Journal of Shandong University (Health Sciences)

Advances of cellular immunotherapy for hematologic malignancies

HUANG Xiaojun

Journal of Shandong University (Health Sciences). 2019, 57(7): 1-5. doi:10.6040/j.issn.1671-7554.0.2019.072

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Immunotherapy has changed the therapeutic method and prognosis of malignant tumors. Hematopoietic stem cell transplantation is one of the earliest applied immunotherapy, which remains the essential treatment of many hematological malignancies. In recent years, new immunotherapy, such as CAR-T, PD-1 and NK cell therapy, has developed rapidly for the treatment of high-risk malignant hematological diseases, and has attracted attention from researchers all over the world. Cellular immunotherapy is suitable for patients with graft failure or contraindications, and is a less toxic alternative for relapsed/refractory patients. This paper reviews the advances of cellular immunotherapy for hematological malignancies.

Advances in targeted therapy for acute myeloid leukemia

WANG Jianxiang, GU Runxia

Journal of Shandong University (Health Sciences). 2019, 57(7): 6-12. doi:10.6040/j.issn.1671-7554.0.2019.191

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Acute myeloid leukemia(AML)is a highly heterogeneous clonal disease. Although traditional cytotoxic chemotherapy is still the fundamental treatment, it fails to meet the clinical requirements. In recent years, advances in deep sequencing and applications of targeted drugs have opened a new era of targeted therapy for AML. However, issues such as drug resistance, overlaid toxicity of combined therapy, and lack of effective targets have gradually emerged and presented new challenges. We believe that in the near future, digging into the pathogenesis of AML, developing and appropriately using targeted drugs and immunotherapy will continue improving the efficacy of AML and promoting the individualized precision therapy.

Current situation and prospect of immunotherapy for lymphoma

WU Depei, CHEN Xiaochen

Journal of Shandong University (Health Sciences). 2019, 57(7): 13-20. doi:10.6040/j.issn.1671-7554.0.2019.208

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Lymphoma is one of the most common hematological malignancies which has many subtypes and high heterogeneity. Traditional treatments include chemotherapy, radiotherapy and surgery. Patients with relapsed, refractory or advanced stage lymphoma still have dismal prognosis. In recent years, the development of immunotherapies for lymphoma has brought patients new hope. This paper reviews the current and novel immunotherapies for lymphoma, including monoclonal antibody therapy, immune checkpoint blockers, and chimeric antigen receptor T cells therapies.

Selecting therapy for chronic lymphocytic leukemia in the era of novel agents

LI Jianyong, XIA Yi, XU Wei

Journal of Shandong University (Health Sciences). 2019, 57(7): 21-30. doi:10.6040/j.issn.1671-7554.0.2019.477

Abstract ( 305 )

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Chronic lymphocytic leukemia(CLL)is the most common type of adult leukemia in Caucasian population. Although CLL is less common in Chinese, an increasing incidence of new cases is observed. Before 2010s, the standard 山东大学学报 (医学版)57卷7期 -李建勇,等.新药时代慢性淋巴细胞白血病的治疗选择 \=-therapy for CLL was chemoimmunotherapy. In recent years, Brutons tyrosine kinase(BTK)inhibitors ibrutinib and acalabrutinib, phosphatidylinositol 3-kinase(PI3K)inhibitors idelalisib and duvelisib, and BCL2 antagonist venetoclax have led to remarkable improvement in the survival of CLL patients. Novel cellular immunotherapy, including chimeric antigen receptor-engineered T(CART), has also shown promising efficacy in the treatment of CLL. How to choose individualized therapeutic regimen from the various approaches is now posing challenges upon clinicians.

Primary central nervous system lymphoma: status and advances in diagnosis, molecular pathogenesis and treatment

ZHOU Daobin, ZHANG Yan

Journal of Shandong University (Health Sciences). 2019, 57(7): 31-39. doi:10.6040/j.issn.1671-7554.0.2019.204

Abstract ( 390 )

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Primary central nervous system lymphoma(PCNSL)is a rare group of extra-nodal non-Hodgkin lymphoma with specific biological characteristics and clinical behaviors. The systemic chemotherapy based on high-dose methotrexate has improved the clinic outcomes, but risk of relapse and tolerance is still substantial. In this paper, 山东大学学报 (医学版)57卷7期 -周道斌,等.原发性中枢神经系统淋巴瘤诊治现状及进展 \=-we will review the status of diagnosis and treatment of PCNSL, especially advances in the diagnosis, molecular pathogenesis and novel agents in relapsed/refractory cases.

Advances in the diagnosis and treatment of multiple myeloma

LU Jin

Journal of Shandong University (Health Sciences). 2019, 57(7): 40-43. doi:10.6040/j.issn.1671-7554.0.2019.362

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The diagnosis, treatment and efficacy evaluation of multiple myeloma are progressing rapidly in recent years. Novel agents including new proteasome inhibitors, new immunomodulators, monoclonal antibodies and cellular therapy have non-stoppingly updated the diagnostic criteria, diagnostic methods and evaluation criteria. This article reviews the current progress in diagnosis and treatment of multiple myeloma in order to guide clinical practice.

Advances in the clinical treatment of hemophagocytic lymphohistiocytosis

WANG Zhao

Journal of Shandong University (Health Sciences). 2019, 57(7): 44-49. doi:10.6040/j.issn.1671-7554.0.2019.507

Abstract ( 491 )

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Hemophagocytic lymphohistiocytosis(HLH)is a life-threatening disease resulted from hereditary or acquired dysfunction of immune system characterized by pathologic inflammatory reaction. The therapeutic guideline for HLH published by the Histiocyte Society in 1994 was a milestone in HLH treatment, which has improved the clinical remission rate of HLH from less than 10% to 50%-70% and has become a first-line treatment. However, HLH is still a refractory disease, for which numerous clinical trials have been conducted in the past decade. The novel approaches of treatment include modified chemotherapy regimens and biologically targeted therapy. This paper reviews the recent advances in treatment of HLH in order to provide new insights.

Development of gene sequencing in the diagnosis and treatment of lymphoma

WANG Xin

Journal of Shandong University (Health Sciences). 2019, 57(7): 50-54. doi:10.6040/j.issn.1671-7554.0.2019.428

Abstract ( 435 )

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High-throughput sequencing technology based on whole-genome sequences has developed rapidly in recent years. Thanks to its high speed, high accuracy and low cost, it has been widely used in various fields of clinical medicine. It has also brought revolutionary changes for the diagnosis and treatment of numerous subtypes of lymphomas. The high-throughput sequencing has greatly promoted the development of lymphoma research, including screening specific diagnostic markers, exploring the pathogenesis of the diseases, finding prognostic indicators and promoting new drug development.

Anti-inflammation effect of baicalin on rat models of nonalcoholic steatohepatitis

AI Zhenglin, HONG Shan, HU Julong, LI Ping, ZHOU Yuling, LIANG Xiuxia, YAO Shukun

Journal of Shandong University (Health Sciences). 2019, 57(7): 55-60. doi:10.6040/j.issn.1671-7554.0.2019.475

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Objective To investigate the efficacy of baicalin in the treatment of non-alcoholic steatohepatitis(NASH)in rat models and the anti-inflammatory effect. Methods After NASH rat models were induced, they were intragastrically given different doses of baicalin 15, 30, 60 mg/(kg·d). The body weight and liver weight were measured. The histopathology changes in hepatic steatosis were observed with hematoxylin-eosin(HE)staining. The serum alanine amiotransferase(ALT)and aspartate aminotransferase(AST)levels were assessed. The changes of hepatic reduced glutathione hormone(GSH), superoxide dismutase(SOD)and hepatic malondialdehyde(MDA)were detected with spectrophotometry. The levels of tumor necrosis factor α(TNFα), interleukin 6(IL-6)and interleukin 1β(IL-1β)in liver tissues were measured with enzyme linked immunosorbent assay(ELASA). Results After baicalin treatment, the body weight and liver weight of NASH rats were significantly reduced(F=1 609.79, P<0.001; F=155.17, P<0.001) 山东大学学报 (医学版)57卷7期 -艾正琳,等.黄芩苷治疗非酒精性脂肪性肝炎大鼠抗炎的疗效 \=-in a dose-dependent manner. The steatosis of hepatic cells gradually decreased, and the infiltration of inflammatory cells was relieved. The serum ALT and AST reduced(F=177.16, P<0.001; F=2 998.11, P<0.001), the activity of GSH and SOD increased(F=398.47, P<0.001; F=256.07, P<0.001); the MDA;TNFα, IL-1β and IL-6 levels decreased(F=237.98, P<0.001;F=399.15, P<0.001; F=314.76, P<0.001; F=108.38, P<0.001), in a dose-dependent manner. Conclusion Baicalin can alleviate the degree of steatosis and inflammation in NASH rats. By increasing the activity of GSH and SOD enzymes, and reducing the levels of TNFα, IL-1β and IL-6, it exerts anti-inflammatory effects and alleviates liver inflammation.

Graft-versus-host disease secondary to allogeneic hematopoietic stem cell transplantation in 57 patients with acute lymphoblastic leukemia

SUN Feifei, FANG Xiaosheng, JIANG Yujie, SUI Xiaohui, LIU Xin, WANG Xianghua, LI Ying, ZHANG Lingyan, XU Hongzhi, WANG Xin

Journal of Shandong University (Health Sciences). 2019, 57(7): 61-66. doi:10.6040/j.issn.1671-7554.0.2019.698

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Objective To explore the incidence and risk factors of graft-versus-host disease(GVHD)secondary to allogeneic hematopoietic stem cell transplantation(allo-HSCT)in patients with acute lymphoblastic leukemia(ALL). Methods The clinical data of 57 ALL patients who received allo-HSCT in our hospital during Oct. 2010 and Oct. 2018 山东大学学报 (医学版)57卷7期 -孙菲菲,等.57例急性淋巴细胞白血病异基因造血干细胞移植后抗宿主病的发生及影响因素分析 \=- were retrospectively analyzed. The information primary diseases, HSCT, overall survival(OS), leukemia-free survival(LFS), relapse rate(RR)and non-relapse mortality(NRM)was collected. The incidence, severity and risk factors of GVHD were analyzed. Results The donors were human leukocyte antigen(HLA)-allele mismatched for 37 cases, and matched for 20 cases(2 of which were unrelated). The donors for 24 cases had the identical blood type as the recipients, while donors for 37 cases had incompatible blood type. The donors for 30 cases were the same gender as the recipients, while donors for 27 cases were different gender. Median day of neutrophil and platelet engraftment was 12 d(range: 6-20 d)and 13 d(range: 9-47 d), respectively. Accumulative incidence of acute GVHD(aGVHD)was 53.4%(grade Ⅰ-Ⅱ: 42.8%; grade Ⅲ-Ⅳ: 10.8%). The cumulative incidence of chronic GVHD(cGVHD)was 20.3%, of which 5.3% was extensive and 15.1% was limited. Survival analysis showed that the 3-year OS and LFS of patients with grade Ⅲ-Ⅳ aGVHD were significantly lower than those without or with grade Ⅰ-Ⅱ aGVHD(20% vs 69.8%, 66.7%, χ2=17.243, P<0.001; 20% vs 60.8%, 71%, χ2=9.463, P=0.009), with RR and NRM increased(60% vs 33.7%, 23.9%, χ2=1.788, P=0.409; 50% vs 0.71%, 0.59%, χ2=21.344, P<0.001). The 3-year OS and LFS of patients with cGVHD were lower than those without cGVHD by no significant difference(44.4% vs 67.6%, χ2=0.142, P=0.706; 50% vs 62.4%, χ2=0.236, P=0.627). Multivariate analysis showed that HLA mismatch was a significantly independent risk factor for aGVHD. Gender difference between donors and recipients was an marginally significant independent factor of cGVHD. Conclusion GVHD is an important complication of allo-HSCT in ALL patients. Patients with grade Ⅲ-Ⅳ aGVHD have poor prognosis. HLA mismatch is an independent risk factor for aGVHD.

Expression and clinical significance of homo sapiens longevity assurance homologue 2 of yeast LAG1 in colorectal cancer

8.GUO Yan, ZHANG Zheying, WANG Yunxi, WEI Xiaojuan

Journal of Shandong University (Health Sciences). 2019, 57(7): 67-71. doi:10.6040/j.issn.1671-7554.0.2019.180

Abstract ( 402 )

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Objective To investigate the expression and clinical significance of homo sapiens longevity assurance homologue 2 of yeast LAG1(LASS2)in colorectal cancer. Methods A total of colorectal cancer 85 cases treated during Aug. 2011 and Aug. 2013 were involved. The protein expression of LASS2 in colorectal cancer and adjacent tissues were detected with immunohistochemistry(SP method). All patients were followed up, and until Aug. 30, 2018, the complete follow-up data of 78(91.76%)cases were obtained. Patients’ survival was analyzed using Kaplan-Meier method and Log-rank test. The influencing factors on prognosis were determined with Cox proportional hazards regression model. Results The positive expression rates of LASS2 in colorectal cancer tissues and adjacent tissues was 32.94% vs 78.82%(P<0.001). The positive expression rates of LASS2 in colorectal cancer tissues with moderately poor differentiation, TNM stage Ⅲ+Ⅳ and lymph node metastasis were lower than that in high differentiation, TNM stage Ⅰ+Ⅱ and without lymph node metastasis(P<0.05). The overall survival of patients with positive versus negative LASS2 expression was 57.60 vs 28.47 months(P<0.001), and cumulative survival rate was 55.60% vs 19.60%(P<0.001). The differentiation, TNM stage, lymph node metastasis and protein expression of LASS2 were influencing factors on the 山东大学学报 (医学版)57卷7期 -郭艳,等.人源性长寿保障基因2在结直肠癌组织中的表达及其临床意义 \=-prognosis(HR=0.134, 2.907, 2.478 and 0.476, P<0.05). Conclusion LASS2 is lowly expressed in colorectal cancer tissues, and is related to the malignant progression and prognosis. It might be a potential biomarker for prognosis assessment.

Changes of intestinal microbiota in patients with chronic kidney disease 5

LÜ Chenxiao, LI Yang, GAO Ying, ZHANG Qunye, ZHANG Lei, WANG Zunsong

Journal of Shandong University (Health Sciences). 2019, 57(7): 72-79. doi:10.6040/j.issn.1671-7554.0.2019.002

Abstract ( 488 )

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Objective To explore the differences of gut microbiota composition between chronic kidney disease 5(CKD5)patients and healthy people. Methods The individuals were divided into the healthy control group(n=69), CKD5-none hemodialysis(NHD)group(n=24)and CKD5-hemodialysis(HD)group(n=29). 16S rRNA gene sequencing technology was used to analyze differences of the gut microbiota composition among the three groups. LDA>2.0 indicated significant differences in the biome between two groups. Based on the sequencing results, the function of intestinal microflora in CKD5 patients was studied by means of STAMP software mapping to KEGG and COG database. Results In the healthy control group, Bacteroidetes, Gammaproteobacteria, and Enterobacteriaceae were dominant. Enterococcaceae, Eubacterium, Rhodobacteraceae were high in CKD5-HD group, while Actinobacteria, Bifidobacterium, Coriobacteriales were dominant in the CKD5-NHD group. In the CKD5 patients, glycerolipid, carbohydrate, protein and amino acid metabolism activity was increased. Conclusion Significant differences were found in the composition and function of the gut microbiota between the CKD5 patients and healthy individuals. Imbalance of the gut micro- 山东大学学报 (医学版)57卷7期 -吕晨箫,等. 慢性肾脏病5期患者的肠道菌群变化 \=-biota in CKD5 patients may increased the risk of complications by influencing a variety of metabolic and signaling pathways.

Exploring molecular characteristics of esophageal squamous cell carcinoma based on next-generation sequencing

FENG Alei, DONG Qing, PANG Jiaohui, YIN Jiani, LI Qiang, HAN Junqing, YANG Zhe

Journal of Shandong University (Health Sciences). 2019, 57(7): 80-85. doi:10.6040/j.issn.1671-7554.0.2019.650

Abstract ( 549 )

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Objective To explore the potential molecular targets and gene mutation characteristics in esophageal squamous cell carcinoma(ESCC)by using next-generation sequencing. Methods DNA was extracted from tissue samples collected from 49 ESCC patients. The 416 cancer-relevant genes were sequenced with Illumina HiSeq4000 platform. The sequencing data were then subjected to bioinformatics analysis. Results TP53 was identified as the most frequently mutated gene, and multiple potential therapeutic targets were revealed. The mutation rate and amplification rate of EGFR 19del mutations were both 4.08%, while no EGFR L858R mutation or KRAS mutation was detected. The amplification rate of HER2 and MET were both 2.04%. The inactivating mutation rate of BRCA1/2 was 8.06%. The positive rate of MSI was 4.76%, indicating that ESCC patients with related target gene variations would potentially benefit from targeted therapies or immunotherapies. Conclusion Multiple potential therapeutic targets in ESCC are identified using next-generation sequencing, which can significantly guide personalized ESCC treatment.

Effects of acarbose on YKL-40 and gut bacteria in coronary heart disease patients with impaired glucose tolerance

LOU Fuchen, LIU Xingxiang, MA Guoyun, ZHUANG Xianghua

Journal of Shandong University (Health Sciences). 2019, 57(7): 86-91. doi:10.6040/j.issn.1671-7554.0.2019.513

Abstract ( 434 )

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Objective To investigate the effects of alpha-glucosidase inhibitor, acarbose, on YKL-40 and gut bacteria in coronary heart disease(CHD)patients with impaired glucose tolerance(IGT). Methods A total of 57 CHD patients with IGT were randomly divided into the control group(group A, n=27)and 300 mg/d acarbose intervention group(group B, n=30). At the baseline and 24-week end point, anthropometrical parameters, fast blood glucose(FBG), 2 h postprandial blood glucose(PBG), serum fast insulin(FINS), lipid profile, HbA1c and serum YKL-40 were measured. The quantification of fecal Bifidobacterium and Lactobacillus faecalis were detected with RT-PCR. Results There were no significant differences between the two groups in terms of the physical and hematological parameters at baseline. Pearson correlation analysis showed that levels of Bifidobacterium and Lactobacillus were negatively correlated with YKL-40. After 24-week acarbose(300 mg/d)treatment, the levels of YKL-40, FBG, PBG, HbA1c and HOMA-IR significantly decreased in group B(P<0.05), while the levels of Bifidobacterium and Lactobacillus significantly increased in group B(P<0.05). Conclusion After 24-week treatment with 300 mg/d acarbose, CHD patients with IGT have improved glucose metabolism, decreased YKL-40 level, but increased number of beneficial gut microbiota.

Clinical efficacy of helmet and face mask noninvasive ventilation on patients with respiratory failure: a Meta-analysis

HONG Shukun, TIAN Yonggang, LI Yahong, QIAO Lujun

Journal of Shandong University (Health Sciences). 2019, 57(7): 92-101. doi:10.6040/j.issn.1671-7554.0.2018.1274

Abstract ( 357 )

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Objective To evaluate the clinical efficacy of helmet and face mask noninvasive ventilation on patients with respiratory failure. Methods By searching literature database including Medline(Pubmed), Cochrane Library, Web of Science, Wanfang, CNKI and Chinese Biological Medicine Database, randomized controlled trials comparing helmet and face mask noninvasive ventilation, which were defined as helmet group and face mask group, for patients with respiratory failure were selected according to inclusion and exclusion criteria. Data were extracted and quality assessment was conducted by using “risk of bias” criteria specified by the Cochrane Collaboration and Jadad scoring system. Meta-analysis was performed by using statistical software of Review manager 5.1.0. Results Overall, ten randomized controlled trials were included, with 228 cases in helmet group and 223 cases in face mask group. The Meta-analysis showed that, compared with face mask, helmet could significantly decrease the incidences of intolerance(RR=0.18,95%CI: 0.08-0.41,P<0.001), skin ulcer(RR=0.19,95%CI: 0.08-0.48,P<0.001)and gastric distension(RR=0.15,95%CI: 0.05-0.42,P<0.001), reduce the respiratory rate (MD=-3.01,95%CI: -4.87 - 1.16,P=0.001), endotracheal intubation rate(RR=0.39,95%CI: 0.26-0.59,P<0.001)and mortality(RR=0.59,95%CI: 0.36-0.96,P=0.030), and increase the oxygenation index of type-I respiratory failure(MD=60.45,95%CI: 20.44-100.46, P=0.003). How- 山东大学学报 (医学版)57卷7期 -洪树坤,等.头罩与面罩无创通气对呼吸衰竭患者临床疗效的Meta分析 \=-ever, the ability of reducing PaCO₂ of type-II respiratory failure of helmet was less than that of face mask(MD=5.86,95%CI: 3.64-8.08,P<0.001). Conclusion Compared with face mask, helmet can improve the patients’ tolerance, reduce the adverse events, increase the oxygenation effect, and decrease the risk of endotracheal intubation. Helmet has no advantage over face mask in eliminating the retention of CO₂.

Incidence and mortality of oral cancer in Shandong Province in 2014

LIU Guanyi, YANG Liyuan, FU Zhentao, XU Aiqiang, GUO Xiaolei

Journal of Shandong University (Health Sciences). 2019, 57(7): 102-107. doi:10.6040/j.issn.1671-7554.0.2019.384

Abstract ( 562 )

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Objective To investigate the incidence and mortality of oral cancer in Shandong Province based on the cancer registration data in 2014, collected by Shandong Center for Disease Control and Prevention(SDCDC). Methods The cancer data submitted by 30 registries to SDCDC were reviewed and data from 25 registries were included. The areas of occurrence(urban/rural), patients gender and age were analyzed. With reference to the population data of Shandong Province, the incidence and mortality of oral cancer were calculated. Chinese population census in 2000 and Segis population were adopted for the analysis of age-standardized incidence/mortality rates. Results The new oral cancer cases and deaths in 2014 in Shandong Province were 2 882 and 1 178, respectively. The crude incidence rate was 3.00/100 000(male 4.41/100 000, female 1.54/100 000). Age-standardized rate of incidence by Chinese population(ASRIC, 2 000)and world population(ASRIW)was 2.19/100 000 and 2.15/100 000, respectively. The ASRIC in urban and rural areas was 2.20/100 000 and 2.19/100 000, respectively. The crude mortality rate of oral cancer was 1.23/100 000(male 1.83/100 000, female 0.60/100 000). Age-standardized rate of mortality by Chinese population(ASRMC, 2 000)and world population(ASRMW)was both 0.87/100 000. The ASRMC in urban and rural areas was 0.85/100 000 and 0.88/100 000, respectively. The cumulative incidence and mortality rate(0-74 years old)was 0.26% 山东大学学报 (医学版)57卷7期 -刘冠邑,等.2014年山东省口腔癌发病和死亡水平分析 \=-and 0.11%, respectively. Conclusion Incidence and mortality of oral cancer in Shandong Province in 2014 were similar to that of national average level. Appropriate prevention and control measures should be established according to the epidemic characteristics and risk factors of oral cancer.

Analysis of dental and basal arch forms of 16 individual normal occlusions using three-dimensional evaluation

LI He, LU Lu, GUO Jing

Journal of Shandong University (Health Sciences). 2019, 57(7): 108-113. doi:10.6040/j.issn.1671-7554.0.2019.406

Abstract ( 503 )

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Objective To investigate the relationship between dental and basal arch forms in individual normal occlusion, and to establish the normal value between the facial-axis(FA)point and Will Andrews and Larry Andrews(WALA)point in Shandong population. Methods A total of 16 individual normal occlusions were selected. The FA points and WALA points were marked on the plaster casts, which were then scanned to obtain the digital data. Curves of dental arch and basal arch forms were illustrated. The distance between the FA points and WALA points was measured. Results The FA and WALA curves were sporadic, which could not be described with same curve. The dispersion degree of the molar area was large. The correlation between the FA and the WALA points in the intercanine width (r=0.700), intermolar width (r=0.805), and intercanine width to intermolar width (r=0.625)were highly significant. In our sample, the mean value of the distance between the FA points and WALA points from central incisor to second molar were(-1.53±0.92)mm,(-0.97±1.11)mm,(0.65±0.90)mm,(1.17±0.64)mm,(2.13±0.93)mm,(3.12±0.72)mm, and(3.55±0.54)mm. Conclusion Both the FA and WALA point-derived arch forms are unique and can not be defined by a generalized shape. The WALA points can be a useful predictor of the dental arch form.

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