Gemcitabine, carboplatin, and Epstein-Barr virus-specific autologous cytotoxic T lymphocytes for recurrent or metastatic nasopharyngeal carcinoma: VANCE, an international randomized phase III trial.

BACKGROUND: Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T-cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous phase II trial of locally recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective antitumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared with conventional chemotherapy treatment. PATIENTS AND METHODS: This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. CLINICALTRIALS: gov identifier: NCT02578641. RESULTS: A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC + EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC + EBV-CTL subjects. The median OS was 25.0 months in the GC + EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% confidence interval 0.91-1.56; P = 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL. CONCLUSIONS: GC + EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date.

[Correlation between weight variability and the risk of diabetic nephropathy in patients with type 2 diabetes mellitus].

Objective: To evaluate the relationship between different indexes of weight variability and the risk of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: A retrospective cohort study. The clinical data of 2 180 T2DM patients without DKD who underwent case management at Lee's United Clinic in Taiwan, China from 2002 to 2018 were retrospectively analyzed, including 1 103 females and 1 077 males, with an average age of (64.8±12.4) years. Regular follow-up was conducted for patients for at least 2 years, and their metabolic indexes were monitored annually. BMI variability independent of the mean (BMI-VIM), average yearly mean square successive difference (BMI-ASV), coefficient of variation (BMI-CV) and standard deviation (BMI-SD) were calculated,based on the body mass index (BMI) recorded annually by the patients. Patients were divided into four groups (Q1-Q4) based on the quartiles of the four weight variability indexes. DKD group and non-DKN group(NDKD group) were defined based on the occurrence of DKD at the end of the follow-up. Cox proportional hazards regression models were used to analyze the relationship between the four weight variability indicators and the incidence of DKD. Subgroup analysis was performed by categorizing patients into non-obesity (BMI<28 kg/m2) and obesity groups (BMI≥28 kg/m2) to investigate the impact of the four weight variability indicators on the risk of DKD. Results: After a follow-up of (4.55±2.13) years, 904 patients developed DKD. Compared with the NDKD group, patients in the DKD group had a higher proportion of females, older age, longer duration of diabetes, more insulin users, higher waist-to-hip ratio, higher levels of BMI-VIM, BMI-ASV, BMI-CV, BMI-SD, systolic blood pressure, diastolic blood pressure, and urine albumin-creatinine ratio, a lower proportion of hypoglycemic drugs, estimated glomerular filtration rate, and high-density lipoprotein cholesterol level, with statistically significant differences between the two groups(all P<0.05). Cox proportional hazards regression analysis results revealed that the risk of DKD in T2DM patients increased with the increase in BMI-SD, BMI-CV, BMI-VIM, and BMI-ASV after correcting a series of influencing factors. In the BMI-VIM subgroup, compared with the Q1 group, the risk of DKD in the Q4 group increased by 22.4% [HR=1.224 (95%CI:1.008-1.487), P=0.041]. In the BMI-ASV group, compared with the Q1 group, the risk of DKD in the Q4 group increased by 51.1% [HR=1.511 (95%CI:1.240-1.841), P<0.01]. In the BMI-CV group, compared with the Q1 group, the risk of DKD in the Q4 group increased by 22.2% [HR=1.222 (95%CI:1.006-1.485), P=0.044]. In the BMI-SD subgroup, compared with the Q1 group, the risk of DKD in the Q4 group increased by 22.2% [HR=1.222 (95%CI:1.002-1.490), P=0.048]. Sub-group analysis showed that when the non-obesity group was grouped by BMI-ASV, after correcting a series of influencing factors, compared with the Q1 group, the highest risk of DKD occurred in the Q4 group [HR=1.551 (95%CI:1.228-1.958), P<0.001];when the obesity group was grouped by BMI-ASV, after correcting a series of influencing factors, compared with the Q1 group, the highest risk of DKD occurred in the Q4 group [HR=1.703 (95%CI:1.168-2.485), P=0.006]. Conclusion: Increases in BMI-VIM, BMI-ASV, BMI-CV, and BMI-SD are associated with an increased risk of DKD in T2DM patients.

Maternal rumen and milk microbiota shape the establishment of early-life rumen microbiota in grazing yak calves.

Early-life gut microbial colonization and development exert a profound impact on the health and metabolism of the host throughout the life span. The transmission of microbes from the mother to the offspring affects the succession and establishment of the early-life rumen microbiome in newborns, but the contributions of different maternal sites to the rumen microbial establishment remain unclear. In the present study, samples from different dam sites (namely, oral, rumen fluid, milk, and teat skin) and rumen fluid of yak calves were collected at 6 time points between d 7 and 180 postpartum to determine the contributions of the different maternal sites to the establishment of the bacterial and archaeal communities in the rumen during early life. Our analysis demonstrated that the dam's microbial communities clustered according to the sites, and the calves' rumen microbiota resembled that of the dam consistently regardless of fluctuations at d 7 and 14. The dam's rumen microbiota was the major source of the calves' rumen bacteria (7.9%) and archaea (49.7%) compared with the other sites, whereas the potential sources of the calf rumen microbiota from other sites varied according to the age. The contribution of dam's rumen bacteria increased with age from 0.36% at d 7 to 14.8% at d 180, whereas the contribution of the milk microbiota showed the opposite trend, with its contribution reduced from 2.7% at d 7 to 0.2% at d 180. Maternal oral archaea were the main sources of the calves' rumen archaea at d 14 (50.4%), but maternal rumen archaea became the main source gradually and reached 66.2% at d 180. These findings demonstrated the potential microbial transfer from the dam to the offspring that could influence the rumen microbiota colonization and establishment in yak calves raised under grazing regimens, providing the basis for future microbiota manipulation strategies during their early life.

[Effects of preoperative quetiapine on postoperative delirium and sleep quality in elderly orthopaedic patients].

Objective: To investigate the effects of preoperative quetiapine on postoperative delirium (POD) and sleep quality in elderly orthopedic patients. Methods: Prospectively, 111 elderly patients, American Society of Anesthesiologists (ASA) grade Ⅱ-Ⅲ, scheduled to undergo knee or hip surgery in the Affiliated Huangyan Hospital of Wenzhou Medical University under continuous spinal anesthesia from August 2021 to March 2023, were selected and randomly divided into two groups by random number table: control group (group C, 1 h preoperative placebo) and quetiapine group (group Q, 1 h preoperative quetiapine 12.5 mg). In group C, 54 cases were enrolled, including 25 males and 29 females, with an average age of (73.5±4.9) years. In group Q, 57 cases were enrolled, including 26 males and 31 females, with an average age of (74.8±5.0) years. The primary outcome measures were the incidence of POD evaluated by using confusion assessment method (CAM) at 24, 48, and 72 hours after surgery, and the secondary outcome measures included Pittsburgh sleep quality index (PSQI) scores at 24 and 48 hours after surgery and satisfaction of pain management within 24 hours after surgery. Results: The incidence of POD at 24, 48, and 72 h after surgery in group Q was 5.4% (3/57), 12.5% (7/57), 14.3% (8/57), respectively, while that in group C was 18.2% (10/54), 21.8% (12/54), 21.8% (12/54), respectively. The incidence of POD at 24 h after surgery in group Q was lower than that in group C (P=0.036). There was no significant difference in the incidence of POD at 48 and 72 h after surgery between two groups (all P>0.05). The PSQI score of patients in group Q at 24 and 48 h after surgery were (3.8±1.2) and (6.9±1.1) scores, respectively, which in group C were (10.5±2.8) and (7.3±1.3) scores, respectively. Compared with group C, the PSQI score of patients in group Q at 24 h after surgery was significantly higher (P<0.001), but there was no significant difference at 48 h after surgery (P=0.068). The satisfaction scores of pain management at 24 h after surgery in group Q was (91±7) scores, which was higher than that in group C of (81±6) scores (P<0.001). Conclusion: Oral intake of low-dose quetiapine 1 h preoperatively can reduce the incidence of POD, improve postoperative sleep quality and enhance postoperative satisfaction of pain management at 24 hours after surgery in elderly orthopedic patients undergoing knee or hip surgery.

[Revision rate of periprosthetic joint infection post total hip or knee arthroplasty of 34 hospitals in China between 2015 and 2017: a multi-center survey].

Objective: To investigate the rate of periprosthetic joint infection (PJI) revision surgeries and clinical information of hip-/knee- PJI cases nationwide from 2015 to 2017 in China. Methods: An epidemiological investigation. A self-designed questionnaire and convenience sampling were used to survey 41 regional joint replacement centers nationwide from November 2018 to December 2019 in China. The PJI was diagnosed according to the Musculoskeletal Infection Association criteria. Data of PJI patients were obtained by searching the inpatient database of each hospital. Questionnaire entries were extracted from the clinical records by specialist. Then the differences in rate of PJI revision surgery between hip- and knee- PJI revision cases were calculated and compared. Results: Total of 36 hospitals (87.8%) nationwide reported data on 99 791 hip and knee arthroplasties performed from 2015 to 2017, with 946 revisions due to PJI (0.96%). The overall hip-PJI revision rate was 0.99% (481/48 574), and it was 0.97% (135/13 963), 0.97% (153/15 730) and 1.07% (193/17 881) in of 2015, 2016, 2017, respectively. The overall knee-PJI revision rate was 0.91% (465/51 271), and it was 0.90% (131/14 650), 0.88% (155/17 693) and 0.94% (179/18 982) in 2015, 2016, 2017, respectively. Heilongjiang (2.2%, 40/1 805), Fujian (2.2%, 45/2 017), Jiangsu (2.1%, 85/3 899), Gansu (2.1%, 29/1 377), Chongqing (1.8%, 64/3 523) reported relatively high revision rates. Conclusions: The overall PJI revision rate in 34 hospitals nationwide from 2015 to 2017 is 0.96%. The hip-PJI revision rate is slightly higher than that in the knee-PJI. There are differences in revision rates among hospitals in different regions.

[Clinical characteristics of Danon disease].

Objective: To review the clinical data of 7 patients with Danon disease and analyze their clinical characteristics. Methods: The medical records of 7 patients with Danon disease, who were hospitalized in Peking Union Medical College Hospital of Chinese Academy of Medical Sciences from April 2008 to July 2021, were reviewed and summarized, of which 6 cases were diagnosed as Danon disease by lysosomal-associated membrane protein-2 (LAMP-2) gene mutation detection and 1 case was diagnosed by clinicopathological features. Clinical manifestations, biochemical indexes, electrocardiogram, echocardiography, skeletal muscle and myocardial biopsy and gene detection results were analyzed, and patients received clinical follow-up after discharge. Results: Six patients were male and average age was (15.4±3.5) years and the average follow-up time was (27.7±17.0) months. The main clinical manifestations were myocardial hypertrophy (6/7), decreased myodynamia (2/7) and poor academic performance (3/7). Electrocardiogram features included pre-excitation syndrome (6/7) and left ventricular hypertrophy (7/7). Echocardiography examination evidenced myocardial hypertrophy (6/7), and left ventricular dilatation and systolic dysfunction during the disease course (1/7). The results of skeletal muscle biopsy in 6 patients were consistent with autophagy vacuolar myopathy. Subendocardial myocardial biopsy was performed in 3 patients, and a large amount of glycogen deposition with autophagosome formation was found in cardiomyocytes. LAMP-2 gene was detected in 6 patients, and missense mutations were found in all these patients. During the follow-up period, implantable cardioverter defibrillator implantation was performed in 1 patient because of high atrioventricular block 4 years after diagnosis, and there was no death or hospitalization for cardiovascular events in the other patients. Conclusion: The main clinical manifestations of Danon disease are cardiomyopathy, myopathy and mental retardation. Pre-excitation syndrome is a common electrocardiographic manifestation. Autophagy vacuoles can be seen in skeletal muscle and myocardial pathological biopsies. LAMP-2 gene mutation analysis is helpful in the diagnose of this disease.

[Changes of brain network characteristics in patients with depression before and after precise repetitive transcranial magnetic stimulation].

Objective: To investigate the changes of brain network characteristics in patients with depression before and after precise repetitive transcranial magnetic stimulation (rTMS) treatment. Methods: Patients with depression in the Second Affiliated Hospital of Xinxiang Medical University and healthy volunteers in the community of Xinxiang city from February 2018 to March 2019 were simultaneously recruited. The left dorsolateral prefrontal cortex was precisely selected as the stimulation target through the latest Human Brainnetome Atlas, and the near infrared navigation was used to achieve accurate brain stimulation treatment in combination with the structural magnetic resonance data. Moreover, functional connectivity was analyzed before and after rTMS treatment in significantly altered brain areas of patients with depression. Results: Nineteen patients (11 males and 8 females) with depression were included, aged (34±11) years. Meanwhile, 22 healthy controls (9 males and 13 females), aged (30±9) years, were also enrolled. Functional connectivity of insular cortex was decreased in depression patients when the insula was analyzed as the target area (P<0.05). The functional connection from insula to middle frontal lobe and superior parietal lobe in patients with depression decreased before rTMS treatment (P<0.05), but increased after rTMS treatment (P<0.05). The functional connection between dIg_L of the insula and the right middle prefrontal lobe was correlated with Beck Anxiety Index (BAI) before rTMS treatment and Beck Depression Index (BDI) after rTMS treatment (r=0.737, P=0.003; r=0.696, P=0.005). Conclusions: Abnormal functional connectivity of insula may be the brain imaging mechanism of rTMS treatment. Precise brain region selection based on Human Brainnetome Atlas provides a new technical method for clinical rTMS precision treatment.

[Malignant solitary fibrous tumors: a clinicopathological and molecular genetic analysis].

Objective: To explore the clinicopathological features, immunophenotype and molecular genetic characteristics of malignant solitary fibrous tumor (MSFT). Methods: Seven cases of MSFT were collected from the First Affiliated Hospital of Zhengzhou University from July 2018 to December 2020. Immunohistochemistry, RNA-based NGS and DNA-based NGS were performed. Results Among the 7 patients, there were 5 males and 2 females with a median age of 53 years (37-69 years). Two tumors located at skull base, and one in the tentorium of cerebellum, parietal occipital region, occipital area, chest and buttock respectively. The maximum diameter of the tumor was 2.5-20.0 cm. Microscopically, typical hemangiopericomatoid structures were noted; the tumor was cellular, fusiform or oval, very pleomorphic, with necrosis and high mitotic figures (>4/10 HPF). In some cases, classical solitary fibrous tumor morphology and dedifferentiated region were observed. Immunohistochemically, the tumor was positive for CD34 (6/7), STAT6 (7/7), bcl-2 (7/7), but negative for S-100 (7/7); CKpan or EMA was positive to varying degrees; mutated p53 was noted (3/7); Ki-67 positive index was more than 10%. NAB2-STAT6 gene fusion was typically detected in all the 7 cases. In 4 cases, ZNF415-FGFR1, COPG1-MET, IPO11-LRRC70_ncRNA-PLAG1 and Clorf198-CD274 (PD-L1) gene fusions were also detected. NOTCH1 mutation was found in 7 cases and TP53 mutation in 4 cases. TERT promoter mutations were not detected in all the cases. Conclusions: MSFT is rare and needs to be differentiated from many other spindle cell tumors. Especially when tumors express epithelial markers, they are easily misdiagnosed as sarcomatoid carcinoma and synovial sarcoma, etc. Immunohistochemistry and molecular detection of NAB2-STAT6 gene fusion have important diagnostic values. NOTCH1 and TP53 mutations may be associated with the progression of MSFT. Some patients have FGFR1 gene fusion and MET gene fusion, which may be potential therapeutic targets.

[Hepatitis C elimination among drug users in China: challenges, strategies and experiences].

The prevalence of hepatitis C among drug users in China is high, and thus it is one of the populations that needs attention to achieve hepatitis C elimination. However, due to the complexities of this population's situation, hepatitis C elimination still faces many challenges, such as difficult screening, low cure rate, poor compliance, and high reinfection rates. Therefore, the existing diagnostic and therapeutic system cannot meet the needs of this population. China has pledged to establish a unified system for drug users that will integrate drug treatment programs, education, medical care, and rehabilitation, creating favorable conditions for integrating hepatitis C diagnosis and treatment and improving the accessibility of drug users. Starting with the current situation and challenges of eliminating hepatitis C among drug users in China, in combination with cases from other countries, this paper discusses the strategy for eliminating hepatitis C and introduces what Hainan Province did to eliminate hepatitis C among drug users.

Comparative genome-wide methylation analysis of longissimus dorsi muscles in Yorkshire and Wannanhua pigs.

DNA methylation was one of the earliest discovered epigenetic modifications in vertebrates, and is an important epigenetic mechanism involved in the expression of genes in many biological processes, including muscle growth and development. Its effects on economically important traits are evidenced in reported differences in meat quality traits between Chinese indigenous pig breeds (Wannanhua pig) and Western commercial pig breeds (Yorkshire pig), and this presents a unique model for analyzing the effects of DNA methylation on these traits. In the present study, a whole genome DNA methylation analysis was performed on the two breeds using methylated DNA immunoprecipitation. GO functional enrichment and pathway enrichment analyses identified differentially methylated genes primarily associated with fatty acid metabolism, biological processes of muscle development and signaling pathways related to muscle development and pork quality. Differentially methylated genes were verified by sodium pyrosequencing, and the results were consistent with the sequencing results. The results of the integrative analysis between DNA methylation and gene expression revealed that the DNA methylation levels showed a significantly negative correlation with gene expression levels around the transcription start site of genes. In total, 41 genes were both differentially expressed and methylated; these genes were related to fat metabolism, lipid metabolism and skeletal muscle development. This study could help further explore the molecular mechanisms and phenotypic differences in pig growth and development among different breeds.

[Impact and clinical value of the revised 2019 Chinese HER-2 testing guidelines on the detect result evaluation of invasive breast cancer cases with equivocal HER-2 immunostaining by using fluorescence in situ hybridization].

Objective: To investigate the impact and clinical significance of the revised 2019 Chinese HER-2 testing guidelines on the detecting result evaluation of invasive breast cancers with equivocal HER-2 immunostaining by using fluorescence in situ hybridization (FISH). Methods: A total of 569 cases of invasive breast cancers with HER-2 (+ + ) immunostaining evaluated according to the immunohistochemistry (IHC) guidelines of 2014 edition and 2019 edition from May to November 2019 were collected and further detected by FISH. The results of HER-2/CEPl7 double probe were respectively interpreted according to both the 2014 and 2019 Chinese HER-2 testing guidelines and the results were compared. Results: According to the 2014 guidelines, the number of HER-2 positive, equivocal and negative cases were 139 (24.43%), 67 (11.78%), and 363 (63.80%), respectively. Whereas according to the 2019 guidelines, 115 cases (20.21%) were the first group, 9 cases (1.58%) were the second group, 15 cases (2.64%) were the third group, 67 cases (11.78%) were the fourth group, and 363 cases were (63.80%) the fifth group, of which 130 cases (22.85%) were positive and 439 cases (77.15%) were negative by FISH detecting. Compared with the guideline of 2014 edition, the HER-2 positive rate of FISH detection reduced from 24.43% (139/569) to 22.85% (130/559) according to the application of the guideline of 2019 edition, but the difference was not statistically significant (P=0.567), while the negative rate increased from 63.80% (363/569) to 77.15% (439/569), with a statistically significant difference (P<0.05). Forty-three cases with incomplete weak to medium intensity of IHC membrane staining which were HER-2 (+ + ) according to 2014 guideline were changed to IHC (+ ) on the basis of the 2019 guideline. According to the FISH guideline of 2014 edition, 1 case (2.33%) was positive, 6 cases (13.95%) was equivocal and 36 cases (83.72%) was negative, while according to the 2019 FISH guideline, all of the 43 cases were negative. Conclusions: According to the guideline of 2019 edition, a proportion of cases changes from HER-2 (+ + ) to (+ ), and the HER-2 positive rate of FISH test decreases slightly, the negative rate increases, the equivocal result is eliminated, which provides a definite reference for screening patients who will be benefited from the targeted treatment of HER-2.

[Diagnostic value of diffusion-weighted imaging and conventional magnetic resonance imaging in testicular tumor].

Apparent diffusion coefficient(ADC) of magnetic resonance imaging≤0.90×10-3 mm2/s and T2-hypointensity, intratuminal septa, and peritumoral infiltration could achieve best diagnostic efficiency. ADC values and cyst or necrosis were independent predictors for the differential diagnosis of nonseminomatous germ cell tumor versus seminoma and nonseminomatous germ cell tumor versus lymphoma. ADC value and intratuminal septa were independent predictors for the differential of seminoma versus lymphoma.

[Analysis of gene mutation profile of adult soft tissue sarcomas using high-throughput sequencing technology].

Objective: To understand the genetic variation of soft tissue sarcomas, and to provide a scientific evidence for the individualized treatment. Methods: The somatic mutation and germline mutation of 45 adult soft tissue sarcomas had been detected by high-throughput sequencing technology, the clinical data were also analyzed. Results: A total of 88 gene mutations were detected in 45 samples, including 78 single nucleotide variation (SNV), 13 insertion/deletion (Indel) and 19 copy number variation (CNV). The most common mutant genes are TP53, CDKN2A, MDM2, CDK4, NF1 and PTEN. Among them, the mutation rates of TP53-MDM2/MDM4-CDKN2A pathway, CDKN2A/CDK4/RB1 pathway, and RAS/NF1/PTEN/PI3K pathway were more frequent (32/88, 36%). In terms of immunotherapy biomarkers among 10 samples, the median value of tumor mutation burden was 2.02 muts/Mb (0-4.24 muts/Mb), and all were microsatellite stable. Conclusions: This study analyzes the genetic variation of soft tissue sarcoma, and determines the high-frequency gene mutations and pathways, which may be the potential drug targets. This finding can provide scientific evidences for the personalized treatment of soft tissue sarcoma.

[Analysis of clinical, pathological features and therapeutic treatments in predicting prognosis of elderly glioblastomas].

Objective: This study was designed to investigate prognostic factors and the potential relationship between the expression of Ki67 and IDH of glioblastoma in the elderly (≥ 65 years old) and the clinical factors such as gender, the KPS score and treatments including surgical resection, radiotherapy and chemotherapy and the prognosis of such patients. Methods: Fifty-four elderly patients (≥ 65 years old) with glioblastoma admitted to the First Affiliated Hospital of Zhengzhou University from 2013 to 2018 were enrolled in this study. The expression of Ki67 was detected by immunohistochemical SP method and the mutation of IDH was detected by Sanger sequencing. Finally, statistical analysis was performed to determine whether Ki67, the mutation of IDH, gender, the KPS score and the extent of resection, radiotherapy and chemotherapy were associated with the clinical prognosis of the patients. Results: Of the 54 elderly patients with glioblastoma, none was detected with IDH mutation. Univariate analysis showed that Ki67(P=0.033), the KPS score (P=0.008), the extent of resection (P<0.001) were factors influencing the prognosis of elderly patients with glioblastoma. Patients receiving postoperative adjuvant radiotherapy (P=0.002) and chemotherapy (P=0.034) had longer survival time. There was no significant correlation between gender (P=0.467) and prognosis. Multivariate analysis demonstrated that radiotherapy (OR 2.446, P=0.009) and the extent of resection (OR 6.976, P<0.001) were independent prognostic factors. Conclusions: No IDH mutation was detected in all the patients in this study, indicating that IDH mutation is indeed rare in elderly glioblastoma, which suggests that geriatric population often harbor a molecular phenotype with poor prognosis. Ki67, KPS score, the extent of resection, radiotherapy and chemotherapy were the factors influencing the prognosis of patients.

[A multicenter randomized prospective study of concurrent chemoradiation with 60 Gy versus 50 Gy for inoperable esophageal squamous cell carcinoma].

Objective: To determine whether 60 Gy is superior to standard 50 Gy for definitive concurrent chemoradiation(CCRT) in esophageal squamous cell carcinoma (ESCC) using modern radiation technology in a phase Ⅲ prospective randomized trial. Methods: From April 2013 to May 2017, 331 patients from 22 hospitals who were pathologically confirmed with stage ⅢA-ⅣA ESCC were randomized to 60 Gy or 50 Gy with random number table. Total of 305 patients were analyzed, including 152 in 60 Gy group and 153 in 50 Gy group. The median age was 63 years, 242(79.3%) males and 63(20.7%) females. The median length of primary tumor was 5.6 cm. The clinical characteristics between two groups were comparable. All patients were delivered 2 Gy per fraction, 5 fractions per week. Concurrent weekly chemotherapy with docetaxel (25 mg/m(2)) and cisplatin (25 mg/m(2)) and 2 cycles consolidation chemotherapy with docetaxel (70 mg/m(2)) and cisplatin (25 mg/m(2), d1-3) were administrated. The primary endpoint was local/regional progression-free survival (LRPFS). The data were compared with Pearson chi-square test or Fisher's exact test. Results: At a median follow-up of 27.3 months, the disease progression rate was 37.5% (57/152), 43.8% (67/153) in the high and standard-dose group, respectively (χ(2)=1.251, P=0.263). The 1, 2, 3-year LRPFS rate was 75.4%, 56.8%, 52.1% and 74.2%, 58.4%, 50.1%, respectively (HR: 0.95, 95%CI: 0.69-1.31, P=0.761). The 1, 2, 3-year overall survival rate was 84.1%, 64.8%, 54.1% and 85.4%, 62.9%, 54.0%, respectively (HR: 0.98, 95%CI: 0.71-1.38, P=0.927). The 1, 2, 3-year progression-free survival rate was 70.8%, 54.2%, 48.5% and 65.5%, 51.9%, 45.1%, respectively (HR: 0.93, 95%CI: 0.68-1.26, P=0.621). The incidence rates in toxicities between the two groups were similar except for higher rate of severe pneumonitis in high dose group (χ(2)=11.596, P=0.021). Conclusions: The efficacy in disease control is similar between 60 Gy and 50 Gy using modern radiation technology concurrent with chemotherapy for ESCC. The 50 Gy should be recommended as the regular radiation dose with CCRT for ESCC.

[Correlation between CTL and Th1 cell proportion in peripheral blood of liver transplantation recipients and the success of hepatitis B vaccination].

Objective: To investigate the correlation between the proportion of CTL and Th1 cells in peripheral blood of liver transplant recipients and the success of hepatitis B vaccination. Methods: The subjects of this study were liver transplantation recipients with chronic HBV-related liver diseases in Organ transplantation institute of the third medical center of PLA general hospital. Subjects were randomly divided into two groups for prospective study. In the rapid group, one dose of 40 µg hepatitis B vaccine was administered at 0, 1, 2and 3 months, and one dose of 20 µg hepatitis B vaccine was administered at 4, 5 and 6 months. In the rapid-enhanced group, one dose of 40 µg hepatitis B vaccine was administered at 0, 1, 2 and 3 months, and one dose of 60 µg hepatitis B vaccine was administered at 4, 5 and 6months. Compare and analyze the success rate of inoculation, the titer of hepatitis B surface antibody (anti-HBs), the proportion of CTL cells in CD8(+)T cells and Th1 cells in CD4(+)T cells. Correlation analysis was performed for CTL and Th1 cells and anti-HBs, Observe the safety of vaccination. Results: The inoculation success rate, anti-HBs growth rate, CTL cell percentage increase and Th1 cell percentage increase in the rapid enhancement group were all higher than those in the rapid enhancement group, and the differences were statistically significant, they were 38.3% (23/60) vs 21.7% (13/60) (P=0.046), 91.3(72.5,124.2) vs 22.1(12.4, 31.6) (P=0.001), 1.4(0.8,1.9) vs 0.4(0.2,1.4) (P=0.001) and 7.4±2.6 vs 5.6±3.7 (P=0.001) respectively. The percentage increase of CTL cells and Th1 cells in the successful group was greater than that in the non-successful group, and the difference was statistically significant. They were 1.9(1.4,2.5) vs 0.1(0.0,1.1) (P=0.024) and 9.6±3.1 vs 2.4±2.0 (P<0.001). There was no significant correlation between anti-HBs increase (105.5±37.1) and CTL increase 1(0,3) (P=0.099), while there was significant positive correlation with Th1 increase 7(2,11) (P<0.001). No rejection reaction occurred during the study period, and there was no special abnormal change in the safety index. Conclusion: Reasonable increase of vaccine dose can up-regulate Th1 cell expression and promote the generation of anti-HBs.

[Consistency of ALK Ventana-D5F3 immunohistochemistry interpretation in lung adenocarcinoma among Chinese histopathologists].

Objective: To understand the consistency of ALK Ventana-D5F3 immunohistochemistry (IHC) interpretation in Chinese lung adenocarcinoma among histopathologists from different hospitals, and to recommend solution for the problems found during the interpretation of ALK IHC in real world, with the aim of the precise selection of patients who can benefit from ALK targeted therapy. Methods: This was a multicenter and retrospective study. A total of 109 lung adenocarcinoma cases with ALK Ventana-D5F3 IHC staining were collected from 31 lung cancer centers in RATICAL research group from January to June in 2018. All cases were scanned into digital imaging with Ventana iSCANcoreo Digital Slide Scanning System and scored by 31 histopathologists from different centers according to ALK binary (positive or negative) interpretation based on its manufacturer's protocol. The cases with high inconsistency rate were further analyzed using FISH/RT-PCR/NGS. Results: There were 49 ALK positive cases and 60 ALK negative cases, confirmed by re-evaluation by the specialist panel. Two cases (No. 2302 and No.2701) scored as positive by local hospitals were rescored as negative, and were confirmed to be negative by RT-PCR/FISH/NGS. The false interpretation rate of these two cases was 58.1% (18/31) and 48.4% (15/31), respectively. Six out of 31 (19.4%) pathologists got 100% accuracy. The minimum consistency between every two pathologists was 75.8%.At least one pathologist gave negative judgement (false negative) or positive judgement (false positive) in the 49 positive or 60 negative cases, accounted for 26.5% (13/49), 41.7% (25/60), respectively, with at least one uncertainty interpretation accounted for 31.2% (34/109). Conclusion: There are certain heterogeneities and misclassifications in the real world interpretation of ALK-D5F3 IHC test, which need to be guided by the oncoming expert consensus based on the real world data.

SOX8 regulates cancer stem-like properties and cisplatin-induced EMT in tongue squamous cell carcinoma by acting on the Wnt/ß-catenin pathway.

A sub-population of chemoresistant cells exhibits biological properties similar to cancer stem cells (CSCs), and these cells are believed to be a main cause for tumor relapse and metastasis. In our study, we explored the role of SOX8 and its molecular mechanism in the regulation of the stemness properties and the epithelial mesenchymal transition (EMT) of cisplatin-resistant tongue squamous cell carcinoma (TSCC) cells. We found that SOX8 was upregulated in cisplatin-resistant TSCC cells, which displayed CSC-like properties and exhibited EMT. SOX8 was also overexpressed in chemoresistant patients with TSCC and was associated with higher lymph node metastasis, advanced tumor stage and shorter overall survival. Stable knockdown of SOX8 in cisplatin-resistant TSCC cells inhibited chemoresistance, tumorsphere formation, and EMT. The Wnt/ß-catenin pathway mediated the cancer stem-like properties in cisplatin-resistant TSCC cells. Further studies showed that the transfection of active ß-catenin in SOX8 stable-knockdown cells partly rescued the SOX8 silencing-induced repression of stem-like features and chemoresistance. Through chromatin immunoprecipitation and luciferase assays, we observed that SOX8 bound to the promoter region of Frizzled-7 (FZD7) and induced the FZD7-mediated activation of the Wnt/ß-catenin pathway. In summary, SOX8 confers chemoresistance and stemness properties and mediates EMT processes in chemoresistant TSCC via the FZD7-mediated Wnt/ß-catenin pathway.

Direct Observation of Twisted Surface skyrmions in Bulk Crystals.

Magnetic skyrmions in noncentrosymmetric helimagnets with D_{n} symmetry are Bloch-type magnetization swirls with a helicity angle of ±90°. At the surface of helimagnetic thin films below a critical thickness, a twisted skyrmion state with an arbitrary helicity angle has been proposed; however, its direct experimental observation has remained elusive. Here, we show that circularly polarized resonant elastic x-ray scattering is able to unambiguously measure the helicity angle of surface skyrmions, providing direct experimental evidence that a twisted skyrmion surface state also exists in bulk systems. The exact surface helicity angles of twisted skyrmions for both left- and right-handed chiral bulk Cu_{2}OSeO_{3}, in the single as well as in the multidomain skyrmion lattice state, are determined, revealing their detailed internal structure. Our findings suggest that a skyrmion surface reconstruction is a universal phenomenon, stemming from the breaking of translational symmetry at the interface.

Experimental Evidence of Kinetic Effects in Indirect-Drive Inertial Confinement Fusion Hohlraums.

We present the first experimental evidence supported by simulations of kinetic effects launched in the interpenetration layer between the laser-driven hohlraum plasma bubbles and the corona plasma of the compressed pellet at the Shenguang-III prototype laser facility. Solid plastic capsules were coated with carbon-deuterium layers; as the implosion neutron yield is quenched, DD fusion yield from the corona plasma provides a direct measure of the kinetic effects inside the hohlraum. An anomalous large energy spread of the DD neutron signal (∼282 keV) and anomalous scaling of the neutron yield with the thickness of the carbon-deuterium layers cannot be explained by the hydrodynamic mechanisms. Instead, these results can be attributed to kinetic shocks that arise in the hohlraum-wall-ablator interpenetration region, which result in efficient acceleration of the deuterons (∼28.8 J, 0.45% of the total input laser energy). These studies provide novel insight into the interactions and dynamics of a vacuum hohlraum and near-vacuum hohlraum.