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H Tilly

Publications and source records attributed to H Tilly.

At least 19 recordsLinked to original sources
PubMed2007

Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas.

Chromosomal translocations joining the immunoglobulin (IG) and MYC genes have been extensively reported in Burkitt's and non-Burkitt's lymphomas but data concerning MYC rearrangements with non-IG partners are scarce. In this study, 8q24 breakpoints from 17 B-cell lymphomas involving non-IG loci were mapped by fluorescence in situ hybridization (FISH). In seven cases the breakpoint was inside a small region encompassing MYC: in one t(7;8)(p12;q24) and two t(3;8)(q27;q24), it was telomeric to MYC whereas in four cases, one t(2;8)(p15;q24) and three t(8;9)(q24;p13) it was located in a 85 kb region encompassing MYC. In these seven cases, partner regions identified by FISH contained genes known to be involved in lymphomagenesis, namely BCL6, BCL11A, PAX5 and IKAROS. Breakpoints were cloned in two t(8;9)(q24;p13), 2.5 and 7 kb downstream from MYC and several hundred kb 5' to PAX5 on chromosome 9, joining MYC to ZCCHC7 and to ZBTB5 exon 2, two genes encoding zinc-finger proteins. In these seven cases, MYC expression measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) was significantly higher when compared to that of patients without 8q24 rearrangement (P=0.006). These results suggest that these rearrangements are the consequence of a non-random process targeting MYC together with non-IG genes involved in lymphocyte differentiation and lymphoma progression.

Adult↗
PubMed2006

Two patterns of chromosomal breakpoint locations on the immunoglobulin heavy-chain locus in B-cell lymphomas with t(3;14)(q27;q32): relevance to histology.

The t(3;14)(q27;q32) is the most common translocation involving BCL6 in B-cell lymphoma. Although this translocation was predominantly associated with diffuse large B-cell lymphoma (DLBCL), recent studies have shown that it can also be found in follicular lymphomas (FL), often associated with a large cell component. To further investigate the relationship that might exist between this translocation and the phenotype of the tumors, we studied 34 lymphomas with a t(3;14)(q27;q32). Twenty cases were DLBCL, 14 FL and most cases, regardless of histology, were negative for the expression of CD10 (26/32, 81%). We identified the IGH switch region involved in the translocation for 32 cases. Our data indicate that in DLBCL most breakpoints involve the switch mu (17/19; 89%), whereas in FL most involve a switch gamma (9/13; 70%) (P=0.0016, Fisher's exact test). This correlation between the histology and the structure of the translocated allele suggests that the lymphomas with Smu and Sgamma translocations may originate from different cells, or that the substituted regulatory regions that come to deregulate BCL6 may affect the presentation of the disease.

Chromosomes, Human, Pair 14↗
PubMed2005

Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte.

PURPOSE: To analyze the long-term outcome of patients included in the Lymphome Non Hodgkinien study 98-5 (LNH98-5) comparing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) in elderly patients with diffuse large B-cell lymphoma. PATIENTS AND METHODS: LNH98-5 was a randomized study that included 399 previously untreated patients, age 60 to 80 years, with diffuse large B-cell lymphoma. Patients received eight cycles of classical CHOP (cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.4 mg/m(2), and prednisone 40 mg/m(2) for 5 days) every 3 weeks. In R-CHOP, rituximab 375 mg/m(2) was administered the same day as CHOP. Survivals were analyzed using the intent-to-treat principle. RESULTS: Median follow-up is 5 years at present. Event-free survival, progression-free survival, disease-free survival, and overall survival remain statistically significant in favor of the combination of R-CHOP (P = .00002, P < .00001, P < .00031, and P < .0073, respectively, in the log-rank test). Patients with low-risk or high-risk lymphoma according to the age-adjusted International Prognostic Index have longer survivals if treated with the combination. No long-term toxicity appeared to be associated with the R-CHOP combination. CONCLUSION: Using the combination of R-CHOP leads to significant improvement of the outcome of elderly patients with diffuse large B-cell lymphoma, with significant survival benefit maintained during a 5-year follow-up. This combination should become the standard for treating these patients.

Aged↗
PubMed2005

Allogeneic stem cell transplantation in second rather than first complete remission in selected patients with good-risk acute myeloid leukemia.

Through two consecutive trials, a policy that considered allogeneic stem cell transplantation (SCT) from a sibling donor in second rather than first complete remission (CR) in selected younger patients with acute myeloid leukemia (AML) with t(8;21)/inv(16) (core binding factor (CBF) group) or a normal karyotype (NN group) was followed by Acute Leukemia French Association (ALFA) centers. The outcome of 92 of these patients in first relapse (32 CBF, 60 NN) was reviewed with the aim of validating this strategy. The presence of an FLT3 internal tandem duplication (ITD) was retrospectively assessed in 50 patients. A total of 61 patients (66%) reached a second CR. Donor availability was an independent prognostic factor for survival in the whole patient population as well as in the CBF subset, but not in NN patients, further supporting this strategy for CBF-AMLs. In NN patients, FLT3-ITD was the main bad-prognosis factor for second CR achievement and survival, leading to consider SCT earlier, at least in FLT3-ITD patients with a donor.

Adult↗
PubMed2005

Clinical and biological relevance of single-nucleotide polymorphisms and acquired somatic mutations of the BCL6 first intron in follicular lymphoma.

Genetic modifications of the BCL6 gene in lymphoma include translocations, deletions, and somatic mutations (SM) of the 5' noncoding region. Three single-nucleotide polymorphisms (SNPs) of the major mutation cluster region (MMC) have been reported, including two substitutions (397G/C, 502G/A) and one deletion (520DeltaT). Clinical and biological relevance of these SNPs are unknown. Based on a case-control study, BCL6 SNPs frequencies were assessed in 97 t(14;18) follicular lymphomas (FL) and in 54 lymphomas with 3q27 rearrangement. Allele frequencies were similar in the FL and controls groups. The 397 G/C genotype was correlated to a higher-grade transformation risk (P=0.02). SM were observed in 39.1% of FL and were characterized by a clustering distribution (hot spots spanning position 420-435, 106-127, and 590-600). No correlation between genotypes or acquired mutational status and BCL6 expression was demonstrated. However, gel mobility-shift assays, using SNPs containing probes show results representative for protein/DNA complexes. This study demonstrates that the first BCL6 intron is a highly variable region as a consequence of both SNP and SM, which may contribute to biology and outcome of FL.

Adult↗
PubMed2004

[Auto-immune manifestations in Non-Hodgkin's lymphoma].

PURPOSE: A wide spectrum of auto-immune manifestations is frequently reported in non-Hodgkin's lymphoma (NHL). The purpose of the review is to describe the immune manifestations observed in NHL, according to their histological subtype and to discuss the current physiopathological hypothesis with their therapeutic relevance. CURRENT KNOWLEDGE AND KEY POINTS: Most of the organs can be targeted by an immune process due to the lymphoproliferative disease: they include skin diseases (paraneoplastic pemphigus, vasculitis, urticaria, acrosyndromes), peripheral and central nervous system involvement (polyneuropathy, multifocal neuropathy), haematological manifestations (immune cytopenia, acquired bleeding disorders), rheumatologic diseases (arthritis, systemic vasculitis, myositis) and renal lesion (cryoglobulinemia, glomerulopathies). A higher prevalence of autoantibodies, such as antinuclear antibodies, Antiphospholipid antibodies, or endomysium antibodies, is observed in NHL but usually without clinical manifestations. In B-cell NHL, clinical and biological immune manifestations are more frequently observed in indolent lymphoma than in aggressive NHL. In T-cell NHL, immune manifestations are frequent and polymorphous, preceding usually the diagnosis of lymphoma. The prognosis value of the immune manifestations in NHL is unclear. Immune manifestations can be also be related to the treatment procedure, including fludarabine, Interferon, autograft or Rituximab. The physiopathology of the immune manifestations may involve auto-antibodies production by natural CD5+ autoreactive B-cell from which is issue the proliferation, a lost of immune tolerance, an abnormality in the Fas/Fas Ligand pathway or a chronic antigenic stimulation. FUTURE PROSPECTS AND PROJECTS: As observed in T-cell lymphoma cases, immunosuppressive treatment can control both immune manifestations and lymphoproliferation, suggesting that lymphoma and auto-immunity may be the two aspects of the same process. The monoclonal antibody anti-CD20 (rituximab), able to suppress the tumoral cells and change the B-cell repertoire is the most promising treatment to cure immune disorders related to NHL. So far, rituximab has been successfully used in mixed cryoglobulinemia and cold agglutinins secondary to NHL.

Antibodies, Antinuclear↗
PubMed2004

Transient anti rhesus alloantibody produced by graft after non-myeloablative allogeneic stem cell transplant.

BACKGROUND: We report the case of a patient who received an allogeneic transplant with peripheral blood compatible ABO, Rhesus mismatched progenitor cells and who developed an asymptomatic transient anti Rhesus alloimmunisation. CASE REPORT: A 56-year-old man with renal cell carcinoma received a non-myeloablative allogeneic PBPC ABO compatible graft from his HLA-identical brother. Graft-versus-host disease prophylaxis consisted of cyclosporine alone. On day + 59, prior to any transfusion, a positive direct antiglobulin test (IgG++, C3d-) was detected. The indirect antiglobulin test (IAT) was considered doubtful, and IAT identification revealed the presence of an active anti Rhesus antibody (anti D specificity) in the patient's serum. This immunisation had no clinical consequence, with no acute hemolytic episode. Further monitoring showed negative antibody screening tests on day + 78. CONCLUSION: To our knowledge this is the first reported case of transient anti Rh (D) allo-immunisation after non-myeloablative allogeneic peripheral blood progenitor cell (PBPC) transplant. The period of occurrence and the specificity of this antibody strongly suggest a donor cell origin.

Carcinoma, Renal Cell↗
PubMed2004

Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab.

BACKGROUND: The incidence of secondary central nervous system (CNS) occurrences in diffuse large-B-cell lymphoma is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The addition of rituximab increases the complete response rate and prolongs event-free and overall survival in elderly patients with such lymphoma. PATIENTS AND METHODS: We analyzed a cohort of 399 elderly patients with lymphoma prospectively treated with eight cycles of CHOP with or without rituximab in order to assess if rituximab decreases the risk of CNS localization. Prophylaxis of CNS disease was not part of the treatment protocol. RESULTS: We observed 20 CNS occurrences: 12 on therapy, four after partial remission and four following complete remission. In three patients, the CNS was the only site of relapse. In a multivariate analysis, increased age-adjusted International Prognostic Index (IPI) was the only independent predictive factor of CNS recurrence. Only three of 20 patients are alive with a follow-up of 24 months. CONCLUSIONS: Rituximab did not influence the risk of CNS occurrence, possibly because of low rituximab diffusion. Direct intrathecal administration of rituximab could overcome this problem. We also confirmed that CNS occurrence is related to IPI as well as very poor prognosis of relapses occurring on therapy.

Aged↗
PubMed2003

[Acute respiratory distress syndrome due to pneumonitis following intrathecal methotrexate administration].

INTRODUCTION: Methotrexate, given orally or systemically, is associated with pneumonitis in 7% of cases. CASE REPORT: This case report describes acute respiratory distress syndrome, due to diffuse pneumonitis, in a patient with malignant non-Hodgkin's lymphoma being treated with combination chemotherapy which included doxorubicin, cyclophosphamide, bleomycin, vindesin and intrathecal methotrexate with G-CSF (filgrastine- Neupogen). The clinical course, the lack of an identifiable infectious agent and the complete response to corticosteroids suggested a drug-induced cause. After ruling out the other chemotherapy agents, methotrexate was considered to be the causal agent. The unusual feature of this case was that pneumonitis developed after intrathecal administration of methotrexate. CONCLUSION: Methotrexate-associated respiratory complications can occur with whichever route the drug is administered.

Anti-Inflammatory Agents↗
PubMed2002

Distribution of BCL2 breakpoints in follicular lymphoma and correlation with clinical features: specific subtypes or same disease?

The t(14;18)(q32;q21) translocation is closely associated with follicular lymphoma (FL), and is routinely assessed with molecular methods exploring BCL2 breakpoints for both diagnosis and minimal residual disease (MRD) monitoring. We and others have previously reported new recurrent breakpoints (3'BCL2 and 5'mcr) which could be easily analyzed. In this study, we characterized the BCL2 breakpoints in 113 untreated patients with t(14;18)-positive FL and correlated their location with the location of JH break and with the clinical features. Breakpoints were respectively located at the major breakpoint region (MBR) in 73 cases (65%), at the minor cluster region (mcr) in 10 cases (9%), at 3'BCL2 in 14 cases (12%) and at 5'mcr in seven cases (6%). Finally, the breakpoint could not be located in nine patients (8%). 5'mcr cases were associated with bulky and high-stage disease, with frequent extranodal involvement and bone marrow infiltration. Survival studies did not show any correlation between breakpoint location and clinical outcome. The joining JH6 segment was the most frequently involved whatever the breakpoint location. In conclusion, unusual BCL2 breakpoints are found in about 20% of newly diagnosed follicular lymphomas and their study should be considered in the investigation of BCL2-JH rearrangement. It was not possible, in this series, to demonstrate any correlation between breakpoint location and either initial characteristics of the disease or survival of the patients.

Adult↗
PubMed2002

Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements.

The BCL-6 gene, located on chromosome 3q27, is implicated in the normal germinal center formation and is frequently rearranged in a wide spectrum of lymphomas. However the links between genetic alterations and expression of the gene are not clearly determined. We established a quantitative RT-PCR assay based on TaqMan technology to quantify BCL-6 mRNA expression in different subtypes of lymphomas and to compare the level of expression in lymphomas characterized by the presence or absence of BCL-6 translocation. Total RNA was extracted from 105 nodes biopsies (35 diffuse large B cell lymphomas (DLBCL); 26 follicle center lymphomas (FCL); 7 marginal zone lymphomas (MZL); 6 mantle cell lymphomas (MCL); 6 chronic lymphocytic leukemia (CLL); 5 T cell lymphomas (TCL); 7 classical Hodgkin diseases (HD); 6 nodal metastasis (NM); and 7 reactive hyperplasia (RH)). BCL-6 gene rearrangement was assessed by Southern blot analysis in 75% of 3q27(+) DLBCL (n = 20) cases and 67% of 3q27(+) cases (n = 10). The highest level of relative BCL-6 expression was observed in FCL (9.12 +/- 7.28) comparatively to the other lymphoma subtypes including DLBCL (2.53 +/- 1.82; P < 0.001), MCL (1.23 +/- 0.73), MZL (1.49 +/- 1.3), HD (1.60 +/- 1.00), TCL (1.75 +/- 1.64), but also RH (3.91 +/- 3.12) or NM (1.95 +/- 2.6). Among the 26 FCL cases, we observed a lower expression in grade 3 (n = 8) than in grade 1/2 (P < 0.001). Conversely, we failed to show any difference between 3q27(+) DLBCL and 3q27(-)DLBCL cases (P = 0.42). Paradoxically BCL-6 expression in 3q27(+) FCL (n = 10) was significantly lower than in 3q27(-) FCL cases (P = 0.035). Finally, this study showed that BCL-6 expression in lymphoma is largely independent of chromosome 3q27 rearrangement and is more related to the histological subtype. Clinical implication and alternative deregulation pathways of BCL-6 expression remain to be determined.

Biopsy↗
PubMed2002

Follicular lymphoma without t(14;18) and with BCL-6 rearrangement: a lymphoma subtype with distinct pathological, molecular and clinical characteristics.

Translocations involving the BCL-6 gene are frequently observed in diffuse large B cell lymphoma, but have rarely been reported in follicular lymphoma (FL). We studied a distinct cohort of FLs with a 3q27/BCL-6 gene rearrangement, but lacking the t(14;18) translocation. In 13/15 cases, translocations involved the 3q27 and the 14q32 regions. All cases displayed a marked follicular growth pattern and, in some instances, a monocytoid component. Tumor cells were CD5(-) CD20(+) CD23(-) CD43(-) BCL-6(+), and in the main CD10 negative (n = 10, 71%) and BCL-2 negative (n = 11, 78%). When compared to 20 typical t(14;18)(+) FLs, the presence of large follicles (P = 0.01) and a CD10(-)/BCL-2(-) phenotype were more frequently observed (P = 0.001) in our cohort. Clonal mutations arising in the BCL-6 first intron were observed in 5/7 cases with evidence of intraclonal heterogeneity, consistent with a germinal center origin. No significant difference was found in comparison to t(14;18)(+) FL regarding age, sex, performance status, bone marrow involvement or overall survival. However, in the 3q27(+) FL group, a stage III/IV disease and a bulky mass were less frequently observed. This study indicates that 3q27(+) FL without t(14;18) translocation have peculiar clinico-pathologic features and may correspond to a rare and distinct subtype of lymphoma originating from the germinal center.

Adult↗
PubMed2001

Outcome is not improved by the use of alternating chemotherapy in elderly patients with aggressive lymphoma.

INTRODUCTION: A prospective randomised study involving 810 elderly patients was conducted in an attempt to compare alternating chemotherapy with conventional first-line chemotherapy in aggressive non-Hodgkin's lymphoma in order to improve prognosis with an acceptable toxicity for elderly patients. PATIENTS AND METHODS: Patients included were 55-69 years old and had at least one adverse prognostic factor. Patients were treated either with ACVBP followed by consolidation (n = 396) or with an alternating regimen (n = 414). This regimen was an association of active drugs in NHL relapsing patients, alternating VIMMM with ACVBP for induction and alternation of VIM and ACVM in consolidation. Eight hundred and sixty-six patients were randomised. After histological review, 810 patients met the inclusion criteria: 396 in arm A, 414 in arm B. RESULTS: The complete response rate after induction was superior for conventional first-line therapy (58.5% vs 48%, P = 0.003) but at the end of treatment, the CR rate was not statistically different (52% vs 48%, P = 0.19). Conventional chemotherapy had a better five-year event-free survival than alternating regimen (33% (95% CI: 30-36%) vs 28% (95% CI: 26-30%), P = 0.0289) but overall survival was not statistically different (40% (CI 95% 38-42%) vs 36% (CI 95% 34-38%), P = 0.068). In this elderly high risk population, the toxicity was very high: 19% in arm A and 26% in arm B died during treatment. CONCLUSION: Alternating regimen did not improve outcome, was less efficient and more toxic.

Aged↗
PubMed2001

Assessing the Cox model assumption as a statistical tool for classifying lymphomas.

INTRODUCTION: The Cox model is widely used in medical research for comparing survival. Lymphomas might exhibit important differences in long-term cure rate despite a similar survival. METHODS: Using log-rank test, we compared event-free survival (EFS), and the survival of 64 patients with mantle cell lymphoma (MCL), 525 patients with follicular lymphoma, and 1136 patients with diffuse centroblastic lymphoma (CB). RESULTS: Although EFS and survival of MCL were significantly shorter than those of follicular lymphoma, checking the validity of the proportional hazards assumption shows that the distribution of rates of events and deaths over time did not differ in MCL and follicular lymphoma. In contrast, the ratios of hazards (events and deaths rates) did not remain constant over time in MCL and CB, because of a decrease in late events and deaths rates in the latter histological type. CONCLUSION: Checking the validity of the Cox model hypothesis might be a useful tool for assessing long-term cure rate in seldom lymphoma subtypes. Despite a short overall survival, MCL should not be considered to be an aggressive lymphoma, in which available chemotherapy may cure a subset of patients.

Adult↗
PubMed2001

Tumor necrosis factor alpha release is a major biological event associated with rituximab treatment.

INTRODUCTION: In patients with low-grade non-Hodgkin's lymphoma, rituximab (MabThera) produces infusion-related toxicity, including fever, rigors, and chills in greater than 50% of those treated. The majority of these reactions are grade 1 or 2. MATERIALS AND METHODS: In the GELA study LNH98-5, a total of 400 elderly patients with previously untreated diffuse large B-cell lymphoma were randomized to treatment with CHOP or with rituximab plus CHOP (R-CHOP). In a detailed investigation of biological events which may be associated with adverse reactions specific to rituximab infusion, a subgroup of 55 patients (26 in the CHOP group and 29 in the R-CHOP group) were selected for measurement of several biological parameters at baseline and at 1, 4 and 8 h (H1, H4 and H8, respectively) after commencing therapy. For 27 patients, measurements included cytokine and complement levels. RESULTS: Baseline demographic and disease characteristics were similar for patients in both treatment groups. Compared with the CHOP treatment group, patients in the R-CHOP group had significantly higher post-treatment changes in neutrophil, lymphocyte, and monocyte counts, LDH levels, C3a levels, and TNF-alpha levels. In the R-CHOP group, neutrophil levels increased at H4 (P<0.05), lymphocyte levels decreased at H1 (P<0.05), H4 (P<0.001) and H8 (P<0.05), monocytes levels decreased at H1 (P<0.01), LDH levels increased at H4 (P<0.05) and H8 (P<0.01), and C3a decreased at H1 (P<0.01). The most statistically significant changes were observed for TNF-alpha levels: Mean values of TNF-alpha increased more than 250% at H1 and H4 and were still increased by 170% at H8 (P<0.001 at all timepoints). Since only six of the 55 evaluated patients had severe adverse events, it was not possible to correlate severe toxicity with these biological variations. CONCLUSION: This analysis demonstrates that rituximab infusion was rapidly followed by activation of complement, B-lymphocyte cytolysis, and TNF-alpha release.

Aged↗
PubMed2000

Chromosome abnormalities in peripheral T-cell lymphoma.

Data on chromosomal abnormalities in T-cell lymphomas are very rare as compared with those reported in B-cell lymphomas. We performed a cytogenetic study in 71 untreated patients with peripheral T-cell lymphoma, classified according to the criteria of the REAL classification. Fifty-seven patients (80.3%) had abnormal clones, whereas 9 karyotypes (12.7%) showed only normal metaphases; 5 karyotypes (7%) could not be analyzed. Recurrent numerical chromosomal abnormalities comprised +3 (21%), +5 (15.7%), +7 (15.5%), +21 (14%), -13 (14%), +8 (12.2%), +19 (12.2%), -10 (10.5%), and -Y (9% of male patients). Chromosomes involved in structural rearrangements were chromosome 6 (31.5%), mainly due to 6q deletions (19.2%), 1q (22.8%), 7q (22.8%), 9p (19.4%), 9q (19.2%), 4q (19.2%), 3q (19.2%), 2p (17.5%), 1p (17.5%), and 14q (17%). Trisomies 3 and 5 mainly correlated with angioimmunoblastic T-cell lymphoma. Isochromosome 7q, associated with trisomy 8, was present in two cases of hepatosplenic gamma/delta T-cell lymphoma. Rearrangements involving the location of T-cell receptor genes were rarely observed (chromosome band 7q35 was rearranged only in three cases, 14q11 in two cases, and 7p15 in none). No correlation could be found between the cytogenetic findings and histologic subgroup or clinical outcome in these patients. Further studies are needed to understand the significance of these abnormalities in peripheral T-cell lymphoma, and to reach a better evaluation of histologic correlations, as many differences persist between the two major classification systems, KIEL and REAL.

Adult↗