[Analysis of nasal microbial characteristics in patients with allergic rhinitis and non-allergic rhinitis].

Objective: To investigate the characteristics of nasal flora and the pathogenic role of differential microbiome in patients with allergic rhinitis (AR) and non-allergic rhinitis (nAR). Methods: Thirty-five patients with AR who attended the rhinology outpatient clinic of the Second Hospital of Harbin Medical University from February to July 2022 were selected. A total of 35 nAR patients were selected as the test group, and 20 cases of healthy people with physical examination at the same period were selected as the control group, including 39 males and 51 females, aged 8 to 55 years. 16SrDNA High-throughput sequencing was used to analyze the relative abundance from nasal flora in the three groups of subjects. Alpha diversity index analysis was conducted with R software, and differences between groups were analyzed with LEfSe, Metastats, and t tests. At the same time, the role of microbiome and its relationship with environmental factors were analyzed with R software. Results: There was a significant difference in the bacterial composition of the samples from the three groups, with the relative abundance of Staphylococcus aureus (P=0.032) and Corynebacterium proinquum (P=0.032) within the AR group being significantly higher than that of the nAR group, and that of Lactobacillus murinus, Lactobacillus kunkeei, and Alcaligenes faecalis (P value was 0.016, 0.005, and 0.001, respectively) being significantly lower than that of the nAR group. The relative abundance of Ackermannia muciniphila within the nAR group was higher than that of the control group (P=0.009). Correlation analysis of environmental factors showed a negative correlation between Lactobacillus kunkeei and IgE (P=0.044), and a positive correlation between Lactobacillus murinus and age (P=0.019). AR and nAR random forest prediction models were constructed for the five genera, respectively, and the area under the curve (AUC) of the models of Streptococcus-SP-FF10, Pseudoalteromonas luteoviolacea, Pseudomonas parafulva, Acinetobacter ursingii, and Azotobacter chroococcum in the AR group was 100% (95%CI: 100% to 100%). The AUC for the Pseudomonas parafulva, Azotobacter chroococcum, Closoridium baratii, Turicibacter-SP-H121, and Streptococcus lutetiensis models in the nAR group was 98.4% (95%CI: 94.9% to 100%). Conclusions: The distribution of nasal flora in AR patients, nAR patients and healthy subjects is significantly different, and the changes of bacterial flora abundance are significantly related to the occurrence of AR and nAR. Combined detection of microbiota has the potential to diagnose AR and nAR patients.

[Incidence and prognosis of olfactory and gustatory dysfunctions related to infection of SARS-CoV-2 Omicron strain: a national multi-center survey of 35 566 population].

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.

[Application of pathological feature clustering in oral pathology teaching].

To propose a new student-guided teaching method, in which students carried out the clustering of different diseases with the same pathological characteristics, and differentiated diagnosis of these diseases. This method was named pathological feature clustering (PFC). Seventy-seven undergraduates of School of Stomatology, Wuhan University were enrolled. Stratified random sampling method was adopted to divide the students into 4 groups with 18-20 students in each group. Each group of students selected a disease from the following four topics as the theme and summarize the histological characteristics of the disease: ①oral mucosal disease;②odontogenic tumors and tumor-like lesions, oral and maxillofacial cysts; ③salivary gland diseases;④epithelial-derived tumors and tumor-like lesions (referred to as topics 1, 2, 3, and 4, respectively). When discussing a specific type of disease, the group which select the topic was the summary group (SG), and the other groups were the non-summary group (NSG). After summarizing, students shared the summary results through PPTs, and teachers made comments and supplements. The teaching effect was evaluated by comparing the results of the pre-class test and the final examination. Students' acceptance of PFC teaching method was evaluated through a questionnaire, which included 8 objective questions and 1 subjective question. Likert-scale was used to design the questionnaire, with 1 to 5 points for each question. Students rated each question according to their own situation. Differences among groups were compared by Mann-Whitney U nonparametric test. The pre-class test results showed that the scores of students in SG group in subjects 1, 2, 3 [(5.6±0.8), 5.0(1.0) and (2.9±1.0) points for subjects 1, 2 and 3, respectively] were higher than those in NSG group [(5.1±1.0), 4.0(2.5) and 1.5(2.5) points] (U=402.50, P=0.047; U=392.00, P=0.026; U=295.00, P=0.003). The final examination results showed that there was no significant difference between the scores of the SG group and the NSG group in subjects 1, 2, 3 and 4 (P>0.05). These results showed that the differences between SG and NSG groups were reduced after the summarizing and share between groups, further demonstrating the effectiveness of the PFC teaching method. The results of questionnaire showed that 81.8%(63/77) students were completely satisfied with PFC teaching method, 13.0%(10/77) students were satisfied and 5.2%(4/77) students were basically satisfied. According to the feedback of Likert scale objective evaluation questionnaire, the mean score of each question ranged from 4.19 to 4.77, indicating that students believed that PFC teaching method had a positive impact on the learning of oral pathology. The PFC teaching method proposed in this study could improve the ability of pathological differential diagnosis of undergraduates.

[Ferroptosis in laryngeal squamous cell carcinoma and its regulation by M2 macrophage-derived exosomes].

Objective: To investigate ferroptosis in laryngeal squamous cell carcinoma (LSCC) and its regulation by M2 macrophage-derived exosomes. Methods: LSCC and adjacent noncancerous tissue samples were collected from 32 patients treated in the Department of Otorhinolaryngology, Head and Neck Surgery of the Second Affiliated Hospital of Harbin between September 2018 and April 2021, including 26 males and 6 females, aged 43-79 years. The expressions of ferroptosis marker glutathione peroxidase 4(GPX4) in LSCC and adjacent noncancerous tissues were detected by immunohistochemistry and reverse transcriptase-polymerase chain reaction(RT-PCR). The correlations between GPX4 expression and clinicopathological factors in LSCC were analyzed. Biological changes of TU212 cells after treated with ferroptosis-induced agent erastin were detected by transmission electron microscope, cell counting kit-8(CCK-8), clone test, reactive oxygen species(ROS), malondialdehyde(MDA), glutathione(GSH), JC-1, RT-PCR and western blot. Exosomes were isolated from the supernatant of M0/M2 macrophages (M0-exos/M2-exos) and co-incubated with erastin-treated TU212 cells to detect the change of ferroptosis in cells of each group. The data were analyzed by SPSS software of version19.0. Results: GPX4 expression in LSCC tissues was significantly higher than that in adjacent noncancerous tissues (2.04±0.65 vs. 0.99±0.09, F=30.36, P<0.001), and was closely related to T stage and clinical stage (Ⅰ-Ⅱvs.Ⅲ-Ⅳ: 1.75±0.39 vs. 2.18±0.71, F=2.25, P<0.05; T1-2 vs. T3-4: 1.71±0.42 vs. 2.20±0.69, F=2.06, P<0.05). In TU212 cells treated with erastin, mitochondrial crest became smaller, membrane density increased, proliferation rate decreased, intracellular ROS level increased, mitochondrial membrane potential depolarized, GSH content decreased, intracellular MDA level increased and expressions of GPX4 mRNA and protein decreased. Change of M0 into M2 macrophages was induced by IL-4 stimulation. When erastin-treated TU212 cells were incubated with M2-exos, cell proliferation was partially restored and GPX4 expression was enhanced, and also with the recoveries of levels of ROS, MDA and GSH (all P<0.05). Conclusions: Ferroptosis is one of the cell death ways of LSCC. M2-exos may inhibit ferroptosis of LSCC cells.

[Roles and mechanisms of m6A modification regulating RP11-426A6.5 in laryngeal squamous cell carcinoma].

Objective: To investigate the roles of N6-methyladenosine (m6A) modification in regulating RP11-426A6.5 in the development of laryngeal squamous cell carcinoma (LSCC). Methods: The methylation and expression levels of lncRNAs were identified and important lncRNAs were screened utilizing long non-coding RNA (lncRNA) m6A methylation microarray. Cancer and para cancer tissue samples were taken from 48 LSCC patients hospitalized to the Department of Otolaryngology-Head and Neck Surgery of the Second Affiliated Hospital of Harbin Medical University between January and September 2017. Expression profiling microarray was performed in 3 of 48 LSCC samples, and methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR) and quantitative real-time fluorescent PCR (qRT-PCR) were performed in the remaining 45 LSCC samples to verify the m6A modification and expression levels of RP11-426A6.5. Correlations between RP11-426A6.5 and clinical factors were anlysed. Laryngeal cancer cell line with low expression of RP11-426A6.5 was created in vitro using RNA interference (RNAi) technology. The 5-Ethynyl-2'-deoxyuridine (EdU) cell proliferation experiment, wound healing experiment, and transwell invasion experiment were used respectively to measure the proliferation, migration, and invasion of LSCC cells. The effect of RP11-426A6.5 down-regulation on the growth of transplanted tumors in vivo was verified by nude mice tumorigenesis assay. The Cancer Genome Atlas (TCGA) database and sequence-based RNA adenosine methylation site predictor (SRAMP) website were used to predict the enzymes and corresponding methylation sites. MazF digestion was chosen to validate the binding sites. RNAi technology was used to observe the changes in cell function after interfering with the expression of the corresponding genes of the modified enzymes. MeRIP-qPCR was used to detect the level of RP11-426A6.5 m6A cell line treated with actinomycin D was used to observe the stability of RP11-426A6.5. Results: RP11-426A6.5 methylation and expression levels were significantly higher in LSCC tissues than those in paracancerous tissues (methylation levels: 23.828±4.975 vs 20.280±3.607; expression levels: 1.197±0.314 vs 1.015±0.170, all P values<0.05). RP11-426A6.5 expression levels were closely correlated with T stage (T1-2: 1.081±0.298 vs T3-4: 1.306±0.292, χ2=5.35, P<0.05). The postoperative survival of patients with high RP11-426A6.5 expressions was significantly lower than that of patients with low RP11-426A6.5 expression (P=0.046). Assays in vitro and in vivo showed that the downregulation of RP11-426A6.5 significantly decreased the proliferation, migration, and invasion abilities of LSCC cells and the growth of transplanted tumors. The binding of methyltransferase-like 3 (METTL3), an m6A-modified enzyme, to the corresponding methylation site of RP11-426A6.5 enhanced its stability and mediated its regulation of malignant behaviors of LSCC cells. Conclusions: RP11-426A6.5 can regulate the malignant behaviors of LSCC cells, which is mediated by the m6A modification process involving in the methyltransferase METTL3.

[The function and mechanism of long non-coding RNA RP11-159K7.2 in sinonasal squamous cell carcinoma].

Objective: To explore the role and mechanism of long non-coding RNA RP11-159K7.2 in the progression of sinonasal squamous cell carcinoma (SNSCC). Methods: Sixty-five cases of SNSCC tissues and adjacent tissues were selected from the Department of Otorhinolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Harbin Medical University from 2009 to 2014. The expression of RP11-159K7.2 in SNSCC and adjacent tissues was detected by RNAscope in situ hybridization to observe its association with prognosis. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated proteins 9 (CRISPR/Cas9) was used to knockout the expression of RP11-159K7.2 in RPMI-2650 cells (SNSCC cell line). Cell counting kit-8 (CCK-8), wound healing and Transwell were performed to observe the changes of proliferation, migration and invasion of SNSCC cells in vitro after down-regulation of RP11-159K7.2. Moreover, the growth of xenograft in nude mice after down-regulation of RP11-159K7.2 was examined in vivo. Mechanically, the protein chip, Western blot and RNA immunoprecipitation were performed to identify the proteins bound by RP11-159K7.2. SPSS 17.0 was used for statistical analysis. Results: The expression of RP11-159K7.2 in SNSCC tissue was significantly higher than that in adjacent tissues. RP11-159K7.2 expression was closely related with T grade, nodal metastasis and differentiation of SNSCC (χ2 value was 4.697, 4.235 and 10.753, respectively, all P<0.05). The five-year survival rate of RP11-159K7.2 high expression patients was significantly lower than that of RP11-159K7.2 low expression ones (P=0.013 7). After the down-regulation of RP11-159K7.2, the proliferation, migration and invasion ability of SNSCC cells decreased significantly, and the growth of SNSCC xenograft was significantly inhibited. There were 31 candidate proteins that may bind to RP11-159K7.2. RP11-159K7.2 directly bound to nuclear factor-κB (NF-κB) in SNSCC cells, and the regulation of RP11-159K7.2 on the proliferation and invasion of SNSCC cells depended on NF-κB. Conclusion: The increased expression of RP11-159K7.2 in SNSCC may serve as a potential molecular marker for SNSCC prognosis assessment. It is currently considered that the carcinogenic mechanism of RP11-159K7.2 in SNSCC is related to the regulation of NF-κB protein.

A New Mutation Genotype of K218T in Myosin-5 Confers Resistance to Phenamacril in Rice Bakanae Disease in the Field.

In 2017 and 2018, a total of 294 Fusarium fujikuroi isolates were collected from bakanae-diseased rice plants in Jinhua, Shaoxing, and Jiaxing in Zhejiang Province, China. Phenamacril sensitivity of these isolates was determined by the 50% effective concentration value or minimum inhibitory concentration methods. Our results indicated that the phenamacril resistance frequency of F. fujikuroi increased from 18% in 2017 to 47% in 2018, and rice plants infected with F. fujikuroi-resistant isolates could not be protected effectively with 50 mg/liter of phenamacril. Phenamacril-resistant F. fujikuroi isolates obtained from rice fields showed stable resistance, because their fitness levels (i.e., mycelial growth, sporulation, and pathogenicity) were similar to the phenamacril-sensitive isolates. In addition to the point mutation at codon 219 in the myosin-5 gene that conferred resistance to phenamacril, our results also showed another point mutation at codon 218 (AAG→ACG) in myosin-5 that also conferred resistance to phenamacril. In this study, we found rapid development and persistence of diversified genotypes of phenamacril resistance, highlighting the importance of proper use of phenamacril in rice fields. Our results may also help researchers develop new fungicides or new control strategies using combinations of different fungicides in the control of phenamacril-resistant F. fujikuroi isolates.

Association of the TLR4-MyD88-JNK signaling pathway with inflammatory response in intracranial hemorrhage rats and its effect on neuronal apoptosis.

OBJECTIVE: To investigate the association of Toll-like receptor 4-myeloid differential protein-88- c-Jun N-terminal kinase (TLR4-MyD88-JNK) signaling pathway with inflammatory response in intracranial hemorrhage (ICH) rats and its effect on neuronal apoptosis. PATIENTS AND METHODS: The autologous blood was drawn and injected into the brain to establish the rat model of ICH (model group), and the control group was set up. The neurological behavior Longa score was given. The blood and brain tissues of rats were then collected to detect the serum indexes, including glucose (GLU), creatinine (CR), K+ and Na+, and the content of interleukin-6 (IL-6), IL-1ß and tumor necrosis factor-α (TNF-α) in each group. The neuronal apoptosis of brain tissues was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Moreover, the expressions of apoptosis- and TLR4-MyD88-JNK pathway-related genes and proteins were detected via Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting. Finally, the association of TLR4-MyD88-JNK signaling pathway with the inflammatory response in ICH rats and its effect on neuronal apoptosis were completely observed. RESULTS: MiR-23b was dramatically down-regulated in CC and the low miR-23b expressions were associated with the poor prognosis and worse OS of CC patients. Additionally, the functional assays demonstrated that miR-23b overexpression obviously repressed CC cell proliferation, invasion and migration abilities through the regulation of the AKT/mTOR pathway and the epithelial-to-mesenchymal transition (EMT) progress. Moreover, the luciferase reporter assay indicated that six1 was one functional target for miR-23b in CC cells, indicating that the inhibitory functions of miR-23b in CC cells were partially regulated by six1. Moreover, miR-23b restoration could prominently repress tumor growth in vivo. CONCLUSIONS: The TLR4-MyD88-JNK signaling pathway can facilitate the inflammatory response in ICH rats, thereby promoting the neuronal apoptosis.

The therapeutic efficacy of pediatric ALL patients with MLL gene rearrangement treated with CCLG-ALL2008 protocol.

OBJECTIVE: In this study, we retrospectively evaluated the therapeutic efficacy of China Children Leukemia Group-ALL2008 (CCLG-ALL 2008) protocol in pediatric patients with mixed-lineage leukaemia (MLL) gene rearrangement of acute lymphoblastic leukemia (ALL) to identify the prognostic factors. PATIENTS AND METHODS: Six hundred and thirty-four patients with ALL were enrolled in this study between June 2008 and Dec 2014. High-risk group (HR) consisted of 217 cases, of which 28 cases were MLL related positive (first group), 22 cases were BCR/ABL positive (second group), and 167 cases were negative with MLL related or BCR/ABL (third group). The therapeutic efficacy was evaluated at the time points of day 8 (TP1), day 15 (TP2), day 33 (TP3) and 12th week (TP4) with the protocol, respectively. Overall-survival (OS) and relapse-free-survival (RFS) and treatment-related mortality (TRD) were analyzed as well. RESULTS: The first group accounted for 4.4% of all patients. Compared with the second and third group, the first group had more cases younger than 2 years, with initial leukocytes ≥50×109/L, and poor response on TP2. Moreover, patients older than 2 years old had a good 5 years OS (84% ± 9% vs. 37% ± 20%, p<0.05) and RFS (84% ± 9% vs. 29% ± 17%, p<0.05). There were no significant differences in the recurrence rate, TRD, 5 years OS and RFS among three groups. For the first group, compared with good response to prednisone, patients with poor response to prednisone had a poor 5 years RFS (41% ± 17% vs. 81% ± 10%, p<0.05). Multivariate Cox regression analysis identified that RFS and OS were influenced by such factors as age, MLL fusion partners, and prednisone response (p<0.05). CONCLUSIONS: Such factors as younger age than 2 years old, MLL/AF4 fusion gene, poor response to prednisone, or no complete remission (CR) on TP3 were poor prognostic parameters in predicting the outcome in childhood ALL with MLL gene rearrangement treated with CCLG-ALL 2008 protocol.

Association between household physical activity level and type 2 diabetes among urban males in northern China.

OBJECTIVES: Physical activity contributes to preventing type 2 diabetes (T2D). Doing housework is an unstructured mild-intensity physical activity. We aimed to investigate the association between household physical activity level (HPAL) and T2D in urban Chinese men. STUDY DESIGN: This is a cross-sectional study. METHODS: This study contained 13,862 male adults aged 35-78 (48.4 ± 7.1) years. According to the self-reported time (hours/day [h/d]) spent on housework, they were stratified into three levels: 0 h/d, >0-2 h/d, and >2 h/d. The association of HPAL with T2D was investigated by logistic regression analysis. RESULTS: The odds ratios (ORs) for T2D across increasing categories of HPAL were 1.00 (reference), 0.80 (95% confidence interval [CI] 0.72-0.89), and 0.60 (95% CI 0.51-0.70), respectively (P for trend <0.001), after adjusting for confounding factors. Further adjustment for waist circumference or body mass index (BMI) had a minimal impact on these ORs. The inverse association of HPAL with T2D was persistent in subgroup analyses based on age, hypertension, family history of diabetes, smoking, BMI, waist circumstance, and fasting plasma glucose level. CONCLUSION: Our findings indicated that HPAL was inversely associated with the risk of T2D among urban males in northern China. This implied that household physical activity may contribute to long-term glucose control. Well-designed longitudinal studies are required to improve our understanding of this association.

Meta-analysis of survival benefit with postoperative chemoradiotherapy in patients of lymph node positive esophageal carcinoma.

BACKGROUND: The effect of postoperative chemoradiotherapy (CRT) for esophageal carcinoma (EC) was investigated. Patients who can obtain benefit from this treatment modality have not yet been well identified. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library for studies published from January 1993 to July 2016. Research comparing surgery alone (SA) with postoperative CRT in patients with resectable EC was procured; collected articles were written in English. RESULTS: Nine studies comparing of postoperative CRT versus SA (n = 1650) in patients with resectable EC met the inclusion criteria. No survival benefit was achieved for postoperative CRT compared with SA. Subgroup analysis was conducted for patients under resection with positive lymph node carcinoma; there was a significant survival benefit at 1 year [risk ratio (RR) = 0.55 95% CI: 0.37-0.82; P = 0.003], 3 years (RR = 0.71 95% CI: 0.61-0.83; P<0.0001), as well as 5 years (RR = 0.86 95% CI: 0.78-0.94; P = 0.0007). Subgroup analysis by tumor histology of squamous cell carcinoma (SCC) was also performed, but there was no significant survival benefit when postoperative CRT was compared with SA. Fail models after surgery were performed; the RR for local control rate and distant metastasis rate were 0.64 (95% CI 0.49-0.85; P = 0.002) and 0.87 (95% CI 0.67-1.15; P = 0.34), which indicates lower local recurrence rates of post-CRT than that of SA. CONCLUSION: This meta-analysis demonstrated a survival benefit of postoperative CRT over SA in resectable EC patients with positive lymph nodes. Improvements of local control rates with postoperative CRT were also detected.

A Pharmacokinetic and Safety Study of Trebananib, an Fc-Fusion Peptibody, in Patients With Advanced Solid Tumors and Varying Degrees of Renal Dysfunction.

Clearance of trebananib (AMG 386), a 64-kD antiangiogenic peptibody, has been associated with estimated glomerular filtration rate (eGFR). We prospectively evaluated trebananib pharmacokinetics and safety/tolerability in advanced solid tumor patients with varying degrees of renal function. Patients were assigned to normal renal function, mild, moderate, or severe renal dysfunction cohorts based on eGFR, received trebananib 15 mg/kg i.v. weekly, and underwent week 1 and week 5 pharmacokinetic and weekly safety assessments. For 28 patients, trebananib clearance decreased from normal renal function (1.52 mL/hr/kg), to mild (1.20 mL/hr/kg), moderate (0.79 mL/hr/kg), and severe (0.53 mL/hr/kg) renal dysfunction (P ≤ 0.001). Treatment-related adverse events showed no association with clearance. Trebananib clearance was proportional to eGFR and unrelated to pretreatment protein excretion. These data confirm a role for renal clearance of a recombinant peptibody with molecular weight <69 kD and support a longer dosing interval for patients with severe renal dysfunction.

Comparative efficacy of whole-brain radiotherapy with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma.

PURPOSE: We explored and compared the clinical effects of whole-brain radiotherapy (wbrt) with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma (nsclc). METHODS: We retrospectively analyzed 62 patients with multiple brain metastases from nsclc who received wbrt (30 Gy in 10 fractions) at Shengjing Hospital of China Medical University from January 2012 to May 2013. In 30 patients, elemene liposomes (400 mg) were injected intravenously via a peripherally inserted central catheter for 21 consecutive days from the first day of radiotherapy. Overall survival (os) and nervous system progression-free survival (npfs) for the two groups were compared by Kaplan-Meier analysis. Factors influencing npfs were examined by Cox regression analysis. Chi-square or Fisher exact tests were used for group comparisons. RESULTS: The median os was 9.0 months in the wbrt plus elemene group and 7.8 months in the wbrt-alone group (p = 0.581); the equivalent median npfs durations were 5.2 months and 3.7 months (p = 0.005). Patient treatment plan was an independent factor associated with npfs (p = 0.002). Tumour response and disease-control rates in the wbrt plus elemene group were 26.67% and 76.67% respectively; they were 18.75% and 62.5% in the wbrt group (p = 0.452). Compared with the patients in the wbrt-alone group, significantly fewer patients in the wbrt plus elemene group developed headaches (p = 0.04); quality of life was also significantly higher in the wbrt plus elemene group both at 1 month and at 2 months (p = 0.021 and p = 0.001 respectively). CONCLUSIONS: The addition of elemene liposomes to wbrt might prolong npfs in patients with multiple brain metastases from nsclc, while also reducing the incidence of headache and improving patient quality of life.

A prospective evaluation of minimal residual disease as risk stratification for CCLG-ALL-2008 treatment protocol in pediatric B precursor acute lymphoblastic leukemia.

OBJECTIVE: The aim of this prospective study was to evaluate the cut-off value of minimal residual disease (MRD) in predicting the efficacy of CCLG-ALL-2008 or CCLG-2008 treatment protocol on pediatric B-precursor ALL (BP-ALL). PATIENTS AND METHODS: Three hundred and seventy-nine Chinese pediatric BP-ALL were enrolled in this study between Dec 2008 and Sep 2013 in two stratified cohorts. One hundred and fifty-three patients enrolled between Dec 2008 and Oct 2010 as the first cohort, and 196 patients enrolled from Nov 2010 to Sep 2013 as the second cohort. Clinical and biological characteristics and 5 years EFS, RFS, and OS were analyzed. RESULTS: Patients with E2A-PBX1 showed a favorable treatment response with a lower minimal residual disease (MRD) level (< 10-4) at the time point 1 (TP1, p = 0.039) and the highest proportion of the 5-year EFS, RFS, and OS. A high level of MRD was associated with high WBC counts, increased age, BCR-ABL1 fusion gene, MLL rearrangements and adverse karyotypes. In comparison with the first cohort, the second cohort with the MRD assay incorporated prospectively, the standard risk (SR) and the intermediate risk (IR) patients showed a better RFS, EFS, and OS while the high-risk (HR) patients displayed worse RFS, EFS, and OS than those of the first cohort, respectively. Patients with MRD level at either 10-4 or 10-3 showed a similar OS at TP1 or TP2, and patients with MRD level above 10-2 had the worst OS. CONCLUSIONS: This study indicated that the levels of MRD to be an adequate guide in risk-adapted treatment under the CCLG-ALL-2008 protocol and can be adapted to the future development of advanced clinical protocols.

Radiation-enhancing effect of sodium glycididazole in patients suffering from non-small cell lung cancer with multiple brain metastases: A randomized, placebo-controlled study.

PURPOSE: Median survival of patients with brain metastases from non-small cell lung cancer is poor. This study was to investigate the radiation-enhancing effect of sodium glycididazole combined with whole-brain radiotherapy of multiple brain metastases from non-small cell lung cancer. PATIENTS AND METHODS: Sixty-four patients with multiple brain metastases from non-small cell lung cancer were included: the study group (n=32) received whole-brain radiotherapy combined with sodium glycididazole at a dose of 700mg/m(2) intravenous infusion 30minutes before radiotherapy, three times a week; the control group (n=32) only received whole-brain radiotherapy. The primary end point was central nervous system (CNS) progression-free survival and overall survival. The treatment-related toxicity was also recorded. RESULTS: The CNS disease control rate was better (90.6% vs 65.6%, P=0.016) in the study group than in the control group at 3 month of follow-up. The median CNS progression-free survival time was longer in the study group than in the control group (7.0 months vs 4.0 months, P=0.038). There was no significant difference of the median overall survival time between the study group and the control group (11.0 months vs 9.0 months, P=0.418). On the other hand, the treatment-related toxicity showed no statistically significant difference between these two groups (P>0.05). CONCLUSIONS: The study indicated that sodium glycididazole was an effective, promising radiation-enhancing agent that improved CNS disease control rate, extended the median CNS progression-free survival time and was well tolerated in patients suffering from non-small cell lung cancer with multiple brain metastases.

[Brain metastases from hepatocellular carcinoma: clinical features and prognostic factors in 31 cases].

OBJECTIVE: Brain metastases (BM) from hepatocellular carcinoma (HCC) are rare and are associated with a poor prognosis. The aim of this study was to analyze the clinical features and evaluate the prognostic factors of brain metastases from hepatocellular carcinoma. METHODS: The clinical data of thirty-one patients with HCC and BM treated in the First Affiliated Hospital of Xinjiang Medical University between January 1998 and December 2013 were retrospectively reviewed. Univariate and multivariate survival analyses were performed to identify possible prognostic factors. RESULTS: Thrity-one patients were diagnosed with BM from HCC, an incidence rate of 0.61%. The median age at diagnosis of brain metastases was 48.5 years. Twenty-six patients were male. The median interval from diagnosis of hepatocellular carcinoma to brain metastases was 14 months. The median survival after the diagnosis of BM was 10 weeks. Univariate analysis showed that treatment modality, number of brain lesions, Karnofsky performance score, recursive partitioning analysis (RPA) class, and Child-Pugh classification had a statistically significant impact on the survival. The multivariate analysis showed that the low RPA class and aggressive brain radiotherapy were positively associated with improved survival. CONCLUSION: BM from HCC is rare and associated with an extremely poor prognosis. However, patients with a low RPA class may benefit from aggressive brain radiotherapy.

Physiologically Based Pharmacokinetic Model to Assess the Influence of Blinatumomab-Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity.

Blinatumomab is a CD19/CD3 bispecific T-cell engager (BiTE®) antibody construct for treatment of leukemia. Transient elevation of cytokines (interleukin (IL)-6, IL-10, interferon-gamma (IFN-γ)) has been observed within the first 48 hours of continuous intravenous blinatumomab infusion. In human hepatocytes, blinatumomab showed no effect on cytochrome P450 (CYP450) activities, whereas a cytokine cocktail showed suppression of CYP3A4, CYP1A2, and CYP2C9 activities. We developed a physiologically based pharmacokinetic (PBPK) model to evaluate the effect of transient elevation of cytokines, particularly IL-6, on CYP450 suppression. The predicted suppression of hepatic CYP450 activities was <30%, and IL-6-mediated changes in exposure to sensitive substrates of CYP3A4, CYP1A2, and CYP2C9 were