Diagnosis status and genetic characteristics analysis of Fanconi anemia in China / 中华儿科杂志

Objective: To analyze the clinical and molecular diagnostic status of Fanconi anemia (FA) in China. Methods: The General situation, clinical manifestations and chromosome breakage test and genetic test results of 107 pediatric FA cases registered in the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) and the Chinese Children Blood and Marrow Transplantation Registry Group (CCBMTRG) from August 2009 to January 2022 were analyzed retrospectively. Children with FANCA gene variants were divided into mild and severe groups based on the type of variant, and Wilcoxon-test was used to compare the phenotypic differences between groups. Results: Of the 176 registered FA patients, 69 (39.2%) cases were excluded due to lack of definitive genetic diagnosis results, and the remaining 107 children from 15 hospitals were included in the study, including 70 males and 37 females. The age at transplantation treatment were 6 (4, 9) years. The enrolled children were involved in 10 pathogenic genes, including 89 cases of FANCA gene, 7 cases of FANCG gene, 3 cases of FANCB gene, 2 cases of FANCE gene and 1 case each of FANCC, FANCD1, FANCD2, FANCF, FANCJ, and FANCN gene. Compound heterozygous or homozygous of loss-of-function variants account for 69.2% (72/104). Loss-of-function variants account for 79.2% (141/178) in FANCA gene variants, and 20.8% (37/178) were large exon deletions. Fifty-five children (51.4%) had chromosome breakage test records, with a positive rate of 81.8% (45/55). There were 172 congenital malformations in 80 children.Café-au-Lait spots (16.3%, 28/172), thumb deformities (16.3%,28/172), polydactyly (13.9%, 24/172), and short stature (12.2%, 21/172) were the most common congenital malformations in Chinese children with FA. No significant difference was found in the number of congenital malformations between children with severe (50 cases) and mild FANCA variants (26 cases) (Z=-1.33, P=0.185). Conclusions: FANCA gene is the main pathogenic gene in children with FA, where the detection of its exon deletion should be strengthened clinically. There were no phenotypic differences among children with different types of FANCA variants. Chromosome break test is helpful to determine the pathogenicity of variants, but its accuracy needs to be improved.

Nosocomial septicemia in the early stage after stem cell transplantation in children with major β-thalassemia / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the clinical characteristics of nosocomial septicemia in the early stage after hematopoietic stem cell transplantation (HSCT) in children with major β-thalassemia.</p><p><b>METHODS</b>The clinical data were retrospectively analyzed of 55 consecutive children with major β-thalassemia who developed septicemia early after HSCT between January, 2011 and June, 2016.</p><p><b>RESULTS</b>Among the total of 416 consecutive children with major β-thalassemia undergoing allogeneic HSCT, the incidence of nosocomial infection early after transplantation was 77.16% (321/416), and 55 (17.13%) children showed positive findings in blood culture test. The infections occurred most commonly in the oral cavity (65.5%), followed by the respiratory tract, intestinal tract and skin. Gram-negative bacteria, including Escherichia coli (27.3%), Klebsiella pneumoniae (21.8%) and Pseudomonas aeruginosa (9.1%), were the most common causes of infections. Fungal (Candida tropicalis) infection caused septicemia in 1 case. Of all the pathogens, extended-spectrum β-lactamase (ESBL)-producing bacteria were found in 6 cases, methicillin-resistant Staphylococcus aureus (MRSA) in 2 cases, and multidrug-resistant (MDR) bacteria in 2 cases.</p><p><b>CONCLUSION</b>Gram-negative bacteria are the major pathogens causing septicemia in children early after HSCT for major β-thalassemia, and the bacteria show a high level of drug resistance. Adequate preventive use of antibiotics and care of the oral cavity, the respiratory tract, and the perianal region following the transplantation are important measures to control nosoconial infection in these children.</p>

Outcome of childhood high-risk acute lymphoblastic leukemia treated with the ALL-BFM 95 protocol / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To evaluate the effectiveness and the practicability of the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster 95 (ALL-BFM 95) protocol in treating childhood high-risk acute lymphoblastic leukemia (HR-ALL).</p><p><b>METHODS</b>A retrospective analysis of 47 children with newly diagnosed HR-ALL between July 2003 and August 2013 was performed. These children were treated by the ALL-BFM 95 protocol. Survival was evaluated by Kaplan Meier analysis and Log-Rank test.</p><p><b>RESULTS</b>Relapse-related death occurred in 12 of 47 patients (26%), and 5 of 47 patients (11%) were treatment-related mortality. Five-year probability of event-free-survival (pEFS) was 62%. Children with hematopoietic stem cell transplantation (HSCT) after chemotherapy achieved significantly better pEFS than those with chemotherapy alone (77% vs 52%; P=0.035). The patients who were only poor responders to prednisone had a better outcome (5-year pEFS 80%) than the Days 15 and 33 bone marrow M3 subgroups (5-year pEFS 60% and 0 respectively).</p><p><b>CONCLUSIONS</b>ALL-BFM 95 protocol can improve the outcome of children with high-risk ALL. The major cause of death is attributed to relapse. Chemotherapy plus HSCT can produce a better outcome than chemotherapy alone. The Days 15 and 33 bone marrow M3 subgroups have a poor prognosis.</p>

Analysis of the risk factors for hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation for beta-thalassemia in children / 南方医科大学学报

<p><b>OBJECTIVE</b>To analyze the risk factors of hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation for beta-thalassemia in children.</p><p><b>METHODS</b>The clinical records of 30 children with beta-thalassemia undergoing allogeneic hematopoietic stem cell transplantation between December, 2008 and November, 2009 were analyzed.</p><p><b>RESULTS</b>Hemorrhagic cystitis occurred in 8 of the 33 patients with an incidence of 24.24%, including 1 with grade I, 6 with grade II and 1 with grade III hemorrhagic cystitis. The median time of hemorrhagic cystitis onset was 22.9 days (range 6-35 days) and the median duration was 11.9 days(range 3-27 days). Univariate analysis indicated that the different types of transplantation and acute graft-versus-host disease affect the occurrence of hemorrhagic cystitis. The children with Allo-PBSCT had higher incidence than those receiving Allo-PBSCT+Allo-UBT and Allo-BMT (P<0.05). The children at an age >or=6 years had obviously higher incidence of hemorrhagic cystitis than those at younger ages.</p><p><b>CONCLUSION</b>Age is the major factor that affects the occurrence of hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation for beta-thalassemia.</p>

Effects of mouse bone marrow mesenchymal stem cells on the expression of chemokine receptors of spleenocytes after phytohemagglutinin stimulation / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To explore the effect of mouse bone marrow mesenchymal stem cells (MSCs) on the expression of chemokine receptors in T lymphocytes in vitro.</p><p><b>METHODS</b>Mouse bone marrow MSCs were separated with Percoll, cultured and expanded in low glucose DMEM. C57BL/6 mouse spleenocytes were cultured in the 24-hole flasks by the density of 1 x10(6)/hole. Phytohemagglutinin (PHA) was then added to the holes and cultured for 72 hrs. This study consisted of three groups. Groups A and B were co-cultured by adding MSCs as the ratio of 0.1 and 0.01 to spleenocytes respectively. The control group was cultured without MSCs. Three days later the suspended spleenocytes were harvested for detecting the expression of three chemokine receptors CXCR3, CCR5 and CCR7 in T lymphocytes by the flow cytometry.</p><p><b>RESULTS</b>The expression of CD3(+)CCR5(+) and CD3(+)CCR7(+) were statistically different among the three groups. Group A had the strongest expression, followed by group B and the control group. The expression of CD3(+)CXCR3(+) in group A was statistically higher than that in group B and the control group.</p><p><b>CONCLUSIONS</b>MSCs could up-regulate the expression of chemokine receptors CXCR3, CCR5 and CCR7 in T lymphocytes stimulated by PHA.</p>

Analysis of therapeutic effectiveness of Nanfang ALL 99 protocol in childhood acute lymphoblastic leukemia patients / 中华儿科杂志

<p><b>OBJECTIVE</b>With more precise diagnostic criteria and risk classifications, more effective therapy administered in clinical trials, and better supportive care, the outcome of children with acute lymphoblastic leukemia (ALL) has been improved dramatically. Today, approximately 80% of children treated for this disease in developed countries enjoy long-term event free survival (EFS) and in most instances, would be cured. In this study, treatment outcome of 82 childhood ALL patients in the hospital were analyzed, and ways for how to improve the EFS rate in childhood ALL were explored.</p><p><b>METHODS</b>Eighty-two patients with ALL were enrolled into the Nanfang ALL 99 protocol which derived from German BFM ALL 95 and Hong Kong-Singapore acute lymphoblastic leukemia 97 (HK-SG ALL 97). Dexamethasone instead of hydrocortisone was used for triple intrathecal therapy. Standard at risk patients who had been irregularly treated in other hospitals for short periods of time were classified as at intermediate risk. When ANC was > or = 1.0 x 10(9)/L and platelet > or = 100 x 10(9)/L, chemotherapy was started. Life table method was used to estimate survival rate and statistical analysis was done by using software SPSS for Windows.</p><p><b>RESULTS</b>From March 1999 to September 2003, 82 childhood ALL patients were treated with the Nanfang ALL 99 protocol and 78 (95.1%) patients attained complete remission (CR) in a median time of 33 days. Out of 82 patients, 13 patients dropped out of the the Nanfang ALL 99 protocol because of financial difficulty or other reasons. Sixty nine patients were consecutively treated with the Nanfang ALL 99 protocol. The overall EFS rate at 2 years, 3 years and 5 years were 91.3%, 85.9% and 75.2%, respectively, with a median observation duration of 34 months. Three patients died of complications (4.3%). The disease relapsed in 6 patients and they died finally.</p><p><b>CONCLUSION</b>The outcome of patients treated with the Nanfang ALL 99 protocol was favorable, and the mortality rate of this chemotherapeutic protocol was low. This protocol was well tolerated by Chinese patients and therefore the protocol is worthy of application in China.</p>

Invasive Fungal Infection after Allogeneic Hematopoietic Stem Cell Transplantation in Children / 实用儿科临床杂志

Objective To explore the incidence,clinical status,risk factors and outcomes of invasive fungal infections(IFIs)after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in pediatric patients.Methods Forty-one Patients who were underwent Allo-HSCT were selected from 2005 to 2006. Of 41 patients, 24 were boys and 17 were girls,aged 2-13 years old. Twenty-six cases with ?-thalassemia, 1 case with adrenoleukodystrophy,and the left 14 cases with other hematologic disorders.Twenty patients underwent bone marrow transplantation,19 patients underwent peripheral blood stem cell transplantation,2 patients underwent bone marrow transplantation and cord blood transplantation.Fourteen patients received Allo-HSCT from HLA-matched sibling donors or HLA mis-matched parents, 27 patients received Allo-HSCT from unrelated donors. Based on different types of transplant, patients were conditioned with busulfan, cyclophosphamide and Anti-thymocyte immune globulin. Fludalabine, total body irration, thiotepa or melphalan was used additionly in some cases. Cyclosporine A and mycophnolate mofetil were used as prophylaxis of graft versus host disease (GVHD).Results IFIs was observed in 5 cases(5/41 cases,12.2%),this comprised cases of proven,probable and possible IFIs at rates of 2.4%,4.9%,4.9%.The time of IFIs was 9-120 d after transplantation,the majority of IFIs in 3/5 cases(60%)children occurred within the first month.The difference of IFIs between patients who recived high-dose corticosteroid and those with no or conventional-dose corticosteroid was significant(?2=8.201 P=0.004);Regarding conditioning regimens,the IFIs of patients who with Thiotepa (TT) was significanthy higher than that of compared with those without TT(?2=9.549 P=0.002).The total effective rate was 40%.The effective rates of the patients with confimed diagnosis,cli-nical diagnosis,and with recommended diagnosis respectively were 100%,0 and 50% respectively.Conclusions IFIs is an important complication after Allo-HSCT,and the high-dose corticosteroid therapy and conditioning regimens with TT are the risky factors for IFIs.Aspergillus is the main pathogen bacteria.

Allogeneic hematopoietic stem cell transplantation for beta-thalassemia major / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the effect of hematopoietic stem cell transplantation (HSCT) for beta-thalassemia major.</p><p><b>METHODS</b>Fifteen beta-thalassemia major patients with a median age of 3. 5 years (range 1 - 10 years) received allogeneic HSCT. According to the Pesaro's classification for thalassemia, 12 patients were grade I - II, and 3 grade III. The bone marrow transplantation (BMT) plus peripheral blood stem cell (PBSC) transplant mobilized by granulocyte colony-stimulating factor (G-CSF) was used when donor is low body-weight.</p><p><b>RESULT</b>Of the fifteen patients, nine were disease-free survival (DFS) at a median follow-up of 2.5 years (range 6 - 54 months). Of eight grade I - II patients received HLA identical sibling BMT, seven were DFS, and of two received HLA mismatched marrow from their mother, one DFS, another not engrafted. Two patients received unrelated cord blood HSCT were both not engrafted. Two patients received PBSC transplantation alone were not engrafted, but one of them soon received BMT from the same donor and was DFS. The incidences of grade I - II and grade III acute graft-versus-host disease (aGVHD) were 20% (3/15) and 6.7% (1/15), respectively. Interstitial pneumonia occurred in 4/15 (26.7%) patients. There were no long-term complications in the survivors.</p><p><b>CONCLUSION</b>Grade I - II beta-thalassemia major patients received HLA identical sibling BMT had higher DFS. It was propitious for engraftment to use BMT plus PBSC, but with a higher incidence of acute and chronic GVHD.</p>