Diagnosis, treatment and genetic analysis of an elderly patient with Gaucher's disease characterized by marked multiple bone destruction.

Gaucher's disease is a rare autosomal recessive genetic disease. Due to the decrease or lack of glucocerebrosidase (GBA) activity in lysosome caused by the mutation of GBA gene, its substrate glucocerebroside is detained in lysosome, resulting in clinical manifestations of liver, spleen, kidney, bone, hematopoietic system and even nervous system involvement. Here, we report a case of elderly patient presenting marked multiple bone destruction, with childhood medical history of splenectomy and "osteomyelitis". The patient has a significantly enlarged liver, accompanied by anemia, thrombocytopenia and osteopenia. Laboratory studies show this patient has low blood GBA activity and high glucosyl sphingosine level and increased chitotriosidase activity. Genetic testing revealed a homozygous missense variant NM_001005741.2 c.770A>G (p.Asp257Gly) in the patient's GBA gene. After 6 months of enzyme replacement therapy, the patient's platelets returned to normal, anemia improved, and liver volume decreased. Further detections show that the mother and brothers of the patient have heterozygous mutations at this locus, which is consistent with Mendelian inheritance law. Although this variant has not been reported in literatures or database, both clinical manifestations, characteristics of enzymology and biomarkers, and the effect of enzyme replacement therapy support the diagnosis of Gaucher's disease. The Asp257Gly variant is therefore assessed as a clinical pathogenic variant. This study expands the spectrum of the GBA gene variants. The diagnosis and treatment process of this case also provide reference for the early identification, diagnosis and early treatment of this kind of patients.

Low prevalence and independent prognostic role of del(11q) in Chinese patients with chronic lymphocytic leukemia.

The 11q deletion (del(11q)) is a conventional cytogenetic aberration observed in chronic lymphocytic leukemia (CLL) patients. However, the prevalence and the prognostic value of del(11q) are still controversial. In this research, we retrospectively explored the prevalence, association, and prognostic significance of del(11q) in 352 untreated and 99 relapsed/refractory Chinese CLL patients. Totally 11.4% of untreated and 19.2% of relapsed/refractory patients harbored del(11q). Del(11q) was more common in patients with ß2-microglobulin > 3.5 mg/L, positive CD38, positive zeta-chain associated protein kinase 70, unmutated immunoglobulin heavy variable-region gene and ataxia telangiectasia mutated mutation. Kaplan-Meier method and univariate Cox regression indicated that del(11q) was an independent prognostic factor for overall survival (OS). Based on the results of univariate Cox regression analysis, two nomograms that included del(11q) were established to predict survival. Desirable area under curve of receiver operating characteristic curves was obtained in the training and validation cohorts. In addition, the calibration curves for the probability of survival showed good agreement between the prediction by nomogram and actual observation. In summary, the prevalence of del(11q) is relatively low in our cohort and del(11q) is an unfavorable prognostic factor for untreated CLL patients. Besides, these two nomograms could be used to accurately predict the prognosis of untreated CLL patients.

High viral loads of circulating Epstein-Barr virus DNA copy number in peripheral blood is associated with inferior prognosis in patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a distinct subtype of B cell non-Hodgkin lymphoma. No research has yet documented to investigate the prognostic implications of Epstein-Barr virus (EBV) infection in MCL. The objective of this study was to determine whether EBV DNA load may influence the heterogeneity in the course of the disease in MCL patients. Eighty-eight MCL patients were retrospectively enrolled in the study. EBV DNA load was detected by real-time quantitative PCR for quantification. The univariate and multivariate Cox proportional hazards models were established for the estimation of prognostic factors. Twenty-seven patients were detected positive for EBV DNA and the median virus titer was 1.72×104 copies/mL (range, 8.20×102 to 4.14×105 copies/mL). With a median follow-up of 39 months (range, 9 to 120 months), patients in EBV DNA-positive group displayed unfavorable progression-free survival (PFS) (P=0.012) and overall survival (OS) (P=0.004) than patients in EBV DNA-negative group. Multivariate Cox regression analysis revealed that EBV DNA-positivity was an independent risk factor for both PFS (HR, 2.04; 95% CI, 1.07 to 3.92; P=0.031) and OS (HR, 2.68; 95% CI, 1.20 to 6.00; P=0.016). Reduction in EBV copies was significantly associated with therapy-response. Circulating EBV DNA load in whole blood proved to be a significant predictor of prognosis in patients with MCL, which needs further validation in large-scale clinical studies.

EBV-miR-BHRF1-1 Targets p53 Gene: Potential Role in Epstein-Barr Virus Associated Chronic Lymphocytic Leukemia.

PURPOSE: The purpose of this study was to investigate the prognostic impact of Epstein-Barr virus (EBV)-microRNA (miRNA, miR)-BHRF1-1 with chronic lymphocytic leukemia (CLL) as well as role of EBV-miR-BHRF1-1 in p53 gene. MATERIALS AND METHODS: Quantitative reverse transcription-polymerase chain reaction and western blotting were used to quantify EBV-miR-BHRF1-1 and p53 expression in cultured CLL. RESULTS: p53 aberration was associated with the higher expression level of EBV-miR-BHRF1-1 (p < 0.001) which was also an independent prognostic marker for overall survival (p=0.028; hazard ratio, 5.335; 95% confidence interval, 1.193 to 23.846) in 97 newly-diagnosed CLL patients after adjusted with International Prognostic Index for patients with CLL. We identified EBV-miR-BHRF1-1 as a viral miRNA regulator of p53. EBV-miR-BHRF1-1 repressed luciferase reporter activity by specific interaction with the seed region within the p53 3'- untranslated region. Discordance of p53 messenger RNA and protein expression was associated with high EBV-miR-BHRF1-1 levels in CLL patients and cell lines. EBV-miR-BHRF1- 1 inhibition upregulated p53 protein expression, induced cell cycle arrest and apoptosis and decreased cell proliferation in cell lines. EBV-miR-BHRF1-1 mimics downregulated p53 protein expression, decreased cell cycle arrest and apoptosis, and induced cell proliferation in cell lines. CONCLUSION: This study supported the role of EBV-miR-BHRF1-1 in p53 regulation in vitro. Our results support the potential of EBV-miR-BHRF1-1 as a therapeutic target in EBV-associated CLL with p53 gene aberration.

A higher percentage of cells with 13q deletion predicts worse outcome in Chinese patients with chronic lymphocytic leukemia carrying isolated 13q deletion.

Previous studies showed that, in chronic lymphocytic leukemia (CLL) patients with isolated 13q deletion (13q-), those carrying higher percentage of leukemic cells with 13q- had more aggressive diseases. However, the prognostic value of the percentage of leukemic cells with 13q- in Chinese CLL patients with isolated 13q- remained to be determined. Using interphase fluorescence in situ hybridization (FISH), we identified 82 patients (25.4%) with isolated 13q deletion from a cohort of 323 untreated CLL patients. Among patients with isolated 13q deletion, cases of 13q- cells ≥ 80% (13q-H) had significantly shorter time to first treatment (TTT) than those of < 80% 13q- cells (13q-L) (median 11 vs. 92 months, p = 0.0016). A higher lymphocyte count (p = 0.0650) was associated with 13q-H, while other clinical, immunophenotypic, or molecular features did not differ between patients with 13q-H and 13q-L. Although 13q-H only showed marginal significance in multivariate analysis of TTT (hazards ratio 2.007; 95% confidence interval 0.975-4.129; p = 0.059), it helped refine the risk stratification based on Binet stage or immunoglobulin heavy chain variable gene (IGHV) status. In cases in Binet A or B stage, patients with 13q-H had a significantly shorter TTT (median TTT 18 months vs. undefined, p = 0.0101). And in IGHV mutated patients, 13q-H was also associated with reduced TTT (median TTT 13q-H. 18 months vs. 13q-L undefined, p = 0.0163). In conclusion, the prognosis of CLL patients with isolated 13q deletion was heterogeneous with 13q-H identifying patients with worse outcome.

Low absolute CD4+ T cell counts in peripheral blood are associated with inferior survival in follicular lymphoma.

Host immunity and tumor microenvironment significantly influence follicular lymphoma (FL) outcomes. Lymphopenia has been identified as a negative prognostic factor for FL. However, there is limited data regarding prognostic value of peripheral blood T lymphocyte subsets, especially absolute CD4+ T cell counts (ACD4C) in FL. We studied 127 consecutive FL patients to investigate whether peripheral blood ACD4C or absolute monocytes (AMC) at diagnosis had an impact on FL prognosis. In our cohort, both low ACD4C and high AMC were the parameters associated with inferior progression-free survival (PFS) (P = 0.021 and P = 0.013, respectively) and inferior overall survival (OS) (P = 0.020 and P = 0.005, respectively) by univariate analysis. Multivariate analysis revealed that only low ACD4C was statistically significant in worse PFS (hazard ratio, 2.811; 95 % confidence interval, 1.137-6.950; P = 0.025) and shorter OS (hazard ratio, 3.393; 95 % confidence interval, 1.037-11.105; P = 0.043) independent of FLIPI-2. Evaluation of blood ACD4C could be a useful indicator of outcome in previously untreated FL patients.