Allogeneic hematopoietic stem cell transplantation for children with aggressive natural killer cell leukemia: one case report with a literature review / 中华器官移植杂志

Objective:To summarize the clinical features, treatments and prognoses of aggressive natural killer cell leukemia (ANKL) in children.Methods:Clinical data and follow-up results were retrospectively reviewed for one hospitalized case of ANKL in June 2019.Through a literature search, the relevant items were retrieved from the databases of China National Knowledge Infrastructure, WanFang and PubMed using the Chinese and English keywords of "aggressive natural killer cell leukemia" and "children" up to December 2021.Results:This 8-year-old girl was diagnosed with ANKL by flow cytometric immunophenotype and immunohistochemical stain.Fever was the initial manifestation accompanied by sallow complexion, fatigue, enlargement of liver, spleen and lymph node and hematopenia of three lines.Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed after chemotherapy.As of April 2022, the child stayed in a disease-free survival state after follow-ups for over 2 years.The literature search finally yielded 7 eligible Chinese and 10 English reports with a total of 17 pediatric ANKLs.In this group, there were fever (n=15), rash (n=1), perineal mass (n=1) and diarrhea, vomiting and other digestive tract symptoms (n=1). Six cases were misdiagnosed during an early stage of disease.4 cases received chemotherapy alone, 3 cases received chemotherapy regimen for acute lymphoblastic leukemia, 1 child died and one death occurred after received chemotherapy regimen of "cisplatin + vincristine + doxorubicin + ifosfamide". Allo-HSCT was performed in 5 patients after remission with chemotherapy and one child died from multiple organ failure at 9 months after allo-HSCT.Nine cases gave up treatment.Conclusions:ANKL has a rapid disease progression, diverse clinical manifestations, easy misdiagnosis and poor prognosis.For suspected ANKL cases, clinicians perform multiple bone perforations at multiple sites and immunophenotype by flow cytometry as soon as possible to confirm the diagnosis.Currently allo-HSCT offers a long-term survival of ANKL patients.

Clinical analysis of Belintoumab in the treatment of 10 children with acute B-lymphoblastic leukemia / 中华实用儿科临床杂志

Objective:To investigate the safety and efficacy of Belintoumab on the treatment of children with acute B-lymphoblastic leukemia (B-ALL).Methods:The clinical data of 10 children with CD 19+ B-ALL who were admitted to the Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University from September 2021 to May 2022 and treated with Belintoumab were analyzed retrospectively. Results:Among the 10 cases, there were 6 recurrent cases, 3 cases with persistent minimal residual disease (MRD) positive after an initial treatment, and 1 case complicated with invasive candidiasis.Before treatment, bone marrow blasts ≥0.25, and that ranged 0.05-<0.25 were detected in 2 cases and 1 case, respectively.Seven cases had a complete remission (CR) of bone marrow, 6 of which were MRD positive and 1 case was MRD negative.After treatment with Belintoumab, the CR rate was 66.7% (2/3). The overall MRD negative rate was 88.9% (8/9), and the negative rate in previously MRD positive children was 100% (6/6). The median follow-up time was 4.1 (1.6-10.0) months after the application of Belintoumab.The overall survival (OS) rate was 70.0% (7/10). Eight MRD negative children received hematopoietic stem cell transplantation, and the OS rate was 75% (6/8). Survived children did not relapse until the last follow-up visit.Fever (90%, 9/10) was the most common adverse events, followed by neutropenia (90%, 9/10). One case (10%, 1/10) of neurotoxicity was seizures (grade 2) and one case (10%, 1/10) suffered cytokine release syndrome (grade 2), which did not influence the therapeutic efficacy of Belintoumab after symptomatic treatment.Conclusions:Belintoumab is safe and effective on the treatment of children with recurrent/refractory CD 19+ B-ALL, and those with MRD positive who have achieved CR in bone marrow have a higher rate of turning negative.Belintoumab can also be used as a bridge scheme for CD 19+ B-ALL children who cannot tolerate chemotherapy.

Clinical analysis of leukemia secondary to malignant solid tumor in children / 国际儿科学杂志

Objective:To investigate the clinical characteristics, diagnosis and treatment and prognosis of children with leukemia secondary to malignant solid tumor.Methods:From January 2012 to January 2022, a total of 2 275 children under 15 years of age with malignant solid tumor were admitted to the First Affiliated Hospital of Zhengzhou University.Six children diagnosed with secondary leukemia after follow-up to August 1, 2022 were selected as the study objects.Their clinical data were retrospectively analyzed and the literature was reviewed.Results:(1)A total of 2 275 children with malignant solid tumors included 1 369 males and 906 females.There were 6 children with secondary leukemia, with an incidence rate of 0.26%, including 4 males and 2 females.The age of onset of solid tumor was 5.5(2.8, 9.7)years, and the age of secondary leukemia was(9.1±3.9)years, and the interval between them was(26.2±17.3)months.(2)Malignant solid tumor types: according to the time of secondary leukemia, there were hip malignant rhabdomyoma in 1 case, intracranial medulloblastoma in 2 cases, intracranial and pelvic malignant germinoma in 1 case respectively, and pancreatic blastoma in 1 case.Intracranial lesion biopsy was performed in 1 case, and tumor resection was performed in the other 5 cases.Three patients with intracranial tumors underwent local tumor bed, whole brain and spinal radiotherapy.All the 6 children received chemotherapy, and the main chemotherapy drugs were doxorubicin, vincristine, cyclophosphamide, platinum, ifosfamide, etoposide, bleomycin, temozolomide, etc.Complete remission was achieved in 3 cases, partial remission in 1 case, stable disease in 1 case, and disease progression in 1 case.(3)The secondary leukemia types were as follows: acute myeloid leukemia(AML)M5 in 3 cases, M1 in 1 case, M2 in 1 case, and acute B-lymphoblastic leukemia(B-ALL)in 1 case.All six cases refused hematopoietic stem cell transplantation(HSCT).One case with B-ALL gave up after receiving hydroxyurea and dexamethasone.Five cases with AML received chemotherapy according to the AML-2006 Protocol of Hematology Group of Pediatrics Society of Chinese Medical Association.The outcome of the disease was as follows: 2 cases died early, 4 cases achieved complete remission after 1 ~ 2 courses of chemotherapy, among which 2 cases did not continue treatment after 3 courses of chemotherapy due to pulmonary infection, deep mycosis, osteomyelitis, etc, and then recurred and died.By the end of follow-up, 2 cases survived and continued treatment, of which 1 case relapsed.After the diagnosis of secondary leukemia, the 1-year overall survival rate of the 6 cases was(33±26)%.Conclusion:Leukemia secondary to malignant solid tumors in children is rare and mostly occurs in older children.The pathogenesis is related to genotoxic injury caused by exposure to chemotherapy or radiotherapy, and the prognosis is unfavourable.HSCT after chemotherapy combined with immunotherapy is the best treatment strategy.

Non-muscle myosin heavy chain 9 gene-related disorders with thrombocytopenia: report of two pedigrees and literature review / 中华儿科杂志

Objective: To summarize the clinical characteristics and gene variants of 2 pedigrees of non-muscle myosin heavy chain 9 related diseases (MYH9-RD) in children. Methods: The basic information, clinical features, gene variants and laboratory tests of MYH9-RD patients from 2 pedigrees confirmed in the First Affiliated Hospital of Zhengzhou University in November 2021 and July 2022 were analyzed retrospectively. "Non-muscle myosin heavy chain 9 related disease" "MYH9" and "children" were used as key words to search at Pubmed database, CNKI and Wanfang database up to February 2023. The MYH9-RD gene variant spectrum and clinical data were analyzed and summarized. Results: Proband 1 (male, 11 years old) sought medical attention due to epistaxis, the eldest sister and second sister of proband 1 only showed excessive menstrual bleeding, the skin and mucous membrane of the their mother were prone to ecchymosis after bumping, the uncle of proband 1 had kidney damage, and the maternal grandmother and maternal great-grandmother of proband 1 had a history of cataracts. There were 7 cases of phenotypic abnormalities in this pedigree. High-throughput sequencing showed that the proband 1 MYH9 gene had c.279C>G (p.N93K) missense variant, and family verification analysis showed that the variant was inherited from the mother. A total of 4 patients including proband 1 and family members were diagnosed with MYH9-RD. The proband 2 (female, 1 year old) sought medical attention duo to fever and cough, and the father's physical examination revealed thrombocytopenia. There were 2 cases of phenotypic abnormalities in this pedigree. High-throughput sequencing showed that there was a c.4270G>A (p.D1424N) missense variant in the proband 2 MYH9 gene, and family verification analysis showed that the variant was inherited from the father. A total of 2 patients including proband 2 and his father were diagnosed with MYH9-RD. A total of 99 articles were retrieved, including 32 domestic literatures and 67 foreign literatures. The MYH9-RD cases totaled 149 pedigrees and 197 sporadic patients, including 2 pedigrees in our study. There were 101 cases with complete clinical data, including 62 sporadic cases and 39 pedigrees. There were 56 males and 45 females, with an average age of 6.9 years old. The main clinical manifestations were thrombocytopenia, skin ecchymosis, and epistaxis. Most patients didn't receive special treatment after diagnosis. Six English literatures related to MYH9-RD caused by c.279C>G mutation in MYH9 gene were retrieved. Italy reported the highest number of cases (3 cases). Twelve literatures related to MYH9-RD caused by c.4270G>A mutation in MYH9 gene were retrieved. China reported the highest number of cases (9 cases). Conclusions: The clinical manifestations of patients in the MYH9-RD pedigrees varied greatly. MYH9 gene c.279C>G and c.4270G>A mutations are the cause of MYH9-RD.

Efficacy and safety of eltrombopag combined with immunosuppressive therapy in the treatment of severe aplastic anemia：a meta-analysis / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of eltrombopag combined with immunosuppressive therapy （IST） for severe aplastic anemia （SAA）， and to provide evidence-based basis for clinical treatment of SAA. METHODS Retrieved from PubMed， Embase， Cochrane Library， ClinicalTrials.gov， VIP， CNKI and Wanfang data， randomized controlled trials （RCTs） and cohort studies about eltrombopag combined with IST （trial group） versus IST alone （control group） were collected from the inception to May 2023. After data extraction and quality evaluation （Cochrane manual 5.1.0） of included studies， meta-analysis， subgroup analysis， sensitivity analysis and publication bias analysis were performed by using RevMan 5.4 software. RESULTS A total of 12 studies were screened， including 1 344 patients. Compared with control group， objective remission rate （ORR） （RR＝1.34， 95%CI was 1.06-1.69， P＝0.01） and complete response rate （CRR） （RR＝1.88， 95%CI was 1.31-2.71， P＝ 0.000 6） at 3 months， ORR （RR＝1.33，95%CI was 1.23-1.43， P＜0.000 01） and CRR （RR＝1.88，95%CI was 1.57-2.25，P＜0.000 01） at 6 months were significantly increased in trial group. There was no statistically significant difference between the two groups in ORR （RR＝0.99， 95%CI was 0.82-1.18， P＝0.88） and CRR （RR＝1.02， 95%CI was 0.78-1.34， P＝0.87） at 12 months， two-year overall survival （OS） rate （HR＝0.61， 95%CI was 0.31-1.22， P＝0.17）， two-year event-free survival （EFS） rate （HR＝0.81， 95%CI was 0.61-1.07， P＝0.14）， clone evolution rate（RR＝1.01， 95%CI was 0.51-2.00， P＝ 0.98） or the incidence of adverse drug reactions such as liver/renal insufficiency， rash （P＞0.05）. Results of subgroup analysis showed that ORR and CRR of trial group at 6 months were higher than those of the control group in RCT and the cohort study subgroups （P＜0.05）. There was no statistically significant difference in the two-year OS rate， two-year EFS rate or clone evolution rate between trial group and control group in the two subgroups （P＞0.05）. The results of sensitivity analysis and publication bias analysis showed that the results of this study were robust and the possibility of publication bias was small. CONCLUSIONS The addition of eltrombopag in the IST regimen of SAA can improve the early hematological remission rate of patients， has no significant impact on short-term survival， and will not increase the occurrence of adverse drug reactions and clonal evolution.

Clinical analysis of 7 children with bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation / 中华实用儿科临床杂志

Objective:To investigate the clinical characteristics and treatment of bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HSCT) in children.Methods:Clinical data of 7 patients with BOS after HSCT in the Department of Hematology and Oncology, Children′s Hospital, the First Affiliated Hospital of Zhengzhou University from September 2015 to June 2019, who had a survival of longer than 100 days were retrospectively analyzed.Results:At the last follow-up visit, the incidence of BOS was 4.6%(7/152 cases), including 5 males and 2 females.The median time from HSCT to the diagnosis of BOS was 15 (9-27) months.Among the 7 cases, 5 cases had dry cough and shortness of breath after activity, and 2 cases had no obvious clinical symptoms.Pulmonary function was moderate in 5 cases and severe in 2 cases of obstructive ventilatory disorder.High-resolution CT showed mosaic sign in 5 cases and bronchial wall thickening in 4 cases.Bronchoalveolar lavage (BAL) was performed in 4 cases, and flocculent secretion was found in the bronchus.Membranous substance was formed in the bronchus in 3 cases, and some lumens were completely occluded and dredged by foreign body forceps.After treatment with Fluticasone, Azithromycin and Montelukast sodium (FAM regimen), the pulmonary function of 5 cases(71.4%) was significantly improved, but ineffective in 2 cases.Conclusions:BOS after HSCT in children mainly begins with dry cough and shortness of breath after activity.Regular screening of pulmonary function is beneficial to identify asymptomatic children.BAL can clear inflammatory cytokines, which is conductive to the following drug treatment.If necessary, foreign forceps should be used to dredge the occluded bronchus to relieve symptoms quickly.FAM regimen is an effective treatment method, and timely adjustment of treatment according to the disease situation can improve the prognosis.

Clinical study of Voriconazole suspension formula for prevention and treatment of invasive fungal infection during allogeneic hematopoietic stem cell transplantation in children / 中华实用儿科临床杂志

Objective:To investigate the clinical efficacy, safety and compliance of Voriconazole suspension formula on the prevention and treatment of invasive fungal infection (IFI) in children with allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Clinical data of 25 children treated Voriconazole suspension formula for the prevention and treatment of IFI during the period of allo-HSCT in the Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University from August 1, 2020 to April 30, 2021 were retrospectively analyzed.The plasma trough concentration of Voriconazole was detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and the genotype of CYP2C19 was detected by polymerase chain reaction-restriction fragment length polymorphism (RFLP). The effect of CYP2C19 genotype on Voriconazole trough concentration was analyzed by rank-sum test, and Fisher′ s accurate test was used to analyze the influence of severity of gastrointestinal mucositis on serum trough concentration of Voriconazole in children with allo-HSCT. Results:A total of 25 children, including 18 males and 7 females were recruited.The median age at allo-HSCT was 6 (2-13) years.After initial administration of conventional dose of Voriconazole suspension formula during transplantation, plasma trough concentration of Voriconazole was intermittently monitored.Only 13 cases (52.0%) reached the target plasma trough concentration, 11 cases(44.0%) reached the target plasma trough concentration after adjusting the dose according to the plasma concentration, and 1 cases(4.0%) failed to reach it after increasing the dose twice.Genotype detection of CYP2C19 was performed in 20 children, involving 4 cases of poor metabolizers (PM), 9 cases of intermediate metabolizers (IM), 6 cases of extensive metabolizers (EM), and 1 case of ultra extensive metabolizer (UEM). A significant difference in plasma trough concentration was detected among all groups ( F=24.012, P<0.01). During the transplantation, 12 cases developed mild to moderate gastrointestinal mucositis, and 7 cases had severe gastrointestinal mucositis.The stan-dard rate of plasma trough concentration in children with severe gastrointestinal mucositis (1/7 cases, 14.3%)was significantly lower than those with mild to moderate gastrointestinal mucositis (9/12 cases, 75.0%) ( P=0.02). Five children (71.4%) with severe gastrointestinal mucositis could reach the target trough concentration after increasing the drug dose, suggesting that severe gastrointestinal mucositis had a great influence on the plasma concentration of Vorico-nazole suspension.The incidence of IFI in 25 children with allo-HSCT was 0, and the compliance of children taking Voriconazole dry suspension was 100.0%.The incidence of adverse reactions was 24.0% and all adverse reactions were relieved after symptomatic treatment. Conclusions:The plasma concentration of Voriconazole varies greatly among children and in different states of the same patient.Therefore, it is necessary to monitor the trough concentration of the drug and adjust the drug dose.The use of Voriconazole suspension formula for the prevention and treatment of fungal infection during allo-HSCT in children is clinically safe and effective, with a good compliance in children.

Case report of unrelated cord blood transplantation for the treatment of recurrent refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with intestinal perforation and literature review / 中华实用儿科临床杂志

Objective:To examine the clinical experience and efficacy of unrelated cord blood transplantation (UCBT) in the treatment of recurrent refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children.Methods:The clinical data of a patient with recurrent refractory EBV-HLH and intestinal perforation who was treated by UCBT in Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University in September 2015 and finally cured were retrospectively analyzed.Meanwhile, literature was reviewed.Results:The patient, male, 1 year and 6 months, was admitted to the hospital with " fever for 15 days, rash for 9 days" as the main complaint, mainly manifested as high fever, large liver, spleen, lymph nodes, rapidly progressing pancytopenia, liver function damage, phagocytic blood cells on bone marrow smear, diagnosed as EBV-HLH in September 2015.The patient received chemotherapy according to the HLH-2004 protocol developed by the International Association of Cell Societies.During the treatment, he suffered two recurrence during the maintenance period, and a second-line rescue treatment was adopted, namely, " Pegaspargase, Doxorubicin liposome, Etoposide and Methylprednisolone" (L-DEP regimen) chemotherapy.The complete relief of diagnostic indexes for hemophagocytic lymphohistiocytosis was evaluated after chemotherapy.The patient developed sudden intestinal perforation and underwent emergency surgical surgery, enteroenterostomy.After the condition was stabilized, the patient was pretreated with the " Fludarabine+ Busulfan+ Cyclophosphamide" (Flu+ BU+ CY) therapy and then treated with UCBT, with intravenous nutritional support provided during the entire process.Neutrophil and platelet implantation was implemented on day 13 and day 35 after transplantation, respectively.The chimeric rate was 100%, and the implantation was a success.Hepatic veno-occlusive disease, fungal pneumonia and skin graft-versus-host disease (GVHD) Ⅱ occurred on the 15 th day, 22 nd day and 26 th day after transplantation, respectively.The corresponding symptoms improved after treatment.On day 49 after transplantation, phase Ⅱ " enterostomy fistula" was performed.The patient was followed up to 70 months after transplantation, and generally in good condition.His symptoms relieved, and no chronic GVHD and other comorbidities occurred. Conclusions:Allogeneic hematopoietic stem cell transplantation is the only possible effective means of treating relapsed refractory EBV-HLH in children.In the absence of a suitable sibling or unrelated donor, unrelated cord blood stem cells can be used as a graft source.Enterostomy after intestinal perforation is not contraindicated for transplantation.

The value of regenerating islet-derived protein 3-alpha, soluble tumor suppressor factor 2 and tumor necrosis factor receptor 1 in the diagnosis and treatment of intestinal acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in children / 中华实用儿科临床杂志

Objective:To investigate the clinical value of the expression levels of biological protein markers regenerating islet-derived protein 3-alpha(REG3α), soluble tumor suppressor factor 2(sST2) and tumor necrosis factor receptor 1(TNFR1) in peripheral blood in the diagnosis and efficacy evaluation of intestinal acute graft-versus-host disease (aGVHD) in children after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Retrospective analysis of 50 children who underwent allo-HSCT, in the Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University from January 2020 to February 2021 were enrolled, including 39 males and 11 females [median age: 8.5 (1-13) years]. The expression levels of above 3 biological proteins were detected before transplantation, 1 week, 2 weeks, 3 weeks, 5 weeks, 7 weeks, 9 weeks, 11 weeks and 13 weeks after transplantation, when intestinal aGVHD occured, and after treatment.Children with intestinal aGVHD were taken as the observation group, and children without intestinal aGVHD were taken as the control group.Whether differences in the expression levels of the 3 biological proteins in the peripheral blood of the 2 groups of children were statistically significant was analyzed.The receiver operating characteristic(ROC) curve was used to evaluate the diagnostic value of the above three biological proteins for intestinal aGVHD, and independent sample t test was performed to compare the expression levels of the 3 biological proteins before and after treatment in children with intestinal aGVHD. Results:(1) The concentrations of REG3α, sST2, and TNFR1 in the peripheral blood of the observation group were (33 985.42±24 631.33) ng/L, (139 899.66±115 825.65) ng/L, (3 041.65±2 418.72) ng/L, respectively, which were higher than the control group of (7 457.39±4 547.49) ng/L, (32 059.57±23 452.85) ng/L, (1 944.51±1 170.35) ng/L, the difference was statistically significant ( t=6.04, 5.19, 2.17, all P<0.05). (2) The area under ROC curve (AUC) of REG3α combined with sST2 in the diagnosis of intestinal aGVHD was 0.952 (95% CI: 0.851-0.992, P<0.001), the maximum Youden index was 0.894, the corresponding sensitivity was 83%, and the specificity was 99%.Its diagnostic value was better than REG3α, sST2 and TNFR1 ( Z=1.763, 1.332, 3.001, all P<0.05). (3) The concentrations of REG3α, sST2, and TNFR1 before treatment in the peripheral blood of children having received effective treatment were (31 343.01±25 364.71) ng/L, (146 629.52±110 501.04) ng/L and (2 489.00±859.70) ng/L, respectively, which were (12 104.37±11 704.60) ng/L, (93 539.55±81 920.93) ng/L and (2 048.15±813.47) ng/L after treatment, lower than those before treatment.The expression levels of REG3α and sST2 were significantly reduced ( t=-3.23, -2.10, all P<0.05), while the difference of the expression level of TNFR1 before and after treatment was not statistically significant ( P>0.05). Conclusions:REG3α and sST2 can be used as important reference indicators for clinical auxiliary diagnosis of intestinal aGVHD, and have good auxiliary diagnostic value.REG3α and sST2 can be used as objective indicators to evaluate the efficacy of clinical treatment of intestinal aGVHD.

Clinical efficacy of Ruxolitinib in combination with Methylprednisolone as a bridge to allogeneic hematopoietic stem cell transplantation for relapse/refractory Epstein-Barr virus-associated hemophagocytic syndrome in pediatric patients / 中华实用儿科临床杂志

Objective:To explore the clinical efficacy and safety of Ruxolitinib, a Janus kinase inhibitor, in combination with Methylprednisolone as a bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for relapsed/refractory Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) in pediatric patients.Methods:The clinical data of 4 patients with relapsed/refractory EBV-AHS treated with Ruxolitinib in combination with Methylprednisolone as a bridge to allo-HSCT at the Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University from August 2018 to February 2020 were retrospectively analyzed, and the disease characteristics, diagnosis and treatment process, clinical experience and related research progress were analyzed and summarized.Results:Among 4 patients with relapsed/refractory EBV-AHS, 2 patients were treated with low-dose Ruxolitinb in combination with Methylprednisolone for 6-10 weeks after partial remission.The disease did not progress, and they survived after being bridged to allo-HSCT.One patient was treated with large-dose Ruxolitinib in combination with Methylprednisolone due to the intolerance to chemotherapy, with the biochemical indicators of hemophagocytic syndrome significantly improved, and then the bridging to allo-HSCT was performed 2 months ago and this patient survived.One patient with EBV-AHS relapsed was relieved by chemotherapy again, then was given maintenance therapy with Ruxolitinib and Methylprednisolone, but the condition still progressed and the treatment was ineffective.This patient underwent allo-HSCT for salvage treatment more than 1 year ago and survived.Except that 1 patient developed mild anemia, the other 3 patients had no significant Ruxolitinib-related toxicities.Conclusions:Ruxolitinib in combination with Methylprednisolone can be safely employed as a salvage treatment for pediatric patients with relapsed/refractory EBV-AHS and a bridge to allo-HSCT, which has favorable safety, efficacy and tolerance in clinical practice.

The expressions and clinical significance of programmed death 1/programmed death ligand 1 in children with acute lymphoblastic leukemia / 中华实用儿科临床杂志

Objective:To investigate the mechanism of programmed death 1(PD-1)/ programmed death ligand 1(PD-L1) signaling pathway and its feasibility as a potential therapeutic target and prognostic predictor by detecting the expressions, of PD-1 and PD-L1 in bone marrow mononuclear cells of children with acute lymphoblastic leukemia (ALL), and to provide new ideas for the diagnosis and treatment of ALL as well.Methods:Bone marrow samples were collected from 59 children with ALL in the First Affiliated Hospital of Zhengzhou University from September 2018 to July 2019.Flow cytometry was applied to detect the expression of PD-1 and PD-L1 in bone marrow mononuclear cells in 59 ALL patients, including 47 newly-diagnosed ALL patients and 12 relapsed ALL patients, respectively, at initial diagnosis, after induction therapy and early intensive treatment.Their relevant clinical data were collected and compared with the bone marrow specimens of 12 children suffering from non-malignant blood diseases as the control group of the same hospital during the same period.Results:There was no significant difference in the expression of PD-1 in the bone marrow mononuclear cells of the primary diagnosis group, recurrence group and control group ( H=2.402, P>0.05). The expression of PD-L1 in the relapsed and refractory group [(7.32±3.60)%] and the newly diagnosed group [(3.18±2.37)%] was higher than that in the control group [(0.84±0.39)%], and the differences were statistically significant ( H= 28.048, P<0.05). In the initial treatment group, the expression of PD-L1 in the bone marrow mononuclear cells was the strongest expression before treatment ( B=1.293), followed by after induction treatment ( B=0.036) and after early intensive treatment ( B=0.000), suggesting that there was a downward trend as the continued treatment.The expression of PD-L1 was the weakest expression in the low-risk group ( B=-3.912) than in the medium-risk group ( B=-3.595) and high-risk group ( B=0.000), revealing that the expression of PD-L1 is related to the risk grades of ALL.The higher the risk rating is, the higher the PD-L1 protein expression is. Conclusions:The high expression of PD-L1 may be involved in the pathogenesis and be used as an adverse predictor of ALL childhood and an evaluation index of chemotherapy efficacy.PD-1 / PD-L1 signaling pathway may be a potential therapeutic target of ALL childhood.

Inhibition Effect of Eriodictyol to Growth of DG-75 Cells and the Related Action Mechanism / 中国实验血液学杂志

OBJECTIVE@#To explore the effects of Eriodictyol to the growth, apoptosis and oxidative stress of Burkitt lymphoma (BL) cells and phosphorylation of protein kinase B (AKT) in children.@*METHODS@#The effects of Eriodictyol (0, 1.25, 2.5, 5, 10, 20, 40, 80, 160, 320 μmol/L) to viability of BL cell line DG-75 cells were detected by CCK-8. The effects of Eriodictyol (0, 10, 20, 40 μmol/L) to the proliferation activity of DG-75, apoptosis rate, levels of apoptosis-related proteins, oxidative stress indexes ［superoxide dismutase (SOD), malondialdehyde (MDA)］, mitochondrial membrane potential (MMP) and phosphorylation level of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycinm (mTOR) were detected by clony formation assay and Wester blot.@*RESULTS@#When the treatment concentration of Eriodictyol was 20 μmol/L, the proliferation activity of the cells was decreased (P<0.05). The concentrations at 10, 20, 40 μmol/L were selected for subsequent experiments. Compared with 0 μmol/L Eriodictyol, the proliferation activity of DG-75, SOD activity, MMP, phosphorylation levels of PI3K, AKT and mTOR in 20 and 40 μmol/L Eriodictyol treatment groups were significantly decreased (P<0.05), while cells apoptosis rate, Cleaved-Caspase-3/Caspase-3, Bax/Bcl-2 and MDA level were significantly increased (P<0.05).@*CONCLUSION@#Eriodictyol may promote the mitochondrial apoptosis pathway by inhibiting the abnormal activation of PI3K/AKT/mTOR to reduce the proliferation activity of DG-75, and inhibit oxidative stress response to increase the apoptosis rate and play anti-tumor roles.

Clinical observation of haploid hematopoietic stem cell transplantation and intensive immunosuppressive therapy for the treatment of severe aplastic anemia in pediatric patients / 中华实用儿科临床杂志

Objective:To compare the efficacy of haploid hematopoietic stem cell transplantation (haplo-HSCT) and intensive immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA).Methods:The medical records of children newly diagnosed as SAA in the First Affiliated Hospital of Zhengzhou University from January 2013 to June 2018 were retrospectively analyzed.Among them, 33 patients received haplo-HSCT and 24 patients received IST that combined anti-thymocyte globulin(ATG) with Cyclosporine (CsA). The effective rate, overall survival (OS) rate, and failure free survival(FFS) rate of children in the haplo-HSCT group and the IST group were compared.Results:The median follow-up period was 25 months (9-60 months). There were 5 cases of early death in the haplo-HSCT group and 4 cases in the IST group, and the differences were not statistically significant ( P=0.822). Leaving out the early death cases, the effective rate in the haplo-HSCT group [100%(28/28 cases)] was higher than that in the IST group [30%(6/20 cases)] after 3 months of treatment, the difference was statistically significant ( χ2=27.671, P<0.01). After 6 months of treatment, the effective rate in the haplo-HSCT group [92.9%(26/28 cases)] was higher than that in the IST group [65.0%(13/20 cases)], and the difference was statistically significant ( χ2=5.943, P=0.015). After 12 months of treatment, the effective rate in the haplo-HSCT group [89.3%(25/28 cases)] was higher than that in the IST group [70.0%(14/20 cases)], but the difference was not statistically significant( P>0.05). The 3-year expected OS rate of children in the haplo-HSCT group and the IST group were 75.0% and 70.3%, respectively, with no statistically significant difference ( χ2=0.133, P=0.716). The 3-year expected FFS rate of children in the haplo-HSCT group (74.2%) was significantly higher than that in the IST group (48.7%), and the difference was statistically significant ( χ2=4.036, P=0.045). Conclusion:For children with SAA, haplo-HSCT is also an effective treatment if there is no sibling donor of hematopoietic stem cell transplantation.

AnaIysis of chemotherapy drug-induced Iiver injury in chiIdren with acute IymphobIastic Ieukemia based on RUCAM scaIe / 中华实用儿科临床杂志

Objective To analezk thk charactkristics of drug-induckd livkr injure( DIFI)in childrkn with acutk lemphoblastic lkuckmia(LFF),so as to improvk thk phesician＇s undkrstanding of chkmothkrape DIFI,and to guidk clinical rational drug usk. Methods Onk hundrkd and forte-thrkk casks with LFF diagnoskd in thk Dkpartmknt of Hk-matologe and Oncologe in thk Pirst Lffiliatkd Hospital of Yhkngzhou Rnivkrsite from Januare 2012 to Dkckmbkr 2016 wkrk analezkd rktrospkctivkle. Baskd on DIFI diagnostic critkria and thk ARCLM scalk,thk casks with a scork of ≥3 points wkrk considkrkd to havk chkmothkrape DIFI. Groupkd be gkndkr,agk,immunoteping,risc and stagk of chkmo-thkrape,thk incidknck of DIFI was comparkd. Thk situation aftkr DIFI prkvkntion was comparkd bktwkkn two groups which was groupkd according to whkthkr thk application of hkpatoprotkctivk drugs. ResuIts Onk hundrkd and kight ca-sks(75. 52﹪)had DIFI,66 casks(61. 11﹪)showkd clinical manifkstations of livkr injure,and 42 casks(38. 89﹪) had no clinical semptoms. Lmong all thk casks 57. 41﹪(62 casks)wkrk mild livkr damagk,25﹪(27 casks)wkrk modkratk livkr injure and 17. 59﹪(19 casks)wkrk skvkrk livkr damagk. Thk clinical tepks which wkrk hkpatockllular accounting for 79. 63﹪(86 casks),cholkstatic 7. 41﹪(8 casks)and mixkd 12. 96﹪(14 casks). Malk wkrk 80 casks (79. 21﹪)and fkmalk 28 casks(66. 67﹪),but thk incidknck of DIFI bktwkkn diffkrknt gkndkr group had no statistical diffkrknck(χ2 ﹦2. 524,P﹦0. 112). Skvknte-fivk casks(77. 32﹪)wkrk ＜7 ekars agk and 33 casks(71. 74﹪)≥7 ekars agk,and thk incidknck of DIFI bktwkkn 2 groups was not statisticalle diffkrknt(χ2 ﹦0. 526,P﹦0. 468). Thkrk was no significant diffkrknck in T-LFF(8 casks,61. 54﹪)and B-LFF(100 casks,76. 92﹪)( χ2 ﹦0. 795,P﹦0. 372). Thk incidknck had significant diffkrknck in diffkrknt risc(P﹦0. 002). Thk incidknck of DIFI bktwkkn thk middlk risc group(60 casks,88. 24﹪)and standard risc(21 casks,58. 33﹪)had statistical diffkrknck( P ＜0. 05 ). Thk incidknck of DIFI bktwkkn thk middlk risc group and skvkrk risc(27 casks,69. 23﹪)had statistical diffkrknck( P﹦0. 015). Thk incidknck was diffkrknt in diffkrknt stagks of chkmothkrape(P＜0. 05). Thk incidknck of DIFI in induckd stagk was diffkrknt comparkd to othkr stagks(P＜0. 05). ARCLM scork ＞8 points accountkd for 21 casks(19. 45﹪), 6-8 points accountkd for 59 casks(54. 63﹪)and 3 -5 points accountkd for 28 casks(25. 92﹪). Eighte -nink patiknts(92. 71﹪)wkrk kffkctivk in thk hkpatoprotkctivk group and 8 patiknts(66. 67﹪)in thk no hkpatoprotkctivk thkrape group. Thk diffkrknck bktwkkn thk 2 groups was statisticalle significant(χ2 ﹦5. 317,P﹦0. 021). ConcIusions Thk clinical semptoms of drug-induckd livkr injure in childrkn with LFF chkmothkrape ark lacc of spkcificite. Thke ark mainle charactkrizkd be mild livkr injure. Thk clinical tepk of hkpatic injure is common in hkpatockllular. Thk ARCLM scork was mostle 6 to 8. Thkrk is no rklationship bktwkkn thk incidknck in LFF and gkndkr,agk,tepk of lkuck-mia. Thk incidknck with modkratk risc tepk is highkr than that of thk standard and high-risc tepk. Thk incidknck in induction rkmission stagk is highkst. Lpplication of hkpatoprotkctivk drugs is bknkficial to DIFI prognosis.

Genetic haploidentical peripheral blood stem cell transplantation for treatment of myelodysplastic syndrome:a 2-year follow-up visit of 21 cases / 中国组织工程研究

BACKGROUND: In recent years, genetic haploidentical peripheral blood stem cell transplantation has been gradually improved, and haploid allogeneic hematopoietic stem cell transplantation has become an important treatment choice for malignant hematopoietic disease. OBJECTIVE: To observe the clinical efficacy of genetic haploidentical peripheral blood stem cell transplantation for myelodysplastic syndrome. METHODS: The clinical data of 21 myelodysplastic syndrome cases undergoing genetic haploidentical peripheral blood stem cell transplantation were retrospectively analyzed. Modified BU/CY+ATG administration was performed as a pretreatment strategy for haploidentical peripheral blood stem cell transplantation, and the combined use of cyclosporine A+mycophenolate mofetil+short-range methotrexate±basiliximab was adopted to prevent graft-versus-host disease (GVHD). RESULTS AND CONCLUSION: (1) The 21 cases were followed for an median of 333 days (22-1 222 days), with 76% (16/21) infection of granulocyte lack period, 100% (21/21) neutrophil reconstruction, the median implantation time of 12 days (7-17 days), 81% (17/21) platelet engraftment, and the median implantation time of 14 days (7-68 days). (2) The accumulative incidence of GVHD was 52.4% (11/21), including 29% (6/21) of acute GVHD and 24% (5/21) of chronic GVHD. The incidence of hemorrhagic cystitis was 38.1% (8/21). The recurrence rate after transplantation was 4.8% (1/21). (3) The 2-year non-relapse mortality was 48% (10/21), and the 2-year disease-free survival rate was 46.8%. These results show that in the absence of HLA-identical related donors and unrelated donor, genetic haploidentical peripheral blood stem cell transplantation is a safe, effective, feasible and alternative treatment option for myelodysplastic syndrome.

Progress of Shwachman-Diamond syndrome / 中华实用儿科临床杂志

Shwachman - Diamond syndrome (SDS)is a rare autosomal recessive disorder,SDS is characte-rized by exocrine pancreatic dysfunction,bone marrow failure,skeletal abnormalities and various other organ dysfunc-tions,and predisposition to MDS and acute myelogenous ceukemia. The Shwachman - Bodian - Diamond syndrome (SBDS)gene located on chromosome 7q11,the common mutation type is 183_184 TA > CT and 258 + 2 T > C. The purpose of this document is to comprehensive analysis the relevant literatures,analyze its clinical characteristics,geno-type,diagnosis and treatment suggestions to improve the clinician knowledge of the disease.

Expression of plasma miRNA-497 in children with sepsis-induced myocardial injury and its clinical significance / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the expression of plasma miRNA-497 in children with sepsis-induced myocardial injury and its clinical significance.</p><p><b>METHODS</b>A total of 148 children with sepsis were enrolled. According to the presence or absence of myocardial injury, these children were divided into myocardial injury group (n=58) and non-myocardial injury group (n=90). The two groups were compared in terms of the changes in plasma levels of miRNA-497, cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), N-terminal pro-brain natriuretic peptide (NT-proBNP), procalcitonin (PCT), and C-reactive protein (CRP) and left ventricular ejection fraction (LVEF). The receiver operating characteristic (ROC) curve was plotted to evaluate the value of plasma miRNA-497, cTnI, and CK-MB in the diagnosis of myocardial injury. A Pearson correlation analysis was used to determine the correlation of miRNA-497 with cTnI, CK-MB, NT-proBNP, PCT, CRP, and LVEF.</p><p><b>RESULTS</b>Compared with the non-myocardial injury group, the myocardial injury group had significantly higher plasma levels of miRNA-497, cTnI, CK-MB, NT-proBNP, PCT, and CRP (P<0.05). Plasma miRNA-497, cTnI, and CK-MB when measured alone or in combination had an area under the ROC curve of 0.918, 0.931, 0.775, and 0.940 respectively. At the optimal cut-off value of 2.05, miRNA-497 had a sensitivity of 90.4% and a specificity of 91.2%. The correlation analysis showed that there was a good correlation between plasma miRNA-497 and cTnI in children with myocardial injury (r=0.728, P<0.01).</p><p><b>CONCLUSIONS</b>Plasma miRNA-497 has a similar value as cTnI in the diagnosis of sepsis-induced myocardial injury in children and may be used as a potential marker for early diagnosis of myocardial injury.</p>

Zinc oxide nanoparticles inhibits Ca2+-ATPase1 expression induced by UVB irradiation in human lens epithelial cells / 眼科新进展

Objective To investigate the effect of ZnO nanoparticles on the expressions of plasma membrane calcium ATPasel (PMCA1) of human lens epithelial cell B-3 (HLEB-3) at both mRNA and protein levels in the presence and absence of ultraviolet B (UVB) irradiation.Methods HLEB-3 was cultured in RPMI 1640 medium,and the cytotoxic effect of different concentrations of ZnO (0 μg · mL-1,2.5 μg · mL-1,5.0μg · mL-1,10.0 μg · mL-1) on HLEB-3 was investigated in the presence and absence of UVB irradiation.DAPI staining was used to monitor the effect of ZnO on HLECB-3 nuclei,and cell apoptosis was evaluated using annexin V-FITC/PI staining in the presence and absence of UVB irradiation.In addition,the intracellular calcium ion (Ca2 +)levels were assayed using Fluo-3/AM staining,and the expression levels of both PMCA1 mRNA and protein within HLEB-3 were detected by real-time PCR and Western blot,respectively.Results DAPI staining showed that the ZnO-treated HLEB-3 displayed a concentration-dependent apoptosis,and UVB irradiation could further aggravate the cytotoxic effect of ZnO on HLEB-3.In addition,in the presence of UVB irradiation,concentration gradient of ZnO (2.5 μg · mL-1,5.0 μg · mL-1,10.0 μg · mL-1) increased the intracellular calcium ion levels [from (156.34 ±4.59) nmol · L-1 to (173.88 ±7.17)umol · L-1,(289.02 ± 9.09) nmol · L-1,(488.36 ± 48.16) nmol · L 1,respectively] and upregulated HLEB-3 apoptosis,with statistical difference (all P ＜ 0.05).Moreover,the expression level of PMCA1 in the 2.5 μg · mL-1,5.0 μg · mL-1,10.0 μg · mL-1 ZnO-treated epithelial cells was accordingly 0.75,0.57 and 0.41 as much as that in the 0μg · mL-1 ZnO-treated cells in the absence of UVB irradiation (all P ＜ 0.05),and was accordingly 0.64,0.24 and 0.09 in the present of UVB irradiation,with significant difference (all P ＜ 0.05).Conclusion Both ZnO nanoparticle and UVB irradiation can exert cosuppression effect on HLEB-3 via calcium-mediated signaling pathway,indicating it has great potential for the treatment of posterior capsular opacification with UVB irradiation.

Surveillance of schistosomiasis transmission risk in Jingmen City,Hubei Province / 中国血吸虫病防治杂志

Objective To investigate the risk factors of schistosomiasis transmission in Jingmen City. Methods The Onco-melania hupensis snails,the wild animal feces,and infection source were selected as the monitoring objects to carry out the schistosomiasis risk monitoring. I-III levels of risk environments were treated with appropriate measures. Results A total of 52 environments and three water systems were monitored and 1542 snails were dissected but no Schistosoma infected snails were found. Nine fecal samples were collected from the areas with snails,and no eggs of Schistosoma were found. Eighty-nine samples of cattle/sheep faces,and mice and dogs were collected,and three samples of cattle feces were found with Schistosoma eggs. Five environments were assessed as Grade II,and 48 environments were assessed as Grade III,and 2 environments were as-sessed as no risk of schistosomiasis transmission. Conclusions In Jingmen City,the mollusciciding work from May to June could decrease the density of snails and the risk of schistosomiasis transmission efficiently. The schistosome-infected cattle were the main infection source,and therefore,the cattle and snails should be administrated simultaneously.

Eosinophilic cystitis in children:a report of 7 cases and literature review / 临床儿科杂志

Objective To explore the clinical and pathological features, diagnosis and treatment of eosinophilic cystitis in children. Method The clinical data of 7 patients with eosinophilic cystitis admitted from 2012 to 2016 were retrospectively analyzed, and the related literature were reviewed. Results The median age of the 7 patients was 9 years, and clinical manifestations were urgent urination, frequent micturition, odynuria, hematuria, abdominal pain and nocturnal enuresis. Ultrasonography and CT examination showed thickened bladder wall and space occupying lesions.All the 7 children received bladder biopsy, and pathology was consistent with eosinophilic cystitis. Six of them were cured after 2 months of drug therapy, and the other one was cured by repeated drug treatment for 1 year.All patients were followed up for 3 months to 4 years until the abnormal symptoms of voiding disappeared and the abnormal changes of bladder disappeared by imaging examination. Conclusion Eosinophilic cystitis in children is a benign lesion, having extremely similar clinical manifestations to bladder tumor. Without biopsy, the diagnosis of eosinophilic cystitis can also be made according to the clinical manifestation, laboratory examination and treatment effect. The treatment for this disease mainly includes hormone, antihistamine and anti-inflammatory drugs.