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Objective:To explore the clinical significance of the MYCN gene, PHOX2B gene and plasma cell-free DNA (cfDNA) in risk stratification and predicting the prognosis of high-risk neuroblastoma (NB). Methods:This was a prospective study involving 94 high-risk NB children admitted to Beijing Children′s Hospital, Capital Medical University from August 2017 to December 2018.Relative levels of MYCN and PHOX2B and cfDNA at diagnosis, and 4 and 6 cycles of chemotherapy were detected, and their differences were compared by the Chi- square test.Kaplan-Meier survival analysis was performed to explore their prognostic potential in high-risk NB. Results:Among the 94 high-risk NB children, 14 cases (14.9%) had MYCN amplification, 76 cases (80.8%) had positive expression of PHOX2B and 56 cases (59.6%) had cfDNA level higher than 100 μg/L.The proportion of high lactate dehydrogenase (LDH, ≥1 500 U/L) level in the MYCN gene amplification group (6/14 cases) was higher than that in the normal group (9/80 cases) ( P=0.009). The proportion of multi-site metastasis (54/76 cases) and high neuron specific enolase (NSE) level (NSE≥370 μg/L, 37/76 cases) in PHOX2B positive group were significantly higher than those in the negative group (5/14 cases, 2/14 cases) ( P=0.015, 0.020). The proportion of high LDH and high NSE in high cfDNA concentration (≥229.6 μg/L)group (13/37 cases, 28/37 cases) were significantly higher than those in low cfDNA concentration group (2/48 cases, 10/48 cases) (all P<0.001). With the decreased tumor burden during the treatment, the copy number of PHOX2B gene and cfDNA level were significantly lower than those at the initial diagnosis [0 (0-719.6) copies vs.1 723.5 (0-186 000.0) copies; 19.0 (1.1-225.5) μg/L vs.200.6 (8.0-5 247.4) μg/L, all P<0.001]. The 2-year event-free survival (EFS) rate of the MYCN gene amplification group was significantly lower than that of the normal group[(33.3±13.1)% vs.(58.5±7.1)%, P=0.020]. The 2-year EFS rate of PHOX2B positive group was significantly lower than that of the negative group[(47.9±7.1)% vs.(79.1±11.1)%, P=0.043]. EFS rate in high cfDNA concentration group was significantly lower than that in cfDNA low concentration group[(38.6±9.8)% vs.( 71.7±8.2)%, P=0.001]. After 6 cycles of chemotherapy, EFS rate in the PHOX2B positive group was significantly lower than that in the negative group [(16.7±14.4)% vs.( 60.6±6.6)%, P=0.014]; which was significantly lower in the Metaiodobenzylguanidine (MIBG) positive group than that of the negative group[(35.2±11.7)% vs.(65.8±7.1)%, P=0.037]. The MYCN gene and cfDNA concentration were not correlated with the prognosis of high-risk NB.Survival analysis of the combination of PHOX2B and MYCN gene ( PHOX2B+ /MIBG + , PHOX2B+ or MIBG + , PHOX2B-/MIBG -) showed a significant difference in the survival among three groups[0 vs.(53.6±1.2)% vs.(65.5±7.4)%, P=0.003]. Conclusions:The MYCN and PHOX2B gene and cfDNA concentration are of significance in risk stratification and predicting the prognosis of high-risk NB.Compared with the MYCN gene and cfDNA concentration, the PHOX2B gene is more suitable for monitoring the curative effect of chemotherapy on high-risk NB.A combined analysis of PHOX2B gene and MIBG before treatment can be more accurate in evaluating the treatment effect and residual lesions.
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Objective To summarize the clinical features of neuroblastoma (NB)with N - myc gene amplifi-cation in order to analyze tumor shrinkage and bone marrow remission in the early stage of chemotherapy,and to eva-luate the children's initial sensitivity to chemotherapy. Methods The medical records of 38 patients with N - myc am-plification of NB were reviewed (bone marrow or tumor tissues were positive during fluorescence in situ hybridization probe),who were treated between February 2012 to December 2016 at the Hematology Oncology Center,Beijing Chil-dren's Hospital,Capital Medical University. The regimens included chemotherapy,surgery,stem cell transplantation, radiotherapy,and maintenance treatment. The data were reviewed for the medical history. The variations of biomarker, bone marrow cells and the primary site were analyzed before and after 2 courses of CAV (Cyclophosphamide + Adriamy-cin + Vincristine)regimen chemotherapy,in order to observe the short - term effect of chemotherapy and the results were described with statistics. Results Total 38 cases were studied,22 boys(58. 9％)and 16 girls(42. 1％). The median age was 30 months. The primary sites of 37 cases of tumor were located in the retroperitoneal and adrenal area,1 case located in the posterior mediastinum. Bone marrow cytology was negative in 12 cases of them,but bone marrow biopsy suggested bone marrow metastasis,while bone marrow cytomorpholigic examinations were positive in the other 26 cases. Of all the 37 cases the lactate dehydrogenase (LDH)levels were reported higher than the normal value. LDH level was under 500 U/ L in one case,9 cases above 4000 U/ L. The neuron specific enolase (NSE)level of all the cases was higher than the normal and NSE level in 36 cases was higher than 100 μg/ L. In one patient the diameter of tumor was less than 5 cm,lager than 10 cm in 32 cases. The lesion of 33 tumor cases before chemotherapy by enhanced CT was ≤100 cm3 in 12 cases,> 100 - 500 cm3 in 11 cases,among which 6 cases ranged from 500 - 1000 cm3 ,4 cases larger than 1000 cm3 . All the 38 cases received 2 courses of chemotherapy. LDH levels of 4 cases became normal,and LDH levels fell under 500 U/ L in 18 cases,while LDH levels of the other 3 cases were above 1000 U/ L. Among 38 cases, the NSE level in 6 cases was reduced to normal,and 16 cases reduced to 25 - 100 μg/ L. The bone marrow examination of 36 cases reversed to negative. According to the image examination,the overall response rate after 2 courses of chemo-therapy was 84. 8％ . One case achieved very good partial remission,21 cases achieved partial response,7 cases a-chieved metastatic remission,2 cases had no remission,while 2 cases showed progression. After 2 courses of chemother-apy,the tumor diameter in 7 cases was less than 5 cm,while that of 22 cases was above 10 cm. Conclusions The ma-jority primary site of NB with N - myc gene amplification is located in retroperitoneal and adrenal area. Patients with the huge tumor have a heavy burden and the biomarker is always high at the early stage. NB with N - myc gene amplifica-tion is sensitive to chemotherapy. After 2 courses of chemotherapy,there is a sharp decrease in the level of biomarker and the tumor burden. Chemotherapy can diminish the burden of tumor in early stage. But because of the huge burden and the huge size of tumor,it's not the best time for surgery and stem cell collection. The patients should go on receiving chemotherapy for remission of disease.
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Objective To characterize the clinical course of biliary complications after right lobe living donor liver transplantation (RL-LDLT) and to identify the independent risk factors for biliary strictures.Methods 105 consecutive RL-LDLT recipients operated from April 2007 to April 2010 were followed up. The clinical and operative data were reviewed. The biliary complications and independent risk factors of biliary stricture were studied.Results The median follow-up duration was 49.5 months ranging from 562 to 1675 days.A total of 40 patients (38.1 ％) experienced 11 bile leak episodes (10.4％ ) and 37 (35.2％) biliary stricture episodes after transplantation.Bile leaks occurred at a median time of 9 days ranging from 4 to 54 days after transplantation.For biliary strictures,the occurring time was delayed and scattered wide with a median of 7.6 months ranging from 12 to 790 days after transplantation. Moreover, the biliary stricture incidence in the first year after transplantation was significantly higher than later.The independent risk factors for biliary strictures were CMV infection,bile leaks and bile duct size (≤3 mm).Conclusion The independent risk factors for biliary strictures after RL-LDLT were CMV infection,bile leaks and bile duct size (≤3mm).In order to avoid biliary complications,careful preoperative evaluations are necessary. The dissection of bile ducts should be meticulous to protect its blood supply.CMV infection should be prevented after transplantation.Close surveillance of biliary complications should be given to RL-LDLT recipients during the first year after transplantation.
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Objective To investigate the short-term acute rejection incidence of the recipients under the steroid-free immunosuppressive therapy after liver transplantation. Methods This retrospective study included 186 patients who were divided into two groups by random number table.The patients in no steroid group (the study group, n =94) received tacrolimus (Tac) with mycophemolate mofetil (MMF) or cyclosporine with MMF,and those in the steroid group (the control group,n =92) received the aforementioned immunosuppressive therapy combined with steroids.The acute rejection incidence was analyzed during six months post-transplantation.Results There was no significant difference in the gender,age,indication for transplantation,Child-Pugh score,MELD score,operating time,bleeding and transfusion volume during the operation,warm ischemia time and cold ischemia time between the two groups (P＞0.05).Liver biopsy was done on 9 cases of each group.The acute rejection incidence had no significant difference between the study group and the control group (5/94 vs 4/92,5.3％ vs 4.4％,P＞0.05).Conclusion The steroid-free immunosuppressive therapy after liver transplantation did not increase the short term acute rejection incidence.
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ObjectiveTo surnmarize the experience of tacrolimus or cyclosporine A-based immunosuppression after pediatric living-donor liver transplamation.Methods The clinical data of 30 children undergoing living-donor liver trarsplantation from October 2006 to January 2010 were analyzed retrospectively.In 30 patients,7 were given Tac-based immunosuppression (group A),10 given CsA-based immunosuppression (group B),and 13 switched from CsA to Tac for complications or adverse effects of drugs.Dosages and blood concentrations of immunosuppressants were recorded.Changes of liver and kidney functions were monitored.Incidence of rejection,infection and adverse effects of drugs were observed.ResultsIn the premise of the stable concentration and liver and kidney functions,the weight of children was increased by about 50％ and the per- kilogram dosage of CNIs was decreased significantly 1year postoperatively.There was no case of rejection in group A and 4 cases of rejection in group B(40％,4/10),and the original symptoms were gradually alleviated after the increased dosage in immunosuppressants.During the first 3 months,there was 1case of abdominal infection in group A (1/7) and 3 cases of lung infection in group B (3/10),and the original symptoms were gradually alleviated after anti-infective therapy.There was 1CMV lgM-positive case in group A (1/7) and 2 CMV IgM-positive cases in group B (2/10),and the original symptoms were gradually alleviated after using ganciclovir.The original symptoms of the 13 children switched from CsA to Tac were gradually alleviated.ConclusionThe two CNIs can be safely used in children undergoing pediatric livlng-donor liver transplantation.Both of them show the same effect in promoting the restoration of liver and kidney functions,but tacrolimus has more satisfactory effect in inhibiting the rejection and it has leas adverse effects.
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Objective To observe the outcomes of living donor liver transplantation (LDLT) for children with biliary atresia (BA) and to summarize the clinical experiences. Methods Forty-four BA patients (26 boys and 18 girls) underwent LDLT between October 2006 and December 2010. Mean (SD) and median (range) age at operation was (12.1 ± 9.0) months and 9 (6-60) months,respectively. The 44 donors were lineal relatives to the consorted recipients. Their mean (SD) and median (range) age at operation was (32. 7 ± 8. 0) months and 31 (20～54) years, respectively. All donor graft types were the left lateral segments with compatible ABO blood groups. Clinical data,including pre-operative evaluations, surgical technique, postoperative management and outcomes in all donors and recipients were retrospectively analyzed. Results All donors were followed up for (17. 5 ± 13. 3) months. No donor mortality was encountered, with a minimal morbidity and no long-term sequelae. Nine out of 44 recipients died. Three patients died of portal vein thrombosis (PVT), one of hepatic artery thrombosis (HAT), two of biliary complications, one of surgical site infections, one of abdominal bleeding and one of pulmonary infection. The overall 1-year and 2-year cumulative survival rate in recipients was 81. 2% and 76. 1 %, respectively. No re-transplantation was done. Postoperative complications included PVT, HAT, biliary leakage and refluxing cholangitis, pulmonary infections,surgical site infections and acute rejection. Conclusion LDLT has been the effective treatment for pediatric recipients with BA and provides favorable prognosis. To improve prognosis of recipients, the key points are pre-operative evaluations, surgical technique, and postoperative management
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Objective To compare the metabolic characteristics, dosages and blood concentrations of tacrolimus (Tac) in patients subject to cadaveric liver transplantation (CLT) vs living-donor partial liver transplantation (LDLT) in order to investigate the usage of Tac in patients undergoing LDLT. Methods The clinical data of 85 patients undergoing liver transplantation from April 2007 to September 2009 were analyzed retrospectively. Thirty-four underwent LDLT (group A)and the remaining 51 underwent CLT (group B). Results The time to reach therapeutic window was shorter in group A (3. 4 ± 1.0 days) than in group B (4. 5 ± 2. 0 days, P = 0. 002). The Tac dosage in group A was significantly less than in group B during the first 28 days post-transplantation. However,the Tac dosage approached gradually and tended to be consistent after 28 days. On the postoperative day7, 14, 21 and 28 days, the Tac dosage in group A was 72.74 ％, 82.26 ％, 83.92 ％ and 88. 87 ％ of that in group B respectively. Correlation analysis revealed that graft-recipient body weight ratio (GR/WR) was significantly correlated with the Tac dosage on the day 7 (mg·day-1 · kg-1) (r =0. 728, P＜0. 01) and Tac concentration/dosage ratio (ng/ml)/(mg/kg) (r = - 0. 644, P＜0. 01 ).Conclusion The early Tac dosages in patients subject to LDLT were correlated significantly with the volume of graft. The early Tac dosages in patients undergoing LDLT were about 70 ％ of those in patients undergoing cadaveric liver transplantation. Moreover, with the regeneration of the liver, they tended to be consistent after 28 days.
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Objective To evaluate liver biopsy for the diagnosis in liver transplant patients with suspected acute rejection. Methods From Oct. 2004 to Apr. 2005, liver biopsies were performed 53 times in 39 transplant cases. Results Based on Banff schema for grading liver allograft rejection, laboratory abnormalities and result of treatment, acute rejection was diagnosed on 16 episodes, preservation injury in 12, bile duct strictures in 9, drug-induced injury in 11, chronic rejection in 3 and acute hepatic failure in 2. Conclusions Hepatocyte ballooning with necrosis features preservation injury. Drug-induced injury commonly has a combination of hepatocyte denaturalization with mild portal inflammation. Histologic features of early bile duct strictures in liver biopsy show prominent bile ductular proliferation and the canalicular cholestasis with mild hepatocyte damage which help to exclude acute rejection.