Multicolour fluorescence in situ hybridization analysis of t(14;18)-positive follicular lymphoma and correlation with gene expression data and clinical outcome

In order fully to identify secondary chromosomal alterations, such as duplications, additions and marker chromosomes that remained unresolved by G banding, 60 cases of t(14;18)-positive follicular lymphoma (FL) were analysed by multicolour karyotyping techniques [multicolour fluorescence in situ hybridization (MFISH)/multicolour banding for chromosome 1 (MBAND1)]. A total of 165 additional structural chromosomal aberrations were delineated. An increased frequency of chromosomal gains involving X, 1q, 2, 3q27-q29, 5, 6p11-p21, 7, 8, 11, 12, 14q32, 17q, 18 and 21 and deletions of 1p36, 3q28-q29, 6q, 10q22-q24 and 17p11-p13 was revealed by the MFISH/MBAND1 analysis. Balanced translocations other than t(14;18) were uncommon, whereas unbalanced translocations were numerous. Deletion of 1p36 and duplication of 1p33-p35, 1p12-p21 and 1q21-q41 were regularly involved in chromosome 1 alterations, seen in 53% of the cases. A strong correlation was demonstrated between gains of individual chromosomal bands and increased gene expression, including 1q22/MNDA, 6p21/CDKN1A, 12q13-q14/SAS, 17q23/ZNF161, 18q21/BCL2 and Xq13/IL2RG. Unfavourable overall survival was associated with del(1)(p36) and dup(18q). These data support the notion that translocation events are primarily responsible for FL disease initiation, whereas the unbalanced chromosomal gains and losses that mirror the gene expression patterns characterize clonal evolution and disease progression, and thus provide further insights into the biology of FL.     

Blood dendritic cells in patients with acute lymphoblastic leukaemia

Myeloid and plasmacytoid dendritic cells (MDCs, PDCs) play a key role in the initiation of immune responses. In this study, we show a severe reduction of MDCs and PDCs in patients with B lineage acute lymphoblastic leukaemia (B-ALL; P = 0.01 vs. controls). DCs from patients with T lineage ALL (T-ALL) were quantitatively and functionally comparable to healthy donors, as demonstrated by secretion of interleukin (IL)-12p70 and interferon-alpha. In vitro, the circulating CD34(+) fraction of B-ALL cases did not generate either CD1a(+) MDCs or PDCs, suggesting that DC development is probably affected in B-ALL, but not in T-ALL.     

Late perforation of a thoracic aortic dacron graft by a metallic stent-graft component.

PURPOSE: To describe a case involving perforation of a previously placed aortic Dacron graft by the uncovered proximal stent of a thoracic stent-graft. CASE REPORT: A 76-year-old man with a surgically treated type A dissection presented with residual type B dissection. Thoracic stent-grafting of the entry site was performed successfully. After 2 years, the patient was admitted for evaluation of a non-pulsating parasternal mass. Computed tomography showed a large, hypodense liquid-like mass affecting the mediastinum up to the subcutaneous tissue. A false aneurysm at the proximal end of the stent-graft was observed arising from an aortic perforation by the uncovered stent. One week later, the mass had almost completely resolved, and the patient has been scheduled for close surveillance. CONCLUSION: This case illustrated the importance of thoroughly examining the long-term durability and compatibility of prosthetic materials.     

Intensive chemotherapy with mitoxantrone administered as a single injection in patients with high-risk acute myeloid leukemia: results of the EMA 2000 trial

Following a dose-escalation study performed to assess the maximally tolerated dose of high-dose mitoxantrone in a single injection combined with chemotherapy, a phase II trial (EMA 2000 regimen) was performed in patients with refractory or relapsed acute myelogenous leukemia (AML) between October 2000 and December 2003. Sixty-two patients entered the study and received mitoxantrone 45 mg/m² on day 1 in combination with cytarabine and etoposide. Overall, 39 patients (63%) achieved complete remission (CR). Four patients died during remission induction, and 19 patients had resistant disease. Median time to granulocyte and platelet recovery was 34 and 39 days, respectively. The predominant non-hematologic toxicity was infection, with 53% severe infections. Thirty-three of the 39 remitters received subsequent treatment consisting of maintenance chemotherapy courses in 17 patients, allogeneic stem cell transplantation (SCT) in 7 patients, and autologous SCT in 9 patients. The median overall survival of the entire cohort was 8.1 months, with 18% at 2.5 years. EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of high-risk AML. CR proportion was significantly higher in patients with a first CR duration 6 months when compared with those from a control trial using standard-dose mitoxantrone (90 vs 70%, p=0.03).     

Conditional ablation of NKp46+ cells using a novel Ncr1greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

To study gene functions specifically in NKp46⁺ cells we developed novel Cre mice allowing for conditional gene targeting in cells expressing Ncr1 (encoding NKp46). We generated transgenic Ncr1^greenCre mice carrying an EGFPcre fusion under the control of a proximal Ncr1 promoter that faithfully directed EGFPcre expression to NKp46⁺ cells from lymphoid and nonlymphoid tissues. This approach allowed for direct detection of Cre‐expressing NKp46⁺ cells via their GFP signature by flow cytometry and histology. Cre was functional as evidenced by the NKp46⁺ cell‐specific expression of RFP in Ncr1^greenCreRosa‐dtRFP reporter mice. We generated Ncr1^greenCreIl2rg^fl/fl mice that lack NKp46⁺ cells in an otherwise intact hematopoietic environment. Il2rg encodes the common gamma chain (γ_c), which is an essential receptor subunit for cytokines (IL‐2, ‐4, ‐7, ‐9, ‐15, and ‐21) that stimulate lymphocyte development and function. In Ncr1^greenCreIl2rg^fl/fl mice, NK cells are severely reduced and the few remaining NKp46⁺ cells escaping γc deletion failed to express GFP. Using this new NK‐cell‐deficient model, we demonstrate that the homeostasis of NKp46⁺ cells from all tissues (including the recently described intraepithelial ILC1 subset) requires Il2rg. Finally, Ncr1^greenCreIl2rg^fl/fl mice are unable to reject B16 lung metastases demonstrating the essential role of NKp46⁺ cells in antimelanoma immune responses.     

Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival,independent of the MCL international prognostic index

Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an “indolent” evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra‐hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of “indolent” patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis. © 2013 Wiley Periodicals, Inc.     

Prevalence and risk factors of cataract after chemotherapy with or without central nervous system irradiation for childhood acute lymphoblastic leukaemia: an LEA study

Corticosteroid and central nervous system (CNS) irradiation can induce cataract in childhood lymphoblastic leukaemia survivors. Few prospective studies with systematic ophthalmological evaluation have been published. Cataract was prospectively assessed by serial slip lamp tests in 517 patients. All had acute lymphoblastic leukaemia, all had been treated by chemotherapy with or without CNS irradiation, and none had received haematopoietic stem cell transplantation. Median ages at last evaluation and follow‐up duration from leukaemia diagnosis were 16·8 and 10·9 years, respectively. Cataract was observed in 21/517 patients (4·1%). Cumulative incidence was 4·5 ± 1·2% at 15 years and reached 26 ± 8·1% at 25 years. CNS irradiation was the only risk factor: prevalence was 11·1% in patients who had received irradiation and 2·8% in those who did not. We did not detect any steroid dose effect: cumulative dose was 5133 and 5190 mg/m² in patients with and without cataract, respectively. Cataract occurrence did not significantly impact quality of life. We conclude that, in the range of steroid dose reported here, the cataract risk proves very low 15 years after treatment without CNS irradiation but an even more prolonged follow‐up is required because of potential very late occurrence.