[Primary central nervous system lymphoma following immunotherapy for metastatic melanoma]. / Lymphome cérébral primitif après immunothérapie d'un mélanome métastatique.

BACKGROUND: Anti-PD-1 and anti-CTLA-4 monoclonal antibodies are used in melanoma, while anti-PD-1 are also used in Hodgkin's lymphoma. Primary central nervous system lymphoma is a rare form of non-Hodgkin's lymphoma with few effective treatments. However, several recent studies have reported multiple cases of non-Hodgkin's lymphoma and primary central nervous system lymphoma treated by anti-PD-1 antibodies with favourable responses. PATIENTS AND METHODS: This study focuses on the case of a 59-year-old man with metastatic melanoma treated by immunotherapy (anti-CTLA-4 followed by anti-PD-1). He underwent 28 courses of therapy with pembrolizumab. Treatment was stopped after clinical and radiological remission. The patient presented left hemiparesis and a primary central nervous system lymphoma was diagnosed two months after discontinuation of immunotherapy. He started urgent high-dose methotrexate chemotherapy but without significant results. Despite second-line chemotherapy with R-ICE (rituximab-ifosfamide, carboplatin and etoposide), the patient died. DISCUSSION: Several hypotheses may be advanced regarding a possible relationship between immunotherapy and the occurrence of this primary central nervous system lymphoma. The lymphoma may have been pre-existing and controlled by immunotherapy, but progressing rapidly after treatment, or it may have been induced by the immunotherapy. However, immunotherapy may have played no role; the relationship between melanoma and lymphoma is well known. CONCLUSION: While immunotherapy cannot be unequivocally incriminated in primary central nervous system lymphoma, this case raises many questions about the imputability of immunotherapy in the occurrence of secondary cancers, including lymphomas.

Combination of baseline FDG PET/CT total metabolic tumour volume and gene expression profile have a robust predictive value in patients with diffuse large B-cell lymphoma.

PURPOSE: This study evaluated the predictive significance of total metabolic tumour volume (TMTV) measured on baseline FDG PET/CT and its value in addition to gene expression profiling using a new method of gene analysis (rapid reverse transcriptase multiplex ligation-dependent probe amplification assay, RT-MLPA) in patients with diffuse large B-cell lymphoma treated with R-CHOP or R-CHOP-like chemotherapies. METHODS: The analysis included 114 patients. TMTV was measured using a 41% SUVmax threshold and tumours were classified into GCB or ABC subtypes according to the RT-MLPA assay. RESULTS: The median follow-up was 40 months. the 5-year progression-free survival (PFS) was 54% and the 5-year overall survival (OS) was 62%. The optimal TMTV cut-off value was 261 cm3. In 59 patients with a high TMTV the 5-year PFS and OS were 37% and 39%, respectively, in comparison with 72% and 83%, respectively, in 55 patients with a low TMTV (p = 0.0002 for PFS, p < 0.0001 for OS). ABC status was significantly associated with a worse prognosis. TMTV combined with molecular data identified three groups with very different outcomes: (1) patients with a low TMTV whatever their phenotype (n = 55), (2) patients with a high TMTV and GCB phenotype (n = 33), and (3) patients with a high TMTV and ABC phenotype (n = 26). In the three groups, 5-year PFS rates were 72%, 51% and 17% (p < 0.0001), and 5-year OS rates were 83%, 55% and 17% (p < 0.0001), respectively. In multivariate analysis, TMTV, ABC/GCB phenotype and International Prognostic Index were independent predictive factors for both PFS and OS (p < 0.05 for both). CONCLUSIONS: This integrated risk model could lead to more accurate selection of patients that would allow better individualization of therapy.

BCL2 expression but not MYC and BCL2 coexpression predicts survival in elderly patients with diffuse large B-cell lymphoma independently of cell of origin in the phase 3 LNH03-6B trial.

BACKGROUND: Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial. PATIENTS AND METHODS: We evaluated 285 paraffin-embedded samples from patients (60-80 years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples. RESULTS: The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81). CONCLUSIONS: Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival. CLINICAL TRIAL NUMBER: NCT00144755.

The costimulatory molecule CD70 is regulated by distinct molecular mechanisms and is associated with overall survival in diffuse large B-cell lymphoma.

In diffuse large B-cell lymphomas (DLBCL), a recurrent deletion of the 19p13 region has recently been described. CD70 and TNFSF9 genes are suspected tumor suppressor genes, but previous studies suggest an oncogenic role for CD70. Therefore, we studied the consequences of variation in CD70 copy number and epigenetic modifications on CD70 expression. Copy-number variation was investigated in 144 de novo DLBCL tissues by comparative genomic hybridization array and quantitative multiplex PCR. Gene expression was assessed by quantitative RT-PCR, and CD70 promoter methylation was determined by pyrosequencing. The 19p13.3.2 region was deleted in 21 (14.6%) cases, which allowed the minimal commonly deleted region of 57 Kb that exclusively includes the CD70 gene to be defined. Homozygous deletions were observed in four (2.7%) cases, and acquired single-nucleotide variations of CD70 were detected in nine (6.3%) cases. CD70 was highly expressed in both germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL compared to normal tissue, with distinct molecular mechanisms of mRNA expression regulation. A gene dosage effect was observed in the GCB subtype, whereas promoter methylation was the predominant mechanism of down regulation in the ABC subtype. However, high CD70 expression levels correlated to shorter overall survival in both the GCB (P = 0.0021) and the ABC (P =0.0158) subtypes. In conclusion, CD70 is targeted by recurrent deletions, somatic mutations and promoter hypermethylation, but its high level of expression is related to an unfavorable outcome, indicating that this molecule may constitute a potential therapeutic target in selected DLBCL.

Prognostic value of the combination of volume, massiveness and fragmentation parameters measured on baseline FDG pet in high-burden follicular lymphoma.

The prognostic value of radiomic quantitative features measured on pre-treatment 18F-FDG PET/CT was investigated in patients with follicular lymphoma (FL). We conducted a retrospective study of 126 FL patients (grade 1-3a) diagnosed between 2006 and 2020. A dozen of PET/CT-derived features were extracted via a software (Oncometer3D) from baseline 18F-FDG PET/CT images. The receiver operating characteristic (ROC) curve, Kaplan-Meier method and Cox analysis were used to assess the prognostic factors for progression of disease within 24 months (POD24) and progression-free survival at 24 months. Four different clusters were identified among the twelve PET parameters analyzed: activity, tumor burden, fragmentation-massiveness and dispersion. On ROC analyses, TMTV, the total metabolic tumor volume, had the highest AUC (0.734) followed by medPCD, the median distance between the centroid of the tumors and their periphery (AUC: 0.733). Patients with high TMTV (HR = 4.341; p < 0.001), high Tumor Volume Surface Ratio (TVSR) (HR = 3.204; p < 0.003) and high medPCD (HR = 4.507; p < 0.001) had significantly worse prognosis in both Kaplan-Meier and Cox univariate analyses. Furthermore, a synergistic effect was observed in Kaplan-Meier and Cox analyses combining these three PET/CT-derived parameters (HR = 12.562; p < 0.001). Having two or three high parameters among TMTV, TVSR and medPCD was able to predict POD24 status with a specificity of 68% and a sensitivity of 75%. TMTV, TVSR and baseline medPCD are strong prognostic factors in FL and their combination better predicts disease prognosis.

Effect of single-unit transfusion in patients treated for haematological disease including acute leukemia: A multicenter randomized controlled clinical trial.

BACKGROUND: Retrospective studies in hematological unit have suggested that single red blood cell (1-RBC) unit transfusion policy may reduce the number of RBC used without negative clinical impact. METHOD: Acute leukemia patients requiring intensive chemotherapy or patients receiving autologous or allogeneic transplantation were randomly assigned to receive either single RBC (1-RBC arm) or double RBC (2-RBC arm) per transfusion with a hemoglobin trigger of 8 g/dL. The primary composite endpoint was the percentage of patients experiencing serious complications, such as a non-hematological adverse event grade ≥ 3 or intensive care admission or death. FINDINGS: A total of 981 and 592 RBC transfusions were required in the 1-RBC arm (n = 125) and the 2-RBC arm (n = 120), respectively. The mean pre-transfusion hemoglobin levels were 7.49 ± 0.83 g/dL in the 1-RBC arm and 7.46 ± 0.67 g/dL in the 2-RBC arm (p = 0.275). The predefined non-inferiority criteria was achieved with 28/125 patients reaching the primary endpoint in the 1-RBC arm (22.4 %) and 28/120 patients in the 2-RBC arm (23.3 %) (Risk difference 0.009; 95 %, Confidence interval [-0.0791 to 0.0978], p = 0.021). The median (IQR) of RBC units transfused per patient was 7 (4-12) in the 1-RBC arm and 8 (4-12) in 2-RBC arm. Hemoglobin levels at discharge were also comparable in both arms. INTERPRETATION: The results of this trial indicate that a single RBC transfusion policy is not inferior to a double RBC transfusion policy for patients receiving a bone marrow transplant or intensive chemotherapy in a hematological intensive care unit. However, the single RBC transfusion policy did not reduce the number of RBC units transfused per stay. FUNDING: This trial was funded by a grant from the French Ministry of Health.

Waved aCGH: to smooth or not to smooth.

Array-based comparative genomic hybridization (aCGH) is a powerful tool to detect genomic imbalances in the human genome. The analysis of aCGH data sets has revealed the existence of a widespread technical artifact termed as 'waves', characterized by an undulating data profile along the chromosome. Here, we describe the development of a novel noise-reduction algorithm, waves aCGH correction algorithm (WACA), based on GC content and fragment size correction. WACA efficiently removes the wave artifact, thereby greatly improving the accuracy of aCGH data analysis. We describe the application of WACA to both real and simulated aCGH data sets, and demonstrate that our algorithm, by systematically correcting for all known sources of bias, is a significant improvement on existing aCGH noise reduction algorithms. WACA and associated files are freely available as Supplementary Data.

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.

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.

Typhlitis as a complication of alemtuzumab therapy.

Alemtuzumab is a humanized monoclonal antibody directed against lymphocytes through the CD-52 receptor, an antigen being found on > 95% of peripheral blood lymphocytes and monocytes, and to a smaller extent on granulocytes. It is an effective immunotherapeutic agent in patients with malignancies such as non-Hodgkin lymphoma, B cell chronic lymphocytic leukemia and T cell pro- lymphocytic leukemia. Adverse side effects are increasingly recognized in patients receiving alemtuzumab, mainly including fever, rigors, nausea/vomiting, skin rash; other severe alemtuzumab-related reactions have also been described, such as lymphopenia and neutropenia leading to both opportunistic (e.g. cytomegalovirus) and non-opportunistic infections. Digestive complications have more rarely been described, i.e.: gastroenteritis and peritonitis. We recently observed a case of particular interest as the patient with T cell prolymphocytic leukaemia treated with alemtuzumab, exhibited symptomatic reactivation of CMV infection and developed subsequently typhlitis.

EZH2 alterations in follicular lymphoma: biological and clinical correlations.

The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36-0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.

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.

Quantitative two-dimensional echocardiography in massive pulmonary embolism: emphasis on ventricular interdependence and leftward septal displacement.

In 14 patients requiring aggressive therapy for circulatory failure resulting from massive pulmonary embolism, hemodynamic and two-dimensional echocardiographic data were obtained at bedside (acute phase) and again after circulatory improvement (intermediate phase) and during recovery. The acute stage was characterized by a low cardiac output state despite inotropic support (cardiac index 1.9 +/- 0.6 liters/min per m2) associated with increased right atrial pressure (12.4 +/- 4.2 mm Hg), increased right ventricular end-systolic and end-diastolic area (12.4 +/- 3.4 and 15.4 +/- 4.1 cm2/m2, respectively) and reduced right ventricular fractional area contraction (20.1 +/- 8.6%). Two-dimensional echocardiography also revealed interventricular septal flattening at both end-systole and end-diastole and markedly decreased left ventricular end-diastolic dimensions. Left ventricular fractional area contraction remained normal. Hemodynamic improvement occurred during the intermediate phase as shown by restoration of cardiac index (3.3 +/- 0.6 liters/min per m2), decrease in right atrial pressure (8.3 +/- 4.8 mm Hg), reduction in right ventricular end-systolic area (9.0 +/- 3.6 cm2/m2 at the intermediate stage and 6.1 +/- 1.8 cm2/m2 at recovery) and end-diastolic area (10.5 +/- 3.6 cm2/m2 at the intermediate stage and 8.9 +/- 2.9 cm2/m2 at recovery) and improvement in right ventricular fractional area contraction (31.5 +/- 16.4%). The interventricular septum progressively returned to a more normal configuration at both end-systole and end-diastole, and left ventricular diastolic dimension steadily increased. It is concluded that circulatory failure secondary to massive pulmonary embolism was mediated through a profound decrease in left ventricular preload, resulting from both pulmonary outflow obstruction and reduced left ventricular diastolic compliance.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterisation of BCL2-JH rearrangements in follicular lymphoma: PCR detection of 3' BCL2 breakpoints and evidence of a new cluster.

Follicular lymphomas (FL) are closely associated with a t(14;18)(q32;q21) translocation, leading to a bcl2 protein over-production. This translocation probably constitutes a very early step in the development of the disease. Besides the cytogenetic assay, t(14;18) detection can be achieved using either Southern blot or polymerase chain reaction (PCR). Since 1990, several publications have reported discrepancies between the results of cytogenetic and molecular analysis of t(14;18). Using methods able to explore long DNA fragments, several authors reported breakpoints located outside the usual breakpoint regions. However, these techniques cannot be easily used in routine. The aim of this study was to develop a simple PCR assay to amplify rearrangements usually not detected in FL. We selected a group of 83 patients with a t(14;18) on cytogenetic analysis: using usual probes and primers, 54/83 (65.1%) showed a MBR rearrangement, 7/83 (8.4%) were mcr positive and 22/83 (26.5%) remained negative. Among these 22 rearrangements, nine could be detected using this new PCR assay. Four breakpoints were located in a 20 bp area suggesting a recurrent breakpoint cluster close to an Alu repetitive sequence. Finally, remaining negative cases (13/83, 15.6%) suggest that other breakpoints are located between the MBR and mcr regions.

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.

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.

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.

[Auto-immune manifestations in Non-Hodgkin's lymphoma]. / Manifestations dysimmunitaires associées aux lymphomes.

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.

Transformation of an Unclassified Myeloproliferative Neoplasm with a Rare BCR-JAK2 Fusion Transcript Resulting from the Translocation (9;22)(p24;q11).

BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1 negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated.

Massive pulmonary embolism with circulatory failure: survival following sixty hours' support with a membrane lung.

A 62-year-old man had circulatory failure from massive pulmonary embolism following a road accident. Despite intensive therapy including urokinase infusion, inotropic drugs, and mechanical ventilation, the patient's circulatory status deteriorated. When it became impossible to maintain the mean systemic arterial pressure above 50 mm. Hg and the cardiac index above 1 L. per minute per square meter, circulatory support by partial cardiopulmonary bypass with a membrane lung was begun. Acute circulatory failure and acute pulmonary hypertension were promptly reduced by this procedure, and patient's status necessitated only intravenous heparin infusion and mechanical ventilation. After 60 hours of bypass the patient was weaned from the membrane lung, and 1 month later he was discharged from the hospital.