CD20 expression predicts survival in paediatric post-transplant lymphoproliferative disease (PTLD) following solid organ transplantation

The prognostic role of CD20 expression and Epstein-Barr virus (EBV) positivity in post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT) in paediatric patients is poorly understood. We retrospectively examined the relationship of CD20 and EBV with the time interval from SOT to PTLD diagnosis, and PTLD-related event-free (EFS) and overall survival (OS) in 45 consecutive PTLD patients (≤25 years) following SOT. These 45 paediatric SOT patients (28 heart, 11 liver, six kidney) were diagnosed with PTLD 45 months (mean; SD 43; range 4-153; median 24·5) after SOT, with PTLD diagnosis at 118 months (mean) (SD 77; range 14-287) of age. Of 40 evaluable tumours (11 monomorphic, 19 polymorphic, five early lesions, five rare subtypes), 32 (80%) had detectable EBV and 28 (70%) were classified as CD20(+) . Patients whose PTLD expressed CD20 or EBV had shorter intervals between SOT and PTLD onset (28 vs. 64 or 77 months for CD20 and EBV respectively) (P < 0·02), even after adjusting for age at SOT. Patients with CD20(+) tumours had higher 5-year PTLD-related EFS (83·7% vs. 28·6%, P < 0·001) and OS (95·8% vs. 56·3%, P = 0·01). EBV expression was unrelated to PTLD-related EFS or OS. CD20 expression is associated with timing of development of PTLD and predicts survival in PTLD diagnosed following paediatric SOT.     

Efficacy and tolerability of high-dose methotrexate in central nervous system positive or relapsed lymphoproliferative disease following liver transplant in children

Childhood post-transplant lymphoproliferative disease (PTLD) is a heterogeneous condition in which treatment varies, from the reduction of immunosuppression to moderately intensive chemotherapy. While low-dose chemotherapy/rituximab has been found to be effective, moderately intensive chemotherapy is required for patients who relapse, have classic non-Hodgkin lymphoma or have fulminant PTLD. Methotrexate (Mtx) is highly effective in lymphomas and crosses the blood-brain barrier. However, there are no data in the literature regarding its safety in post-liver transplant patients. We describe four cases of high-grade lymphomas (three diffuse large B cell and one T-cell lymphoblastic), post-liver transplant, for which chemotherapy including high-dose Mtx (HDMTX) was the treatment of choice. In total, 20 doses of HDMTX (1–5 g/m²) were given. The treatment was well tolerated and all four patients had a good response. One case of central nervous system (CNS) diffuse large B-cell lymphoma was treated with HDMTX alone. We conclude that, in the absence of significant organ damage, HDMTX can safely be given to liver transplant patients, but should only be administered in specialist oncology units. Proof of effectiveness as a single agent in CNS lymphoma needs further studies.     

The role of antiviral and immunoglobulin therapy in the prevention of Epstein–Barr virus infection and post-transplant lymphoproliferative disease following solid organ transplantation

Abstract: The recognition of the importance of Epstein–Barr virus (EBV) infection, including EBV-associated post-transplant lymphoproliferative disease (PTLD), has led to a new focus on the prevention of this problem. This paper reviews the scientific rationale behind, and clinical experience with, the use of chemoprophylaxis (using acyclovir or ganciclovir) and immunoprophylaxis (using intravenous immunoglobulin) in the prevention of EBV/PTLD. While some centers have already introduced the use of one or both of these agents as standard prophylaxis against the development of this complication, published data in support of these protocols are currently lacking. Well designed clinical trials are necessary to evaluate the potential role of both antiviral and immunoglobulin agents in the prevention of EBV/PTLD in organ transplant recipients.     

Risk factors and clinical outcomes of pediatric liver transplant recipients with post‐transplant lymphoproliferative disease in a multi‐ethnic Asian cohort

Background

We aimed to evaluate clinical characteristics, risk factors, and disease outcomes for liver transplant recipients (LTR) with post‐transplant lymphoproliferative disease (PTLD) at our center.

Methods

Retrospective review of data of all pediatric LTR (1991‐2015) was conducted.

Results

The overall incidence of PTLD was 16.4% (18/110), the majority (13/18) were early lesions, while 3/18 were polymorphic/monomorphic PTLD. The risk factors significant on univariate analysis were as follows: mean age (years) at transplant (1.66 vs 4.76, P = .006); age <2 years at transplant (odds ratio [OR] 3.53 [95% confidence interval [CI]: 1.16‐10.73], P = .026); cytomegalovirus (CMV) primary infection (OR 11.39 [95% CI: 3.44‐37.7], P < .001); recipient CMV seronegativity (OR 7.50 [95% CI: 2.02‐27.78], P = .003); presence of CMV end‐organ disease (OR 4.00 [95% CI: 1.22‐13.16], P = .022); Chinese ethnicity; and higher mean duration of intravenous ganciclovir prophylaxis. In multivariate analysis, CMV primary infection (OR 5.22 [95% CI: 1.25‐21.87], P = .024), CMV seronegativity (OR 5.91 [95% CI: 1.13‐30.90, P = .035]), and having acute cellular rejections (ACR) prior to PTLD (OR 5.53 [95% CI: 1.43‐21.48, P = .013]) were significant risk factors for PTLD, with the latter two factors having a synergistic effect in increasing PTLD risk in a stratified analysis. The final multivariate model in predicting the risk of PTLD, utilizing CMV primary infection, recipient CMV seronegativity, and ACR before PTLD as predictive variables, was statistically significant (likelihood ratio chi square statistic = 25.18, P < .0001 with df = 3).

Conclusions

We report a unique clinicopathologic and risk factor profile in our cohort—early lesion PTLD accounts for the majority and the incidence of monomorphic PTLD remains low. In addition, we show a synergism between CMV naivety and ACR on PTLD risk, a higher prevalence of gastrointestinal manifestations, and a lack of significant association with Epstein‐Barr virus seronegativity.     

Diagnosis and management of post-transplant lymphoproliferative disease following solid organ transplantation in children,adolescents, and young adults

Post-transplant Lymphoproliferative Disease (PTLD) remains a major complication of solid organ transplantation (SOT) in pediatric patients. The majority are Epstein-Barr Virus (EBV) driven CD20⁺ B-cell proliferations responsive to reduction to immunosuppression and anti-CD20 directed immunotherapy. This review focusses on the epidemiology, role of EBV, clinical presentation, current treatment strategies, adoptive immunotherapy and future research in EBV + PTLD in pediatric patients.     

Recombinant tissue plasminogen activator (rt-PA) for veno-occlusive liver disease in pediatric autologous bone marrow transplant patients

The pathogenesis of veno-occlusive disease (VOD) of the liver appears to be secondary to endothelial damage of terminal hepatic venules, which leads to activation of the coagulation cascade, fibrin deposition, and eventual fibrous obliteration of the hepatic venules. Patients with VOD usually present with jaundice, hepatomegaly, weight gain, and ascites. This complication is usually associated with a high mortality rate. We report here the frequency and treatment of VOD in our autologous bone marrow transplant (BMT) patient population. Three of 15 (20%) children (median age 9 years) developed VOD and were treated with recombinant tissue plasminogen activator (rt-PA). Two of these three patients were prepared for BMT with busulfan (16 mg/kg) and cyclophosphamide (Cytoxan, 200 mg/kg), while the other child received cytosine arabinoside (ARA-C 18 g/m²), Cytoxan (3,600 mg/m²) and total body irradiation (TBI, 1,400 r). VOD developed between days 7–24 posttransplant. Clotting studies obtained pretransplant and during VOD included prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrin-degradation product (FDP), proteins C and S, and platelet count. There was no correlation between the incidence of VOD and coagulation status. All patients had normal pretransplant clotting studies. However, protein C levels were noted to be consistently low for those patients at the time of VOD. All three patients received rt-PA at a dose of 0.25–0.5 mg/kg for 4 days. This dose produced increased levels of FDP but did not significantly prolong PT nor PTT. Two of the patients had dramatic responses and had complete resolution of VOD within 6–12 days from the start of therapy. The other patient died of fulminant hepatic failure. It seems that rt-PA is effective in VOD of the liver, which may be associated with low protein C level. © 1994 Wiley-Liss, Inc.     

SLC11A1 (formerly NRAMP1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis.

OBJECTIVE: Although many case-control studies have investigated the association between the SLC11 A1 gene polymorphisms and tuberculosis (TB) susceptibility, results were conflicting due to limited power. We reviewed the literature systematically by means of meta-analysis, provided a quantitative summary estimate on the association with TB, and examined some sources of between-study heterogeneity. DESIGN: We searched databases (MEDLINE, PUBMED and OVID) from January 1995 to December 2004 using 'gene' or 'SLC11A1' or 'NRAMP1', in combination with 'tuberculosis', performed a manual search of citations from relevant original studies and review articles, or corresponded with authors. RESULTS: The summary ORs for studies with 3'UTR, D543N, INT4 and 5'(GT)n loci allele variants in the SLC11A1 gene were 1.33 (95%CI 1.08-1.63), 1.67 (95%CI 1.36-2.05), 1.14 (95%CI 0.96-1.35) and 1.32 (95%CI 1.03-1.68), respectively, compared with their corresponding common alleles. The pooled ORs by sub-group analyses for the four loci described above were 1.20 (95%CI 0.86-1.68), 1.69 (95%CI 1.14-2.50), 1.50 (95%CI 1.17-1.91), and 1.31 (95%CI 1.05-1.64) in subjects of African descent, 1.46 (95%CI 1.10-1.94), 1.65 (95%CI 1.29-2.12), 0.91 (95%CI 0.66-1.25) and 1.86 (95%CI 1.33-2.62) in Asian subjects, 1.81 (95%CI 0.66-4.93), 1.79 (95%CI 0.72-4.47), 0.87 (95%CI 0.61-1.22) and 1.02 (95%CI 0.35-2.99) in European subjects. CONCLUSIONS: Polymorphisms at the four loci had no statistically significant association between the SLC11A1 variants and susceptibility to TB in subjects of European descent, while they showed a statistically significant association in Asian subjects (except the INT4 variant), African subjects (except the 3'UTR variant) and the population as a whole (except the INT4 variant).     

Influence of polygenetic polymorphisms on the susceptibility to non‐alcoholic fatty liver disease of Chinese people

Background and Aim: The aim of this study was to investigate the influence of polygenetic polymorphisms, which play a role in the pathogenesis of metabolic syndrome, on the susceptibility to non‐alcoholic fatty liver disease (NAFLD) of Chinese people. Methods: The subjects were selected from an epidemiological survey in the Guangdong province of southern China. In each polymorphism study, 50–117 subjects who met the diagnostic criteria of NAFLD and had typical clinical and ultrasonographic findings were placed into the case group. Using a nested case–control design, the same numbers of matched people without NAFLD were included as controls. Single nucleotide polymorphisms (SNP) at nine positions in seven candidate genes were tested. These SNP were found to be associated with the pathogenesis of metabolic syndrome. Genetic analyses were performed using genomic DNA extracted from peripheral blood leukocytes. Polymerase chain reaction–restriction fragment length polymorphism was applied to detect SNP. Results: Most candidate genes' SNP were associated with susceptibility to NAFLD. Some showed positive relationships (increased risk): tumor necrosis factor‐α‐238, adiponectin‐45, leptin‐2548, peroxisome proliferator‐activated receptors‐161 and phosphatidyletha‐nolamine N‐methyltransferase‐175. Other SNP demonstrated a negative association (decreased risk): adiponectin‐276 and hepatic lipase‐514. Only two were not associated: tumor necrosis factor‐α‐380 and peroxisome proliferator‐activated receptors‐γ co‐activator‐1α‐482. Conclusion: Most candidate genes' SNP examined in metabolic syndrome patients were associated with susceptibility to NAFLD.     

细胞色素P4502E1酶与非酒精性脂肪肝的关系

目的:探讨细胞色素P4502E1(CYP2E1)酶基因多态性与非酒精性脂肪性肝病(NAFLD)的关系及NAFLD的遗传学发病机制.方法:采用聚合酶链反应——限制性片段长度多态性分析法(PCR-RFLP)对40例非酒精性脂肪肝患者,20例酒精性肝病患者,20例非脂肪肝对照者,20例正常对照者分析CYP2E1基因多态性,并进行相关性分析.结果:NAFLD中c2等位基因型与正常对照组(x~2=8.376,P=0.004)和非脂肪肝对照组(x~2= 6.769,P=0.005)相比明显升高,差异有统计学意义(P<0.01),NAFLD中基因型分布与酒精性肝病相比无明显改变,差异无统计学意义(P =0.896).在NAFLD中肝脏病变程度不同,c2等位基因频率不同,在脂肪性肝炎(P=0.04)和肝硬化(P=0.000)中,差异有统计学意义(P<0.05).结论:NAFLD与CYP2E1酶基因多态性有关,同时也为研究NAFLD遗传易感性提供了新的思路.     

酒精性肝病的随访(附28例11～17年随访)

目的观察ALD的远期预后。方法经统一发信及笔者前往一个专区用电话向患者单位及到生存者家中随访。结果仅获得有反馈信息者28例，占随访病例之20．6％，其中已死亡12人，占有信息病例之42．9％。仅2例再获14年后肝穿活检对比。按2006年2月中华医学会肝脏病学分会脂肪肝和酒精性肝病学组修订诊断标准。①轻症ALD41人获4人复信均健在。②酒精性脂肪肝（AFL）15例有1人复信，继续饮酒（精）100g／d，12年后两次脑出血，已偏瘫。③酒精性肝炎（AH）24例，获信息反馈7例，其中2例已死于肝硬化，另3例已肝硬化，此型最终多合并糖尿病。④45例酒精性肝纤维化（AF）有反馈信息者11例。其中7例已死亡。⑤酒精性肝硬化（AC）11例，有反馈信息者5例，其中3例已死亡。结论轻症ALD远期预后较好。AFL如不戒酒远期效果差，AH、AF预后不良凶险。ALD合并ABV／HCV感染者远期预后不佳，多发展为肝硬化，合并肝癌死亡。     

Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation

This study investigated the efficacy of a pre‐emptive strategy based on the combination of Epstein–Barr virus (EBV) viraemia and poor T cell reconstitution in preventing post‐transplant lymphoproliferative disease (PTLD) following T cell depleted stem cell transplant (SCT). EBV viral load and immune reconstitution were prospectively monitored in 70 consecutive children undergoing SCT following reduced intensity conditioning with alemtuzumab. Patients who developed significant EBV viraemia (>40 000 copies/ml blood) were treated pre‐emptively with rituximab if they were within 3 months of SCT or their CD3 count was <0·3 × 10⁹/l. Of 20/70 patients who developed significant EBV viraemia, 13 received pre‐emptive rituximab. The incidence of PTLD was significantly reduced in the pre‐emptive cohort compared to historical controls (1·4% vs. 21·7%, P = 0·003). This difference was more marked among viraemic patients (2·7% vs. 62·5%P < 0·0001). Patients treated with rituximab demonstrated significantly delayed B cell reconstitution at 1 year post‐SCT but this was not associated with an increase in infectious mortality. In 6/6 patients >3 months post‐SCT who had a CD3 count >0·3 × 10⁹/l, reduced immunosuppression only resulted in successful resolution of EBV viraemia without PTLD. This strategy is safe and highly effective in preventing PTLD following T cell depleted SCT, and directs rituximab therapy to patients at highest risk of this complication.     

Tropheryma whipplei infection (Whipple's disease) in a patient after liver transplantation

Whipple's disease (WD) is a rare infection caused by the bacterium Tropheryma whipplei that can affect multiple organs and most commonly occurs in the immunocompetent host. Only 3 cases of WD have been reported in the setting of immunosuppression for organ transplantation. Here, we report the first case of WD, to our knowledge, in a patient after liver transplantation with comorbid graft‐versus‐host‐disease. We discuss the diagnostic challenges in this setting and the value of electron microscopy and in situ hybridization methods for confirming the infection. WD may be under‐diagnosed in immunosuppressed transplant patients because the disease can present with atypical clinical and histological features that suggest other conditions.     

Very early‐onset of Cryptococcus neoformans disease following liver transplantation: Report of two cases and a review of the literature

Cryptococcosis is the third most common invasive fungal infection following solid organ transplantation, and mortality is high. Most cases occur late and are due to reactivation of latent infection; however, very early reactivation and donor‐derived transmission can occur. Routine screening pre‐transplant and antifungal prophylaxis for cryptococcosis post‐transplant in solid organ transplantation are not standard practice. We present two cases of very early‐onset Cryptococcus neoformans disease following liver transplantation to highlight the need to consider individualized pre‐transplant screening and be aware that reactivation of Cryptococcosis neoformans can occur in the immediate post‐transplant period.     

PEMT基因G175A和rs12325817位点多态性与非酒精性脂肪肝的关系

目的:研究磷脂酰乙醇胺N甲基转移酶基因(PEMT)G175A和rs12325817位点多态性与非酒精性脂肪性肝病(NAFLD)的关系.方法:运用聚合酶链反应一限制性片段长度多态性检测156例NAFLD患者和188名健康对照PEMT基因G175A和rs464396基因型,等位基因频率分布,分析NAFLD患者与对照组临床各...