Early Detection of Molecular Residual Disease and Risk Stratification for Children with Acute Myeloid Leukemia via Circulating Tumor DNA.

PURPOSE: Patient-tailored minimal residual disease (MRD) monitoring based on circulating tumor DNA (ctDNA) sequencing of leukemia-specific mutations enables early detection of relapse for pre-emptive treatment, but its utilization in pediatric acute myelogenous leukemia (AML) is scarce. Thus, we aim to examine the role of ctDNA as a prognostic biomarker in monitoring response to the treatment of pediatric AML. EXPERIMENTAL DESIGN: A prospective longitudinal study with 50 children with AML was launched, and sequential bone marrow (BM) and matched plasma samples were collected. The concordance of mutations by next-generation sequencing-based BM-DNA and ctDNA was evaluated. In addition, progression-free survival (PFS) and overall survival (OS) were estimated. RESULTS: In 195 sample pairs from 50 patients, the concordance of leukemia-specific mutations between ctDNA and BM-DNA was 92.8%. Patients with undetectable ctDNA were linked to improved OS and PFS versus detectable ctDNA in the last sampling (both P < 0.001). Patients who cleared their ctDNA post three cycles of treatment had similar PFS compared with persistently negative ctDNA (P = 0.728). In addition, patients with >3 log reduction but without clearance in ctDNA were associated with an improved PFS as were patients with ctDNA clearance (P = 0.564). CONCLUSIONS: Thus, ctDNA-based MRD monitoring appears to be a promising option to complement the overall assessment of pediatric patients with AML, wherein patients with continuous ctDNA negativity have the option for treatment de-escalation in subsequent therapy. Importantly, patients with >3 log reduction but without clearance in ctDNA may not require an aggressive treatment plan due to improved survival, but this needs further study to delineate.

Analysis between macrophage-related genes with prognosis and tumor microenvironment in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a highly morbid and fatal disease that exhibits individualized differences in prognosis and drug efficacy. Therefore, understanding the molecular mechanism of the occurrence and progression of lung cancer can improve early diagnosis, treatment and prognosis. Macrophages are a crucial component of the tumor microenvironment (TME) due to their high plasticity and heterogeneity. They play a multifaceted role in tumor initiation and progression. In order to elucidate the pathogenesis of tumor-associated macrophages (TAMs) related genes in NSCLC, transcriptomic sequencing, univariate COX regression, LASSO regression and multivariate COX regression analyses were conducted to identify the 11 genes that have the most significant association with prognosis. These genes include FCRLA, LDHA, LMOD3, MAP3K8, NT5E, PDGFB, S100P, SFXN1, TDRD1, TFAP2A and TUBB6. The risk score (RS) was computed, and all samples were split into high- and low-risk groups based on the median RS. The correlation of RS and 11 genes with macrophages was verified by the CIBERSORT deconvolution algorithm. These above results suggest that the risk score developed in this study can be utilized for predicting patients' prognosis and evaluating their immune infiltration status. This study can serve as a guide for subsequent tumor immunotherapy and gene targeting therapy.

Galla Chinensis, a Traditional Chinese Medicine: Comprehensive review of botany, traditional uses, chemical composition, pharmacology and toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Galla chinensis (GC), a traditional Chinese medicine (TCM), has a wide range of pharmacological properties which have been widely used for more than 1400 years. Based on shape, GC is divided into two groups: jiaobei and dubei. It is a bitter, sour, cold and astringent substance which is usually used for treating diarrhea, constipation, bleeding, cough, vomiting, sweating, hemorrhoids, and anal and uterine prolapse. It is distributed in Japan, North Korea, and all parts of China. AIM OF STUDY: This study was aimed at carrying out a comprehensive overview of the current status of research on Galla chinensis (GC) for better understanding of it characteristics, while providing a clear direction for future studies. It has aroused the interest of researchers, leading to development of medicinal value, expansion of its application, and provision of wider and more effective drug choices. This study was focused on the traditional uses, botany, chemical composition, pharmacology and toxicology of GC. Finally, the study focused on possible future research directions for GC. MATERIALS AND METHODS: A comprehensive analysis was done based on academic papers, pharmaceutical monographs, ancient medicinal works, and drug standards of China. This review used Galla and Galla chinensis as keywords for retrieval of information on GC from online databases such as PubMed, Elsevier, CNKI, Web of Science, Google Scholar, SCI hub, and Baidu academic. RESULTS: It was found that the chemical constituents of GC included tannins, phenolic acid, amino acids and fatty acid, with polyphenol compounds (especially tannins and gallic acid) as the distinct components. In vitro and in vivo studies revealed that GC exerted numerous biological effects such as anti-caries, antibacterial, antiviral, anticancer, and antioxidant effects. The therapeutic effect of GC was attributed mainly to the biological properties of its bioactive components. CONCLUSIONS: GC is an important TCM which has potential benefit in the treatment of a variety of diseases. However, the relationship amongst the structure and biological activity of GC and its components, mechanism of action, toxicity, pharmacokinetics and target organs need to be further studied. Quality control and quality assurance programs for GC need to be further developed. There is need to study the dynamics associated with the accumulation of chemical compounds in GC as well as the original plants and aphid that form GC.

[The Correlation of Minimal Residual Disease with Prognosis in TCF3-PBX1+ Acute Lymphoblastic Leukemia in Children].

OBJECTIVE: To investigate the consistency between FCM and PCR on the detecting of MRD in TCF3-PBX1+ ALL, and to investigate the prognosis value of these 2 methods. METHODS: 55 cases of paediatric TCF3-PBX1+ ALL patients from April 2008 to April 2015 were enrolled and analyzed. The FCM and PCR was used to detect the MRD in 239 bone marrow samples of 55 patients. All statistical analyses were carried out by using SPSS software version 16. RESULTS: Among the 55 children with TCF3-PBX1+ ALL, there were 30 male and 25 female. The median age was 5 (1-14) years. 20 patients relapsed during follow-up. The MRD results from PCR and FCM showed a strong correlation between both methods (K=0.774, P<0.001). There was no significant difference in 5-years DFS and OS between the patients in PCR+ and PCR- groups on day 15 or day 33. The 5 year DFS rate between the patients in FCM- and FCM+ was 63.9%±7.0% and 0; the 5 year OS rate was 66.5%±7.9% and 0. Combined with the result of FCM and PCR, at the d 33 of treatment, the 5-year DFS rate in FCM-/PCR- and single positive group was 65.4%±7.2% and 25.0%±15.3% (P<0.01). CONCLUSION: The detection result of MRD in TCF3-PBX1 detect by FCM and PCR shows better consistency. MRD positivity detected by FCM at the end of induction therapy (day 33) predicts a high risk of relapse in TCF3-PBX1 ALL patients.

Removal efficiency and mechanism of phycocyanin in water by zero-valent iron.

The efficiencies and mechanism of phycocyanin removal from water by zero-valent iron (ZVI) were studied. The trend for dissolved organic nitrogen removal was similar to phycocyanin and the removal efficiency was high at ∼81% and 95%, respectively, in 90 min. The experimental results showed that the phycocyanin removal efficiency was higher at pH < 6, with an almost complete removal. However, only 68% was removed at pH 9. Within 30 min, the removal efficiency of phycocyanin for 1-4 tested cycles was reduced from 55.8% to 15.2%. Scanning electron microscopy and energy dispersive spectroscopy, Fourier transform infrared spectroscopy analysis and X-ray photoelectron spectroscopy were used to analyze the mechanisms of phycocyanin removal, which indicated that a small amount of phycocyanin was immobilized on the ZVI surface by adsorption. In addition, the main removal pathway was coagulation by dissolved iron ions. The Fe oxide formed in situ from ZVI had a higher removal efficiency than that in FeCl3, which can play improved roles in charge neutralization. The production of disinfection byproducts also decreased because of the decrease of precursors.

[Clinical characteristics of clonal evolution after immunosuppressive therapy in children with severe/very severe aplastic anemia].

OBJECTIVE: To evaluate the clinical characteristics and risk factors of clonal evolution after immunosuppressive therapy (IST) in children with severe/very severe aplastic anemia (SAA/VSAA). METHODS: The clinical data of 231 children with newly-diagnosed SAA/VSAA who received IST were retrospectively studied. The incidence and risk factors of clonal evolution after IST were analyzed. RESULTS: The 5-year overall survival rate of the 231 patients was 82.7%. Except for 18 cases of early deaths, 213 patients were evaluated for IST efficacy. Among the 231 patients, cytogenetic abnormalities for at least two chromosome metaphase were detectable in 14 (7.4%) patients, and PNH clones were detectable in either peripheral red blood cells or neutrophils for 95 patients. Among the 213 patients evaluated for IST efficacy, 15 patients experienced clonal evolution after IST. Five patients had PNH and trisomy 8 which were defined as favorable progressions, and ten patients experienced monosomy 7 and MDS/AML as unfavorable progressions. The 5-year accumulative incidence of favorable and unfavorable progression were (2.2±2.2)% and (4.8±3.3)%, respectively. Until the last follow-up, 100% (5/5) of patients with favorable progressions and 50% (5/10) of patients with unfavorable progressions survived. WBC>3.5×109/L, CD3+T cell percentage>80%, dosage of antithymocyte globulin >3.0 mg/(kg·d) and no response to IST were related to unfavorable progressions by univariate analysis. Cox multivariate analysis revealed that an increased CD3+T cell percentage (>80%) and no response to IST were independent risk factors for unfavorable progressions. CONCLUSIONS: The children with SAA/VSAA who have an increased CD3+T cell percentage at diagnosis or have no response to IST are in high risks of unfavorable progressions.

[Prognostic Value of Prednisone Response in CCLG-ALL 2008].

OBJECTIVE: To ovaluate the prognostic value of prednisone response in treatment regimes of children with acute lymphoblastic leukemia. METHODS: A total of 598 newly diagnosed ALL patients were enrolled and received prednisone pre-treatment. Based on the peripheral lymphoblast count on day 8, these patients were divided into 2 groups: prednisone good response (PGR) and prednisone poor response (PPR). PPR patients were classified into high risk group immediately and then received intensed chemotherapy. The all enrolled patients were followed up and the clinical features and treatment outcomes of the two groups were analyzed. RESULTS: Compared with PGR group, PPR group had different characteristics. They were older in age and had higher initial white blood cell count (P<0.05). T-cell ALL (T-ALL) and Philadelphia chromosome positive ALL (Ph+ ALL) were frequent in PPR group (P<0.05). Event-free survival (EFS) rate of PPR group was significantly lower than that of PGR group (P<0.05). 2 year event-free survival(EFS) rate of PGR group was (88.3±1.5)%, while the 2-year EFS rate of PPR group was (58.4±5.3)%. 5 year EFS rates of PGR and PPR were (80.8±2.1)% and (53.4±6.0)%, respectively. The EFS rate of PPR group was falling rapidly within 2 years. PPR group had higher relapse rate, and most relapses occurred within 18 months (P<0.05). PPR group had more high incidence of minimal residual disease (MRD) both on day 33 and on week 12 (P<0.05). No significant difference of EFS and relapse time was found between PPR and high risk PGR patients (P>0.05). In multi-variate regression analysis, the PPR, the presence of BCR-ABL1 and MLL were significantly unfavorable factors (P<0.05). CONCLUSION: Prednisone response has been confirmed to be still great prognostic value and PPR children patients have poor outcomes generally. It is likely that the response to prednisone does not make much sense to high risk ALL patients.

[Clinical features of childhood refractory cytopenia].

OBJECTIVE: To study the clinical features of patients with refractory cytopenia of childhood (RCC). METHODS: The clinical data of 1 420 children (0-14 years old) with an initial diagnosis of non-severe aplastic anemia between January 1990 and June 2013 were retrospectively analyzed. Bone marrow cell morphology and histopathology were re-evaluated, and the patients were re-classified using the criteria proposed in the 2008 edition of the World Health Organization classification of RCC in hematopoietic and lymphoid tumor tissues. The clinical outcomes were followed up every 3-6 months. RESULTS: Among all the 1 420 cases, 152 (10.7%) were reassessed as RCC. Patients with RCC had a lower level of hemoglobin and a higher percentage of fetal hemoglobin than those with non-severe aplastic anemia. Of the patients with RCC, 21.5% showed abnormal karyotypes at diagnosis. The median follow-up period for all patients was 36 months (ranging from 1 to 283 months). The rates of complete response, partial response, and no response to cyclosporine and androgen treatment in RCC patients were 19.0%, 26.7%, and 54.3%, respectively. The 5- and 10-year prospective overall survival rates of RCC patients were 87.9% and 72.4%, respectively. The 5- and 10-year prospective clonal evolution rates were 15.3% and 20.0%, respectively. The 2-year prospective incidence of newly diagnosed karyotype abnormality after the initial diagnosis was 3.6%. The 5- and 10-year prospective leukemia transformation rates were 10.0% and 20.0%, respectively. CONCLUSIONS: RCC shows clinical features similar to adult myelodysplastic syndrome. Children with RCC have a poor prognosis, an increased risk of transformation to leukemia, and a low response rate to cyclosporine treatment.

[Research progress in molecular biology of pediatric myelodysplastic syndrome].

Marked differences have been found in molecular characteristics between pediatric and adult myelodysplastic syndrome (MDS) patients. The incidence of gene mutations associated with myeloid malignances in pediatric patients is lower than in adults, while the incidence of aberrant methylation is similar between them. It is also worth noting that novel molecular factors such as mitochondrial DNA mutations may play a role in the pathogenesis of childhood MDS. This article summarizes research advances in molecular biology of pediatric MDS.

[Clinical application of Sniffin' Sticks olfactory psychophysical measurements].

OBJECTIVES: To establish the normal value of Sniffin' Sticks test in Chinese population and to explore it's clinical application in China. METHODS: One hundred and five healthy volunteers were choosen from the department of physical examination of Beijing Tongren Hospital between 2007 and 2013. Another 165 patients complained of abnormal olfactory function were obtained from the outpatient clinic of the department of otorhinolaryngology head and neck surgery in the same period and were divided into two groups: 92 in hyposmia and 73 in functional anosmia group. The 270 subjects were divided into 3 subgroups:younger group ( <35 years of age), middle-age group (35-55 years of age) and older group ( > 55 years of age). The olfactory functions were examined with Sniffin' Sticks test and T & T test, respectively. All analyses were performed using SPSS 12.0 software. RESULTS: For the normal value of Sniffin' Sticks test, TDI score was > 30.12 for younger group, > 27.37 for middle-age group and > 20.43 for older group; the mean TDI score was 32.12 ± 3.95 for healthy group, 17.52 ± 10.37 for hyposmia and 3.56 ± 3.49 for functional anosmia group; the differences in TDI score, olfactory threshold, discrimination threshold and identification threshold between healthy group and olfactory dysfunction group with different ages had statistical significance (Younger group: FTDI = 125.136, P = 0.000; FT = 49.454, P = 0.000;FD = 89.037, P = 0.000; FI = 39.888, P = 0.000; Middle-age group: FTDI = 190.240, P = 0.000; FT = 128.374, P = 0.000;FD = 174.122, P = 0.000;FI = 178.945, P = 0.000;Older group: FTDI = 72.992, P = 0.000; FT = 26.599, P = 0.000; FD = 77.119, P = 0.000; FI = 88.107, P = 0.000, respectively) . The mean T & T value was -1.00 ± 0.98 for healthy group, 2.27 ± 2.01 for hyposmia and 5.89 ± 0.14 for functional anosmia group. T & T score between healthy group and olfactory dysfunction group with different ages had statistical significance (Fyounger = 158.144, P = 0.000; Fmiddle-age = 247.695, P = 0.000; Folder = 70.579, P = 0.000, respectively). TDI score of the Sniffin' Sticks test result was correlated with T & T value (r = -0.927, P < 0.01); T & T threshold was correlated with the olfactory threshold, discrimination threshold and identification threshold of Sniffin' Sticks test (rT = -0.846, P < 0.01, rD = -0.908 P < 0.01, rI = -0.864, P < 0.01, respectively). CONCLUSIONS: Sniffin' Sticks test and T & T olfactometry are able to differentiate normosmia from hyposmia and anosmia with high reliability and consistency in test results.Sniffin' Sticks test can assess subject's olfactory function status more thoroughly and is suitable for application in Chinese population.

[Effect of erlotinib on proliferation and differentiation of JAK2V617F-positive cells in vitro].

The aim of this study was to investigate the effect of erlotinib on proliferation and differentiation of JAK2V617F-positive cells in vitro, and to provide experimental evidence of erlotinib for potential target therapy in polycythemia vera. Colony forming assays were used to detect the effect of erlotinib on differentiation of hematopoietic progenitor cells from bone marrow of polycythemia vera patients, and MTT method was used to measure the proliferation of HEL cell line containing the JAK2V617F mutation. The results showed that erlotinib 5 µmol/L inhibited the differentiation of JAK2V617F-positive hematopoietic progenitor cells into hematopoietic colonies in vitro, while it had almost no effect on normal hematopoietic progenitor cells from the patients. Erlotinib had inhibitory effect on the proliferation of HEL cell line in a dose dependent manner. The IC(50) was 4.1 µmol/L. It is concluded that erlotinib can inhibit proliferation and differentiation of JAK2V617F-positive cells to a certain extent in vitro.

[Survey of quality of life scale for patients with congenital ear malformation].

OBJECTIVE: To explore the congenital ear malformation (CEM)-specific quality of life (QOL) and examine the effects of total ear reconstruction surgery for QOL of CEM patients. METHODS: A self-composed QOL scale was used for 129 patients with congenital external and middle ear malformation. All patients were requested to fill in the QOL scale before and 1 month after ear reconstruction surgery. RESULTS: The level of QOL varied according to the degree of ear malformation. The total QOL score of patients with unilateral and bilateral CEM was 28.5 ± 18.4 and 51.6 ± 23.6, respectively. The total QOL score of patients pre- and post-operation was 21.0 ± 14.0 and 14.2 ± 9.7 respectively. Physiological functions, psychological status and social interactions of the patients were of statistical significance after ear reconstruction surgery compared to that of at pre-operation. CONCLUSION: Congenital ear malformation-specific QOL scale can show sensitively the changes of QOL of CEM patients. And ear reconstruction surgery is beneficial for the patients.

[Development and evaluation of a quality of life scale specific to patients with congenital external and middle ear malformation].

OBJECTIVE: To develop a quality of life scale for patients with congenital external and middle ear malformation, and to explore its reliability and validity. METHODS: The initial quality of life scale for patients with congenital external and middle ear malformation was constructed based on quality of life scales from home and abroad. A total of 140 patients with congenital external and middle ear malformation had been recruited in the study. After pretest and item sifting, the quality of life scale was constructed, and its reliability and validity were evaluated. RESULTS: Eighteen-item quality of life scale for patients with congenital external and middle ear malformation was constructed, which included three parts: physiological function, psychological status and social interaction. The retest reliability was 0.878; split-half reliability coefficient and Cronbach's alpha coefficient were 0.927 and 0.899, respectively. The results of factor analysis showed satisfactory construct validity. The reliability and validity of this scale was consistent with the demands of psychometrics. CONCLUSION: Congenital external and middle ear malformation quality of life scale is believable and effective, which can be used for clinical practice.