enriched in extracellular structure organization, external encapsulating structure organization, extracellular matrix organization, and gated channel activity. They were mainly involved in neuroactive ligand-receptor interaction signaling pathway. Some miRNAs and mRNAs in clustering modules were found to be associated with the prognosis of LUAD. Four targeting networks consisting of 22 miRNAs and 531 mRNAs were constructed. Conclusion: The miRNA and mRNA related to the prognosis of LUAD were screened out, which provided a valuable preliminary basis for the follow-upin-depth clinical research and basic experimental research of LUAD.

NF-κB/ABCA1 pathway aggravates ox-LDL-induced cell pyroptosis by activation of NLRP3 inflammasomes in THP-1-derived macrophages.

OBJECTIVE: NF-κB (nuclear transcription factor-kappa B) plays a well-known function in the regulation of immune responses and inflammation, but growing evidences support a major role of it in atherosclerosis. Currently, the regulatory mechanism of NF-κB pathway involved in atherosclerosis remains unclear. METHODS: To investigate the role of ox-LDL (oxidized low-density lipoprotein) in NF-κB regulation, the protein expression of phosphorylated NF-κB, a marker of NF-κB pathway activation was measured. The pyroptosis of macrophage was evaluated by western blot and fluorescence microscope. Cholesterol efflux capacity was determined by fluorescence assay and oil red O staining. The inhibitor of activation of NF-κB signal was used to assess the effect of NF-κB signal on macrophage pyroptosis and cholesterol efflux in macrophage. Small interfering RNA of ABCA1 (cholesterol transporters ATP binding boxes A1) was used to assess the effect of ABCA1 on macrophage pyroptosis. RESULTS: In this study, we reported THP-1 derived macrophage can be stimulated to increase pyroptosis by ox-LDL in a concentration-dependent manner. Macrophage pyroptosis was correlated with enhanced activation of NF-κB signal. After using inhibitor of NF-κB phosphorylation to attenuate activation of NF-κB signal, we identified and confirmed the decrease of macrophage pyroptosis and the occurrence of ox-LDL-induced cholesterol efflux disorder. Furthermore, we found that the downregulation of ABCA1 led to increased cell inflammation death. But pyroptosis was blocked, may led to cholesterol efflux dysfunction. CONCLUSION: Taken together, the present results indicate that the mechanism of NF-κB involved in the development of atherosclerosis depends on mediating cell pyroptosis and cholesterol efflux and provide significant light on macrophage NF-κB signal in atherosclerosis.

Cardioprotection of M2 macrophages-derived exosomal microRNA-24-3p/Tnfsf10 axis against myocardial injury after sepsis.

OBJECTIVE: Some reports have suggested the involvement of microRNA-24-3p (miR-24-3p) in heart diseases. Here, the intention of this work was to unmask whether miR-24-3p from M2 macrophages-derived exosomes (M2-exo) could protect against myocardial injury after sepsis. METHODS: Mice model of sepsis was induced by intraperitoneal injection of lipopolysaccharide (LPS). miR-24-3p and tumor necrosis factor superfamily member 10 (Tnfsf10) expression levels were measured in the myocardial tissue of septic mice. M2-exo were isolated, in which miR-24-3p expression was altered. Then, septic mice were alone or in combination injected with the miR-24-3p-modified M2-exo or siRNA of Tnfsf10. Subsequently, cardiac function, apoptosis and serum inflammatory response were examined. RESULTS: miR-24-3p expression dropped while Tnfsf10 expression raised in the myocardial tissue of septic mice. M2-exo-derived miR-24-3p or deficiency of Tnfsf10 had cardioprotective effects on LPS-induced myocardial injury in mice through improving cardiac function and reducing cardiomyocyte apoptosis in the myocardial tissue and serum inflammation. A binding relation exhibited between miR-24-3p and Tnfsf10, and M2-exo-derived miR-24-3p alleviated LPS-induced myocardial injury by inhibiting Tnfsf10. CONCLUSION: Up-regulating miR-24-3p from M2-exo imposes cardioprotection against myocardial injury after sepsis through reducing Tnfsf10 expression.

A feedback loop: Interactions between Inflammatory Signals and Clonal Hematopoiesis in Cardiovascular Disease.

Age and inflammation are powerful drivers of cardiovascular disease. With the growing recognition that traditional cardiovascular risk factors are not fully accurate predictors of cardiovascular disease, recent studies have revealed the prevalence of positive selection of somatic cell mutations in hematopoietic stem cells in the elderly population, which can cause clonal hematopoiesis. Interestingly, clonal hematopoiesis is not only associated with cancer and death, but also closely related to the risk of increased cardiovascular disease due to mutations in TET2, DNMT3A, ASXL1, and JAK2. However, the mechanism of the interaction of clonal hematopoiesis and cardiovascular disease is only partially understood. In mice, somatic mutations have led to significantly increased expression of inflammatory genes in innate immune cells, which may explain the relationship between mutations and cardiovascular disease. Here, we further discuss the association between inflammatory signaling, clonal hematopoiesis, and cardiovascular disease,and using two hypotheses to propose a feedback loop between inflammatory signaling and clonal hematopoiesis for getting insight into the pathogenesis of cardiovascular diseases in depth. Therapies targeting mutant clones or increased inflammatory mediators may be useful for ameliorating the risk of cardiovascular disease.

Autophagy blockage promotes the pyroptosis of ox-LDL-treated macrophages by modulating the p62/Nrf2/ARE axis.

Atherosclerosis, a chronic comprehensive cardiovascular disease, is characterized by the lipid infiltration, formation of foam cells derived from macrophages and inflammation in the vessel wall. Substantial evidence confirms that the activity of autophagic bodies plays a pivot role in regulating cell deaths, but the mechanisms of autophagy to regulate the pyroptosis of macrophages in atherosclerosis remain unclear. In our study, we explored that ox-LDL decreased the cell viability and destroyed the integrity of cell membrane, resulting in the pyroptosis of THP-1 derived macrophages in a dose-dependent manner. Western blotting, qRT-PCR and ELISA also showed that chloroquine (CQ) could up-regulate the expression of p62 through impairing autophagy and induce the pyroptosis of macrophages treated by ox-LDL, as evidenced by the decrease of cell viability and membrane integrity, and the increase of pro-caspase-1, GSDMD, and proinflammatory factors IL-1ß and IL-18. Further researches demonstrated that Nrf2, a nuclear factor activated by p62, was linked to macrophage pyroptosis. Overactivating or suppressing Nrf2/ARE signaling would correspondingly aggravate or alleviate pyroptosis, in which the level of p62 was regulated by Nrf2 feedback. Then, bioinformatic analysis verified that there was a close interaction between p62, Nrf2/ARE signaling proteins and pyroptosis-related proteins. Taken together, our results show that blocking autophagy promotes the pyroptosis of ox-LDL-treated macrophages via the p62/Nrf2/ARE axis, providing a novel therapeutic target for atherosclerosis.

Improving smallholder farmers' maize yields and economic benefits under sustainable crop intensification in the North China Plain.

To meet the food demands of a growing population, the maize production systems deployed by smallholders in China have tended towards extremely intensive planting and excessive use of fertilizers, which have caused serious environmental impacts. This study investigated the balance between the maize yield and nitrogen (N) input in the North China Plain (NCP), which is one of the most important grain-producing region in China. Our study compared yield simulations generated by the DSSAT-CERES-Maize model with actual data from a number of multi-site field experiments and an extensive household surveys encompassing 1671 farmers. The smallholders' maize cultivars, plant population, and amount of N input on the crop yield and how these affects the economic benefits were analyzed. The results showed that the average traditional farming methods' yield was 72% of the attainable yield, which means that farmers have ample room to improve their yields. We also found that the maize yields varied widely between farmers, and that most of them applied excessive amounts of N but failing to achieve an optimal yield due to poor fertilization management techniques. The study found that the economic benefits achieved by the farmers were low, but after deploying high-yield (HY) methods, the yield was increased by 34.9% and the economic benefits by 14.4%. The greenhouse gas (GHG) emissions associated with the traditional farming methods were high and could potentially be reduced by 48.6%. All in all, farmers should be given guidance on how to appropriately increase the plant population, reduce the input of N fertilizer, and optimize farmland management measures, so that China can achieve intensive but sustainable agricultural production at a lower environmental cost. It was concluded that there are still numerous biological and abiotic factors that restrict production increases by smallholders. These factors vary from region to region and require further investigation.

Study protocol: a multicentre, prospective, phase II trial of isotoxic hypofractionated concurrent chemoradiotherapy for non-small cell lung cancer.

INTRODUCTION: Concurrent chemoradiotherapy with conventional fractionation has been acknowledged as one of the standard treatments for locally advanced non-small cell lung cancer (NSCLC). The radiotherapy dose of 60 Gy is far from enough for local tumour control. Due to this fact, hypofractionated radiotherapy can shorten the total treatment duration, partially counteract the accelerated repopulation of tumour cells and deliver a higher biological effective dose, it has been increasingly used for NSCLC. In theory, concurrent hypofractionated chemoradiotherapy can result in an enhanced curative effect. To date, the vast majority of radiotherapy prescriptions assign a uniform radiotherapy dose to all patients. However this kind of uniform radiotherapy prescription may lead to two consequences: excess damage to normal tissues for large tumours and insufficient dose for small tumours. Our study aims to evaluate whether delivering individualised radiotherapy dose is feasible using intensity-modulated radiotherapy. METHODS AND ANALYSIS: Our study of individualised radiotherapy is a multicenter phase II trial. From April 2019, a total of 30 patients from three Chinese centres, with a proven histological or cytological diagnosis of inoperable NSCLC, will be recruited. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 69 Gy is reached. The primary end point is feasibility, with response rates, progression-free survival and overall survival as secondary end points. The concurrent chemotherapy regimen will be docetaxel plus lobaplatin. ETHICS AND DISSEMINATION: The study has been approved by medical ethics committees from three research centres. The trial is conducted in accordance with the Declaration of Helsinki.The trial results will be disseminated through academic conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03606239.

Cryoablation combined with radiotherapy for hepatic malignancy: Five case reports.

BACKGROUND: The survival of patients treated with monotherapy for hepatic malignancies is not ideal. A comprehensive program of cryoablation combined with radiotherapy for the treatment of hepatic malignancies results in less trauma to the patients. It may provide an option for the treatment of patients with advanced hepatic malignancies. CASE SUMMARY: We reported 5 cases of advanced-stage hepatic malignancies treated in our hospital from 2017-2018, including 3 cases of primary hepatocellular carcinoma and 2 cases of metastatic hepatic carcinoma. They first received cryoablation therapy on their liver lesions. The procedure consisted of 2 freeze-thaw cycles, and for each session, the duration of freezing was 13-15 min, and the natural re-warming period was 2-8 min. Depending on the tumor size, the appropriate cryoprobes were selected to achieve complete tumor ablation to the greatest extent possible. After cryoablation surgery, intensity-modulated radiotherapy (IMRT) for liver lesions was performed, and the radiotherapy regimen was 5400 cGy/18f and 300 cGy/f. None of the 5 patients had adverse events above grade II, and their quality of life was significantly improved. Among them, 4 patients were free of disease progression in the liver lesions under local control, and their survival was prolonged; 3 patients are still alive. CONCLUSION: Our clinical practice demonstrated that cryoablation combined with IMRT could be implemented safely. The definitive efficacy for hepatic malignancies needs to be confirmed in larger-size sample prospective studies.

High-intensity focused ultrasound combined with transcatheter arterial chemoembolization and radiotherapy for advanced hepatocellular carcinoma: A case report.

INTRODUCTION: Primary hepatocellular carcinoma (HCC) is one of the most common malignancies, only 10% to 20% of HCC patients are surgically resectable as most of the patients are diagnosed at advanced stages at presentation. The efficiencies of transcatheter arterial chemoembolization (TACE), high-intensity focused ultrasound (HIFU), and three-dimensional conformal radiation therapy (3D-CRT) in patients with advanced HCC have been clinically confirmed. We here report a patient with HCC accompanied by venous tumor thrombus, who was treated with the combination of these 3 therapies. The patient survived for 16 months with good quality of life. PATIENT CONCERNS: The patient was a 72-year-old male with a primary multicentric HCC accompanied by tumor thrombus in the right hepatic vein. The patient had the symptoms of abdominal distention and liver pain. He refused sorafenib treatment because of personal reason. DIAGNOSIS: Primary multicentric HCC stage IIIB cT4N0M0, accompanied by tumor thrombus in the right hepatic vein; chronic viral hepatitis B; and hepatitis B virus-related decompensated liver cirrhosis. INTERVENTIONS: TACE + HIFU + 3D-CRT. OUTCOMES: The patient had an overall survival of 16 months with good quality of life. Compared with monotherapy, the combined therapy significantly prolonged patient survival time with improved clinical benefits. CONCLUSION: The combination of TACE, HIFU, and 3D-CRT is safe and effective in the treatment of advanced HCC, which provides a possible comprehensive treatment strategy for advanced HCC.

One stone two birds: cobalt-catalyzed in situ generation of isocyanates and benzyl alcohols for the synthesis of N-aryl carbamates.

An efficient method for the synthesis of N-aryl carbamates from N-Boc-protected amines has been developed. The cobalt-catalyzed in situ generation of isocyanates from N-Boc-protected amines and benzyl alcohols from benzyl formates has been achieved for the first time, which in turn furnished the corresponding benzyl carbamates in moderate to high yields. The reaction was catalyzed by CoI2 with tris-(4-dimethylaminophenyl)-phosphine as the ligand and zinc powder as the reductant. The developed reaction conditions were found to be compatible for aromatic amines with both electron-donating and -withdrawing substituents.

Progress in image-guided radiotherapy for the treatment of non-small cell lung cancer.

Lung cancer is one of the most common malignant tumors. It has the highest incidence and mortality rate of all cancers worldwide. Late diagnosis of non-small cell lung cancer (NSCLC) is very common in clinical practice, and most patients miss the chance for radical surgery. Thus, radiotherapy plays an indispensable role in the treatment of NSCLC. Radiotherapy technology has evolved from the classic two-dimensional approach to three-dimensional conformal and intensity-modulated radiotherapy. However, how to ensure delivery of an accurate dose to the tumor while minimizing the irradiation of normal tissues remains a huge challenge for radiation oncologists, especially due to the positioning error between fractions and the autonomous movement of organs. In recent years, image-guided radiotherapy (IGRT) has greatly increased the accuracy of tumor irradiation while reducing the irradiation dose delivered to healthy tissues and organs. This paper presents a brief review of the definition of IGRT and the various technologies and applications of IGRT. IGRT can help ensure accurate dosing of the target area and reduce radiation damage to the surrounding normal tissue. IGRT may increase the local control rate of tumors and reduce the incidence of radio-therapeutic complications.

Preparation of CaO-containing carbon pellet from recycling of carbide slag: Effects of temperature and H3PO4.

CaO-containing carbon pellets (CCCP) was prepared by mixing carbide slag (Ca(OH)2) and powdered char to produce CaC2, achieving the recycling of carbide slag during CaC2 production process. The thermal strength of CCCP was the focus of most attention when employing arc furnaces as reactors for CaC2 production in industry. To improve the thermal strength of CCCP, H3PO4 was used as a binder in this study. The results indicated that Ca3(PO4)2 reacted by H3PO4 and Ca(OH)2 could help refine the average particle sizes of CaO, resulted in a relatively uniform pore diameter distribution of CCCP with low porosity, therefore improving the thermal strength of CCCP. When H3PO4 content was more than 8 wt%, some over-sintering and melting structure for CaO particles appear, and thus resulting in the decrease in thermal strength of CCCP. The experimental results show that CCCP with 3% H3PO4 has the best thermal strength at 1100 °C. The non-isothermal shrinkage kinetics of CCCP indicated that the addition of 3% H3PO4 reduced the apparent activation energy of sintering reactions and accelerated the sintering of CaO particles in CCCP. Furthermore, the addition of H3PO4 has a positive effect on the formation of CaO sintered necks, enhancing the strength of CCCP.

Regulation between two alternative splicing isoforms ZNF148FL and ZNF148ΔN, and their roles in the apoptosis and invasion of colorectal cancer.

OBJECTIVE: To investigate the effect of two alternative splicing isoforms of zinc finger protein (ZNF) 148 gene on the invasion and metastasis of human colorectal cancer (CRC) cells and their related mechanisms. METHODS: Quantitative RT-PCR assays were used to detect the expression of twoZNF148 alternative splicing isoforms in SW480 cells. ZNF148FL-siRNA, ZNF148FL-over express vector, ZNF148ΔN-siRNA, and ZNF148ΔN-over express vector were introduced into SW480 cells. The transfection efficiency was confirmed by RT-PCR. The proliferation, invasion, and migration in vitro as well as the apoptosis of SW480 cells were detected by MTT, transwell, scratch assay and flow cytometry, respectively. RESULTS: Both ZNF148FL and ZNF148ΔN were expressed in SW480 cells, and the level of ZNF148FL protein was higher than ZNF148ΔN. After ZNF148FL-siRNA and ZNF148ΔN-over express transfection, the expression level of ZNF148FL and ZNF148ΔN were significantly decreased and increased, respectively. In contrast, the expression of ZNF148FL and ZNF148ΔN were significantly increased and decreased, respectively, after ZNF148FL-over express and ZNF148ΔN-siRNA transfection (all P < 0.05). The proliferation of SW480 cells was increased in ZNF148FL-over express group and the ZNF148ΔN-siRNA group, while decreased in ZNF148FL-siRNA group and ZNF148ΔN-over express group. The invaded cell number and migrated distance in ZNF148FL-siRNA group and ZNF148ΔN-over express group were significantly decreased, but the apoptotic rate was significantly increased. In contrast, ZNF148FL-over express and ZNF148ΔN-siRNA group showed the significantly increased ability of invasion and migration but decreased apoptosis rate (all P < 0.05). CONCLUSION: ZNF148FL could increase proliferation, invasion, and migration of CRC cells, while ZNF148ΔN showed opposite effect; the two splicing isoforms of ZNF148 may exert a mutual antagonistic effect to each other on the malignant biological activities.

Overexpression of VpPR10.1 by an efficient transformation method enhances downy mildew resistance in V. vinifera.

KEY MESSAGE: Putrescine and spermidine increase the transformation efficiency of Vitis vinifera L. cv. Thompson seedless. Accumulation of VpPR10.1 in transgenic V. vinifera Thompson seedless, likely increases its resistance to downy mildew. A more efficient method is described for facilitating Agrobacterium-mediated transformation of Vitis vinifera L. cv. Thompson Seedless somatic embryogenesis using polyamines (PAs). The efficacies of putrescine, spermidine and spermine are identified at a range of concentrations (10 µM, 100 µM and 1 mM) added to the culture medium during somatic embryo growth. Putrescine (PUT) and spermidine (SPD) promote the recovery of proembryonic masses (PEM) and the development of somatic embryos (SE) after co-cultivation. Judging from the importance of the time-frame in genetic transformation, PAs added at the co-cultivation stage have a stronger effect than delayed selection treatments, which are superior to antibiotic treatments in the selection stage. Best embryogenic responses are with 1 mM PUT and 100 µM SPD added to the co-culture medium. Using the above method, a pathogenesis-related gene (VpPR10.1) from Chinese wild Vitis pseudoreticulata was transferred into Thompson Seedless for functional evaluation. The transgenic line, confirmed by western blot analysis, was inoculated with Plasmopara viticola to test for downy mildew resistance. Based on observed restrictions of hyphal growth and increases in H2O2 accumulation in the transgenic plants, the accumulation of VpPR10.1 likely enhanced the transgenic plants resistance to downy mildew.

Accelerated hypofractionated three-dimensional conformal radiation therapy (3 Gy/fraction) combined with concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer: preliminary results of an early terminated phase II trial.

BACKGROUND: Increasing the biological effective dose (BED) of radiotherapy for non-small cell lung cancer (NSCLC) can increase local control rates and improve overall survival. Compared with conventional fractionated radiotherapy, accelerated hypofractionated radiotherapy can yield higher BED, shorten the total treatment time, and theoretically obtain better efficacy. However, currently, there is no optimal hypofractionated radiotherapy regimen. Based on phase I trial results, we performed this phase II trial to further evaluate the safety and preliminary efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy(3-DCRT) combined with concurrent chemotherapy for patients with unresectable stage III NSCLC. METHODS: Patients with previously untreated unresectable stage III NSCLC received 3-DCRT with a total dose of 69 Gy, delivered at 3 Gy per fraction, once daily, five fractions per week, completed within 4.6 weeks. At the same time, platinum doublet chemotherapy was applied. RESULTS: After 12 patients were enrolled in the group, the trial was terminated early. There were five cases of grade III radiation esophagitis, of which four cases completed the radiation doses of 51 Gy, 51 Gy, 54 Gy, and 66 Gy, and one case had 16 days of radiation interruption. The incidence of grade III acute esophagitis in patients receiving an irradiation dose per fraction ≥2.7 Gy on the esophagus was 83.3% (5/6). The incidence of symptomatic grade III radiation pneumonitis among the seven patients who completed 69 Gy according to the plan was 28.6% (2/7). The median local control (LC) and overall survival (OS) were not achieved; the 1-year LC rate was 59.3%, and the 1-year OS rate was 78.6%. CONCLUSION: For unresectable stage III NSCLC, the accelerated hypofractionated radiotherapy with a total dose of 69 Gy (3 Gy/f) combined with concurrent chemotherapy might result in severe radiation esophagitis and pneumonitis to severely affect the completion of the radiotherapy. Therefore, we considered that this regimen was infeasible. During the hypofractionated radiotherapy with concurrent chemotherapy, the irradiation dose per fraction to esophagus should be lower than 2.7 Gy. Further studies should be performed using esophageal tolerance as a metric in dose escalation protocols. TRIAL REGISTRATION: NCT02720614, the date of registration: March 23, 2016.

A phase I clinical trial of dose escalation of lobaplatin in combination with fixed-dose docetaxel for the treatment of human solid tumours that had progressed following chemotherapy.

In this study, the maximum tolerated dose (MTD) of lobaplatin (LBP) when it was combined with docetaxel (TXT) for the treatment of solid tumours that had progressed following chemotherapy was determined, and toxicities to this regimen were evaluated. A modified Fibonacci method was used for the dose escalation of LBP. The patients received TXT (at a fixed dose of 60 mg/m2) on day one (d1) and LBP (at an initial tested dose of 30 mg/m2) on day two (d2) of a treatment cycle that was repeated every 21 days. Each dose group consisted of at least three cases. In the absence of dose-limiting toxicity (DLT), we proceeded to the next dose group, with a dose increment of 5 mg/m2 between groups, until DLT occurred. The dose immediately below the dose that produced DLT was regarded as the MTD. The 17 patients examined in this study completed a total of 58 cycles of chemotherapy, and a total of three dose-escalation groups (30 mg/m2 LBP, 35 mg/m2 LBP, and 40 mg/m2 LBP) were established. The main adverse event that was observed was myelosuppression. DLT occurred in four patients, including three patients in the 40 mg/m2 LBP group and one patient in the 35 mg/m2 LBP group. In total, three out of the four patients in the 40 mg/m2 LBP group exhibited DLT. We determined that the treatment administered to the 35 mg/m2 LBP group represented the MTD. Thus, our phase I trial revealed that the MTD for the tested LBP combination regimen was 35 mg/m2 LBP and 60 mg/m2 TXT. This regimen resulted in mild adverse reactions and favourable patient tolerance. Therefore, we recommend the use of these dosages in phase II clinical trials.

DCF intraperitoneal and intravenous dual chemotherapy regimen for advanced gastric cancer: A feasibility study.

Gastric cancer is the fourth most common type of cancer globally and accounts for the second highest cancer-associated mortality rate in the world. Current treatment strategies for gastric cancer include surgery, radiotherapy, chemotherapy and targeted therapy. Intraperitoneal (IP) chemotherapy may increase the IP concentrations of chemotherapy drugs and reduce the systemic toxicity. At present, IP chemotherapy is used to treat patients with advanced gastric cancer, which has a high rate of peritoneal recurrence. The present study evaluated the feasibility of using docetaxel, cisplatin and fluorouracil (DCF) in an IP and intravenous (IV) dual chemotherapy regimen for the treatment of advanced gastric cancer. The treatment-associated adverse reactions and preliminary efficacy were reported. The first dose level utilized the full dose of DCF: Docetaxel, day one, 45 mg/m2 (IP) and day eight, 30 mg/m2 (IV); cisplatin (DDP), day one, 75 mg/m2 (IP); and fluorouracil (FU), days one to five, 750 mg/m2 (continuous IV). A total of six patients were treated at this level and two patients withdrew due to serious adverse reactions. Taking into account that the the tolerated doses used in combination regimens for Eastern populations are lower than that of the corresponding doses for Western populations, the dosages of the three drugs were all reduced by 20% in the application of the second dose level: Docetaxel, day one, 30 mg/m2 (IP) and day eight, 30 mg/m2 (IV); DDP, day two, 60 mg/m2 (IP); and FU, days one to five, 600 mg/m2 (continuous IV). A total of 26 patients were treated at this level. The main adverse reaction was bone marrow suppression, with grade III/IV neutropenia, leukopenia and febrile neutropenia accounting for 61.5, 53.8 and 19.2% of reactions, respectively, and grade III/IV anemia and thrombocytopenia accounting for 19.2 and 15.4% of reactions, respectively. Gastrointestinal adverse reactions primarily consisted of abdominal pain, with grade III/IV abdominal pain accounting for 30.8% of reactions. Only 7.7% of the patients withdrew from the treatment. The median time to progression (TTP) was five months [95% confidence interval (CI), 1.0-9.0 months], and the median overall survival (OS) was nine months (95% CI, 7.4-10.6 months). It was concluded that the DCF regimen with reduced dosage should be applied. IP and IV dual chemotherapy for the treatment of unresectable advanced gastric cancer is tolerated and demonstrated a good initial efficacy. Strategies for mitigating and reducing the adverse gastrointestinal reactions, particularly abdominal pain, may be the focus of future studies.

Phase II clinical trial of whole-brain irradiation plus three-dimensional conformal boost with concurrent topotecan for brain metastases from lung cancer.

BACKGROUND: Patients with brain metastases from lung cancer have poor prognoses and short survival time, and they are often excluded from clinical trials. Whole-cranial irradiation is considered to be the standard treatment, but its efficacy is not satisfactory. The purpose of this phase II clinical trial was to evaluate the preliminary efficacy and safety of the treatment of whole-brain irradiation plus three-dimensional conformal boost combined with concurrent topotecan for the patients with brain metastases from lung cancer. METHODS: Patients with brain metastasis from lung cancer received concurrent chemotherapy and radiotherapy: conventional fractionated whole-brain irradiation, 2 fields/time, 1 fraction/day, 2 Gy/fraction, 5 times/week, and DT 40 Gy/20 fractions; for the patients with ≤ 3 lesions with diameter ≥ 2 cm, a three-dimensional (3-D) conformal localised boost was given to increase the dosage to 56-60 Gy; and during radiotherapy, concurrent chemotherapy with topotecan was given (the chemoradiotherapy group, CRT). The patients with brain metastasis from lung cancer during the same period who received radiotherapy only were selected as the controls (the radiotherapy-alone group, RT). RESULTS: From March 2009 to March 2012, both 38 patients were enrolled into two groups. The median progression-free survival(PFS) time , the 1- and 2-year PFS rates of CRT group and RT group were 6 months, 42.8%, 21.6% and 3 months, 11.6%, 8.7% (χ2 = 6.02, p = 0.014), respectively. The 1- and 2-year intracranial lesion control rates of CRT and RT were 75.9% , 65.2% and 41.6% , 31.2% (χ2 = 3.892, p = 0.049), respectively. The 1- and 2-year overall survival rates (OS) of CRT and RT were 50.8% , 37.9% and 40.4% , 16.5% (χ2 = 1.811, p = 0.178), respectively. The major side effects were myelosuppression and digestive toxicities, but no differences were observed between the two groups. CONCLUSION: Compared with radiotherapy alone, whole-brain irradiation plus 3-D conformal boost irradiation and concurrent topotecan chemotherapy significantly improved the PFS rate and the intracranial lesion control rate of patients with brain metastases from lung cancer, and no significant increases in side effects were observed. Based on these results, this treatment method is recommended for phase III clinical trial.