Comparison of the efficacy and safety of cisplatin, etoposide, and irinotecan combined with chemotherapy and topotecan monotherapy as second-line treatment for patients with sensitive relapsed SCLC / 中国肿瘤临床

Objective: To investigate whether combination chemotherapy with cisplatin, etoposide, and irinotecan was better than topotecan alone as second-line chemotherapy in patients with sensitive relapsed small cell lung cancer (SCLC). Method: Between September, 2014 and September, 2017, the patients'data were collected in Jilin Province Cancer Hospital. All patients were diagnosed with sensitive relapsed SCLC. Thirty-six patients received combination chemotherapy containing cisplatin plus etoposide plus irinotecan, and 42 patients received topotecan alone. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m2 on days 1 and 8, intravenous etoposide 60 mg/m2 on days 1-3, and intravenous irinotecan 90 mg/m2 on day 8. Topotecan therapy consisted of at least one course of intravenous topotecan 1.5 mg/m2 on days 1-5, every 3 weeks. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and safety was assessed in all patients who received at least one dose of drugs. Results: PFS was significantly longer in the combination chemotherapy group [median 5.3 months, 95% confidence interval (CI) 4.3-5.8] than in the topotecan group (3.2 months, 95% CI: 2.7-4.0;P=0.0030); OS was also significantly increased in the combination chemotherapy group (median 16.3 months, 95% CI: 13.8-19.1) than in the topotecan group (13.1 months, 95% CI: 10.2-15.4; P=0.0097). The most common grade 3/4 adverse events were neutropenia [31 (86.1%) patients in the combination chemotherapy group vs. 28 (66.7%) patients in the topotecan group], anemia [26 (72.2%) vs. 10 (23.8%)], leucopenia [29 (80.6%) vs . 21 (50.0%)], and thrombocytopenia [13 (36.1%) vs . 11 (26.2%)]. One treatment-related death (febrile neutropenia with pulmonary infection) occurred in the combination chemotherapy group, and none occurred in the topotecan group. Conclusions:Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered a treatment option in second-line che-motherapy for selected patients with sensitive relapsed SCLC. However, the combination chemotherapy group had a higher incidence of adverse events than the topotecan group, and appropriate drug dosages should be explored.

Expression of silent information regulator in brains of rats with chronic fluorosis and its correlation with the ability of learning and memory / 中华地方病学杂志

Objective To study the expression of silent information regulator (SIRT) in brains of rats with chronic fluorosis and reveal the correlation between SIRT1 and the ability of learning and memory of rats.Methods Sixty SD rats were selected and their body weight was (100 ± 20) g,according to the body mass of the rats,random number table method was used to divide rats into control group,low and high fluoride groups,experimental period was 3 and 6 months (ten rats in each experimental period,half males and half females).In control group,the rats were fed with drinking water containing no more than 0.5 mg/L fluoride;the rats in low and high fluoride groups were fed drinking water containing 5.0 and 50.0 mg/L fluoride,respectively.All of rats were fed the same standard food containing no more than 0.6 mg/kg fluoride.Three degree method was used to check the formation of dental fluorosis.Rat urinary fluoride was determined via the fluoride electrode method;Morris water maze method was used to detect the ability of learning and memory of rats (the escape latency time,the number of crossing the platform and stay time in platform quadrant);the protein and mRNA expression levels of SIRT1 were detected by Western blotting and Real-time PCR,respectively.Results In the experimental period of 3 and 6 months,no dental fluorosis was observed of rats in control group,but there were different degrees of dental fluorosis in low and high fluoride groups,especially in high fluoride group.The urinary fluorine contents [(1.60 ± 0.09),(1.91 ± 0.16) mg/L;(1.94 ± 0.19),(2.31 ± 0.18) mg/L] of rats fed with low and high fluoride for 3 or 6 months were significantly higher than those in control group [(1.08 ± 0.15),(1.09 ± 0.17) mg/L,P ＜ 0.05].The escape latency time [(18.36 ± 2.80) s] of rats in the high fluoride group at the end of 3 months was higher than that of control group [(6.68 ± 3.01) s,P ＜ 0.05],the number of stay time in platform quadrant [(12.91 ± 3.25) s] was lower than that of control group [(19.97 ± 3.30) s,P ＜ 0.05].The escape latency time [(15.46 ± 4.56),(28.16 ± 4.00) s] of rats in low and high fluoride groups at the end of 6 months were all higher than that of control group [(6.62 ± 2.31) s,P ＜ 0.05];the number of crossing the platform and stay time in platform quadrant [(2.25 ± 1.71) times,(12.73 ± 3.55) s;(1.40 ± 1.15) times,(9.26 ± 1.72) s] of these rats were significantly lower than those of the control group [(4.00 ± 1.58) times,(19.53 ± 4.36) s,P ＜ 0.05].The expression levels of protein [(73.84 ± 9.68)％,(73.23 ± 4.51)％;(53.30 ± 17.63)％,(54.69 ± 18.71)％] and mRNA [(70.33 ± 4.89)％,(66.27 ± 3.38)％;(37.72 ± 4.89)％,(44.15 ± 1.74)％] of SIRT1 in the hippocampus and cortex of rats fed with high fluoride for 3 or 6 months were significantly lower than those in control group [(100.00 ± 13.51)％,(100.00 ± 13.60)％;(100.00 ± 15.37)％,(100.00 ± 12.19)％;(100.00 ± 2.65)％,(100.00 ± 4.34)％;(100.00 ± 3.40)％,(100.00 ± 4.52)％,P ＜ 0.05].Whereas,the decreased expression levels of protein [(77.65 ± 14.51)％,(71.51 ± 8.27)％] and mRNA [(57.78 ± 1.96)％,(63.76 ± 2.16)％] of SIRT1 in the hippocampus and cortex of rats in the low fluoride group were only observed at the end of 6 month of experiment (P ＜ 0.05).The expression of protein of SIRT1 in the hippocampus and cortex of rats in 3 or 6 months was negatively correlated with the escape latency time of rats (r=-0.598 5,-0.493 2;-0.782 6,-0.777 3,P＜ 0.05),and it was positively correlated with the number of crossing the platform (r =0.547 7,0.523 3;0.720 5,0.715 4,P ＜ 0.05).Conclusion The decrease of the ability of learning and memory in rats with chronic fluorosis may be related to the decreased expression of SIRT1 influenced by chronic fluorosis.

Correlation between expression of peroxisome proliferator-activated receptor γ and oxidative stress in brains of rats with chronic fluorosis / 中华地方病学杂志

Objective To detect the expression of peroxisome proliferator-activated receptor γ (PPARγ) in the brains of rats with chronic fluorosis and elucidate the relationship between PPARγand oxidative stress in chronic fluorosis.Methods According to body weight (100-120 g),sixty healthy SD rats were divided into control group (less than 0.5 mg/L fluoride in drinking water),low fluoride group (5.0 mg/L fluoride in drinking water,prepared by NaF),and high fluoride group (50.0 mg/L fluoride in drinking water) via the random number table method,20 rats in each group (half male and half female).The experiment periods were 3 and 6 months,respectively.Then 24-hour urine samples of rats were collected from each group,all rats were put to death and brain tissues were taken.The fluoride contents in urine and brain tissue were measured with fluoride-ion selective electrode;the levels of PPARγ protein and mRNA in the cortex and hippocampus were determined by Western blotting and Real-time fluorescence quantitative PCR,respectively;and the activities of superoxide dismutase (SOD) and level of malondialdehyde (MDA) in serum were detected by xanthine oxidase method and thiobarbituric acid method;the correlation between PPARγ protein expression and oxidative stress was analyzed.Results After 3 and 6 months of treatment,the contents of fluoride in urine and brain in low fluoride group [(1.57 ± 0.18) mg/L,(3.43 ± 0.70) μg/g;(1.79 ± 0.17) mg/L,(7.40 ± 1.21) μg/g] were higher than those of control group [(1.11 ± 0.17) mg/L,(2.39 ± 0.50) μg/g;(1.02 ± 0.15) mg/L,(2.87 ± 0.82) μg/g,P ＜ 0.05],and the values in high fluoride group [(1.91 ± 0.23) mg/L,(6.70 ± 0.87) μg/g;(2.44 ± 0.51) mg/L,(12.10 ± 1.30) μg/g] were significantly higher than those in low fluoride group (P ＜ 0.05).In high fluoride group after 3 months of treatment,the expression of PPARγprotein [(79.00 ± 3.46)％,(80.35 ± 2.50)％] and mRNA [(79.11 ± 11.18)％,(82.10 ± 9.94)％] in hippocampus and cortex of rat brains were significantly lower than those of low fluoride group [(104.01 ± 5.77)％,(101.17 ± 6.35)％;(112.88 ± 22.15)％,(101.14 ± 8.60)％,P＜ 0.05];the expression of PPARγprotein [(64.32 ± 10.43)％,(60.20 ± 10.92)％] and mRNA [(41.03 ± 9.93)％,(52.25 ± 11.48)％] in the same brain regions of the rats after 6 months of treatment in high fluoride group were significantly lower than those of control group [(99.99 ± 11.19)％,(100.00 ± 11.30)％;(100.00 ± 10.00)％,(100.00 ± 9.00)％] and low fluoride group [(73.88 ± 3.36)％,(81.50 ± 14.90)％;(76.02 ± 8.65)％,(73.36 ± 7.43)％,P ＜ 0.05].The activities of SOD in serum in low and high fluoride groups after 6 month treatment [(37.94 ± 1.92),(35.54 ± 2.53) U/ml] were significantly lower than that of control group [(41.24 ± 0.66) U/ml,P ＜ 0.05],and the value in high fluoride group was lower than that in low fluoride group (P ＜ 0.05);serum MDA contents in high fluoride group after 3 and 6 month treatment [(8.29 ± 1.49),(11.63 ± 1.04) nmol/mg pr] were higher than those in low fluoride group [(6.39 ± 0.69),(7.50 ± 1.64) nmol/mg pr] and control group [(5.02 ± 0.71),(5.87 ± 1.03) nmol/mg pr,P ＜ 0.05].The correlation analysis results showed the levels of PPARγprotein in hippocampus and cortex of rats were negatively correlated with fluoride contents in brain tissues (3 month:r=-0.769,-0.793;6 month:r =-0.832,-0.870;P ＜ 0.05),positively correlated with SOD activities (3 month:r =0.550,0.826;6 month:r =0.822,0.896;P ＜ 0.05) and negatively correlated with MDA contents (3 month:r =-0.703,-0.609,6 month:r =-0.792,-0.657;P ＜ 0.05) in serum.Conclusions Declined expression of PPARγat protein and mRNA levels has been detected in brains of rats with chronic fluorosis,which might be related to the increase of oxidative stress.PPARγ may be involved in the occurrence of chronic fluorosis.

Comparison of EGFR mutation between supernatant and pellets of malignant pleural effusion from patients with advanced non-small cell lung cancer / 国际肿瘤学杂志

Objective To compare the epidermal growth factor receptor (EGFR) mutation differences between supernatant and pellets of malignant pleural effusion (MPE) in advanced non-small cell lung cancer (NSCLC) patients and provide the evidence for clinical accurate detection.Methods A total of 386 consecutive MPE specimens were collected in the study (202 in experimental group and 184 in validation group).Specimens in experimental group were divided into 4 groups depending on tumors cell concentration in the samples:zero cell (n =77),(1-5) × 104/ml cells (n =43),(6-10) × 104/ml cells (n =52) and ＞ 10 × 104/ml cells group (n =30).Amplification refractory mutation system (ARMS) was performed to detect EGFR gene mutation in supernatant and pellets of each individual case respectively,and the EGFR mutation positive rates were compared between the two groups.EGFR mutation test was carried out using either supematant or pellets in validation group to verify the established method.Results In the experimental group,the total EGFR mutation positive rate was 30.7％ (62/202).In the zero cell group,EGFR mutation positive rate was higher in supernatant than that in pellets (37.6％ vs.33.8％).In the (1-5) × 104/ml cells group and (6-10) × 104/ml cells group,EGFR mutation positive rate was equal but not concordant between supematant and pellets (25.6％ and 21.1％ respectively).In the ＞ 10 × 104/ml cells group,EGFR mutation positive rate was equal (33.3％) with 100％ concordance between supernatant and pellets.In the validation group (n =184),EGFR mutation rate was 32.7％ (36/110) in supernatant and 32.4％ (24/74) in pellets,and there was no statistical significance (x2 =0.02,P =0.97).Conclusion Tumor cell free MPE specimens from patients with advanced NSCLC are suitable for EGFR mutation test.Heterogeneity of MPE results in difference with respect to EGFR gene mutation status between cell-free supernatant and pellet.Pathological evaluation based on the quantity and quality of tumor cells in MPE patients prior to test and optional samples selection are necessary to increase EGFR mutation positive rate.

Disparities of EGFR mutations between Biopsy and Rebiopsy in Non-small Cell Lung Cancer Patients / 中国肺癌杂志

BACKGROUND@#Epidermal growth factor receptor (EGFR)-based targeted therapy improves the survival of patients with advanced lung adenocarcinoma harboring EGFR mutations. However, factors including treatment or heterogeneity partly contribute to EGFR genetic status alteration between baseline and disease progresses (PD). The aim of this study is to compare difference of EGFR mutations between biopsy and rebiopsy in real world.@*METHODS@#Data from 61 paired specimens performed EGFR testing in Jilin Provincial Cancer Hospital between January 2015 and December 2017 were collected and analyzed. The specimens were collected at baseline and PD, confirmed by histology or cytology and categorized as tumor tissue, malignant pleural effusion or plasma. All patients were naive and received chemotherapy or targeted therapy as first-line treatment. Amplification Refractory Mutation System (ARMS) was used to detect EGFR mutations.@*RESULTS@#EGFR mutation rate in tumor tissue, pleural effusion or blood was 90.2% vs 88.5%, 6.6% vs 6.6% and 3.2% vs 4.9% at baseline or PD respectively and discrepancy was 72% and 36.3% for the same (n=50) or different (n=11) type of specimens. The EGFR mutation rate was 95.1% and 91.8% in patients before and after treatment, and the discrepancy was 63.9%, among which, 69.2% and 92.3% in chemotherapy-treated patients (n=13) with discrepancy to 46.1% (6/13), and 100.0% and 91.7% in EGFR-TKI-treated patients (n=48) with discrepancy to 70.8%. There were four types of alterations in terms of EGFR mutations: wild type turned into mutation (4.9%), mutation disappeared (8.2%), sensitive mutations transformed (1.6%), and new mutations appeared (49.1%).@*CONCLUSIONS@#In real world, the EGFR mutation status in advanced non-small cell lung cancer (NSCLC) patients altered significantly, due to tissue resources and therapeutic approaches, implying the importance of rebiopsy and real-time detection of EGFR mutation, in order to provide data to guide precise strategy in the following treatment.

Antagonism of lovastatin on oxidative stress and apoptosis in primary rat hippocampal neurons induced by β-amyloid peptide / 中华病理学杂志

Objective@#To investigate the effect of lovastatin on oxidative stress and apoptosis in neurons induced by β-amyloid peptide (Aβ).@*Methods@#Primary culture of rat hippocampal neuron was treated with Aβ oligomers alone or combined with lovastatin. The levels of OH-, H2O2, O2·-, malondialdehyde, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were measured by biochemical methods and protein expression of caspase-3 and bcl-2 was detected by Western blot.@*Results@#As compared with the control group, treatment of 0.5 μmol/L Aβ oligomers for 48 h led to significant increase of OH-, H2O2, O2·- and malondialdehyde content, inhibition of SOD and GSH-PX activities, enhanced caspase-3 expression and decreased bcl-2 expression. Interestingly, these neurotoxic modifications on the levels of OH-, H2O2, O2·- and malondialdehyde content, SOD and GSH-PX activities, and the protein expression of cleaved caspase-3 and bcl-2 were significantly attenuated when the cells were pretreated with 0.1 μmol/L lovastatin for 24 h before exposure of Aβ oligomers.@*Conclusion@#Lovastatin may play an important role in antagonizing the neurotoxicity of Aβ through a mechanism likely related to the inhibition of oxidative stress.

Comparison of efficacy and safety of different chemotherapy regimens for progressive patients with brain metastasis of small cell lung cancer after radiotherapy / 肿瘤研究与临床

Objective To analyze the efficacy and safety of different chemotherapy regimens for treatment of progressive patients with small cell lung cancer (SCLC) brain metastasis after radiotherapy. Methods 96 SCLC brain metastasis patients with progressive intracranial lesions after radiotherapy were divided into four groups: carmustine group (Group A, 28 cases), temozolomide group (Group B, 19 cases), topotecan group (Group C, 24 cases) and no chemotherapy group (Group D, 25 cases). Results In terms of brain metastases, there were no complete response cases in the whole groups. The rates of partial remission (PR), stable disease (SD) and progression of disease (PD) in Group A were 17.8%(5/28), 53.6%(15/28) and 28.6 % (8/28), respectively, the response rate (RR) of intracranial lesions was 17.9 % (5/28), and disease control (CR+PR+SD) rate was 71.4%(20/28). The rates of PR, SD and PD in Group B were 15.8%(3/19), 63.2 % (12/19) and 21.1 % (4/19), respectively, the RR of intracranial lesions was 15.8 % (3/19), and disease control rate was 78.9 % (15/19). The rates of PR, SD and PD in Group D were 8.3 % (2/24), 54.2 %(13/24) and 37.5 % (9/24), respectively, the RR rate of intracranial lesions was 8.3 % (2/24), and disease control rate was 62.5 % (15/24). In Group D, there was no response case, and 20 patients with PD (80.0 %) were found. The median progression-free survivals (PFSs) were (3.64 ±0.43) months, (4.68 ±0.49) months,(3.58 ±0.50) months, (2.60 ±0.31) months in Group A, B, C and D, respectively, and the median overall survivals (OSs) were (18.80±1.74) months, (18.76±1.85) months, (19.10±1.64) months and (9.64±0.84) months, respectively. The median OS of Group A, B or C was longer than that of Group D (P=0.002). The differences of grade Ⅲ-Ⅳhematologic toxicities among the four subgroups were not statistically different. Patients in Group B had better tolerance to nausea and vomit. In Group D, the central nervous system symptoms such as fatigue and headache occurred frequently. Conclusions The response rate and OS of SCLC brain metastasis patients with progressive intracranial lesions after radiotherapy are improved after chemotherapy, however, PFS is not significantly prolonged. The efficacies of carmustine, temozolomide and topotecan are similar in short and long term, besides, temozolomide shows less adverse events and a higher disease control rate. The application of chemotherapy that could penetrate the blood-brain barrier can improve the efficacy on SCLC brain metastasis patients with progressive intracranial lesions after radiotherapy with well tolerance.

Expression of bcl-2 and c-Met genes in non-small cell lung cancer cell lines harboring different mutations of epidermal growth factor receptor / 肿瘤研究与临床

Objective To detect the expression of bcl-2 and c-Met genes in lung cancer cell lines with different mutations of epidermal growth factor receptor (EGFR), in order to explore the association between expression of bcl-2 and c-Met genes and drug resistance in non-small cell lung cancer (NSCLC). Methods Direct sequencing was used to detect EGFR mutations status in HCC827 cells, A549 cells and H1975 cells. Immunocytochemistry was conducted to test bcl-2 and c-Met expression. RT-PCR was performed to analyzed bcl-2 gene expression and ARMS was used to detect EGFR mutations status in malignant pleural effusion of NSCLC patients. Results A549 cells, HCC827 cells and H1975 cells were EGFR wild type, EGFR exon 19 deletion (19del), and EGFR exon 21 L858R and exon 20 T790M double mutations. c-Met and bcl-2 protein located in cytoplasm and the intensity of positive expression was highest in HCC827 cells, followed by A549 cells and H1975 cells. The bcl-2 mRNA expression was higher in HCC827 and A549 cells than that in H1975 cells (10.93±1.90 vs. 0.83±0.15, P=0.013; 7.13±1.33 vs. 0.83±0.15, P= 0.000). However bcl-2 mRNA expression was not associated with EGFR mutations (wild type, 19del and L858R) in malignant pleural effusion of NSCLC patients. Conclusion bcl-2 and c-Met gene in HCC827 cells (EGFR 19del) expression is significantly higher than those in H1975 cells (EGFR L858R/T790M), implying EGFR L858R mutations and 19del mutations may be regulated by different signaling pathways.

Identification and clinical significance of myeloid-derived suppressor cells in peripheral blood of small-cell lung cancer patients / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the presence, frequency and clinical value of myeloid-derived suppressor cells (MDSCs) in peripheral blood of patients with small cell lung cancer (SCLC).</p><p><b>METHODS</b>Flow cytometry using antibodies against CD11b, CD33, CD14 or HLA-DR was conducted to explore the unique cell surface markers of MDSCs and statistical analysis was performed to explore the correlation of MDSCs and clinical features.</p><p><b>RESULTS</b>MDSCs were present in 36 patients with SCLC and uniquely marked by CD11b and CD33-positive, but HLA-DR-negative on cell surfaces and possessed mononuclear phenotype. The levels of CD11b(+)CD33(+)HLA-DR(-)cells (MDSCs) in the SCLC patients and healthy controls were (26.87 ± 6.87)% and (11.04 ± 3.76)%, respectively, with a statistically significant difference (P < 0.001). MDSCs level was significantly associated with clinical stage and tumor distant metastasis (P < 0.05) , but not with age, sex, smoking status and performance status. The later was the clinical stage, the higher was the MDSCs level (r = 0.665, P < 0.001). The level of MDSCs was higher in SCLC patients with distant metastasis than in those without metastasis (r = 0.489, P = 0.003). The level of MDSCs was higher before treatment than after treatment and the difference was statistically significant (P = 0.003).</p><p><b>CONCLUSIONS</b>The results of our study demonstrate the existence of MDSCs in SCLC patients and the MDSCs level is associated with SCLC stage, metastasis and treatments. MDSCs might be a novel biomarker for early diagnosis and prognosis for SCLC patients.</p>

Application of iodins-125 interstitial implantation in cancerous pain / 国际肿瘤学杂志

Pain is one of usual symptons of mid-late cancer patients, radioactive particle interstitial im- plantation can not only control tumor advancement,but also alleviate pain in different degree by inactivating part nerves or relieving compression. It has showed significant effect in system tumor--gastric cancer, colon cancer and head and neck cancer without severe cemplication,effering a new method of curing cancerous pain.

Changes of soluble tumor necrosis factor receptors，tumor necrosis factor-alpha in rheumatoid arthritis / 免疫学杂志

Objective　To investigate the relationship between soluble tumor necrosis factor receptors (sTNF-R), TNF-α, TNF-α/sTNF-R and rheumatoid arthritis. Methods　 Serum levels of sTNF-RⅠ, sTNF-RⅡ and TNF-αwere measured in 28 patients with active RA and 12 patients with inactive RA and 30 healthy controls, using double antibodies sandwiched ELISA. Results　The results showed that serum levels of sTNF-RⅠ, sTNF-R Ⅱ and TNF-α　were significantly higher in the group of patients with active RA than those　found　in healthy group and　in the patients with inactive RA. Serum levels of both sTNF-RⅠ, sTNF-RⅡ and TNF-α　were also significantly higher in patients with inactive RA than in healthy group(P＜0.01 for all). In RA, the serum concentrations of sTNF-RⅠ and sTNF-RⅡ were positively correlated with the levels of ESR，CRP，Ritchie index. Conclusions　These results suggest that the serum levels of sTNF-RⅠ and sTNF-RⅡwere significantly increased and positively correlated with the disease activity. The determination of serum levels of sTNF-RⅠ and sTNF-RⅡ can be regarded as a useful laboratory parameter for diagnosis of RA,monitoring of the disease activity and assessment of prognosis.