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Primary pulmonary lymphoma is a rare entity. Furthermore, simultaneous bilateral spontaneous pneumothorax (SBSP) is a very rare condition which is often related to therapeutic complications. We present, to the best of our knowledge, the first case of primary pulmonary mucosa associated lymphoid tissue (MALT) lymphoma revealed by SBSP. A 50-year-old female was diagnosed with organizing pneumonia. One month later, she presented with sudden chest pain and shortness of breath due to SBSP. Bilateral chest tubes were inserted. A scan- guided right lung biopsy led to the diagnosis of primary pulmonary MALT lymphoma. The patient was treated with R-CHOP chemotherapy. The association between lymphoma and pneumothorax is extremely rare, often related to therapeutic toxicity. We report the case of SBSP as the first manifestation of primary pulmonary MALT lymphoma.

Lysosomial diseases and autoimmune diseases are systemic disorders. Their clinical manifestations can overlap with the broad spectrum of one another. Their association has been rarely reported. We report a new case of systemic lupus erythematous (SLE) associated to antiphospholipid syndrome (APS) and Hashimoto thyroiditis occurring in Niemann-Pick disease (NPD) type B patient. A 42-year-old woman with a familial history of NPD was diagnosed with a NPD type B at the age of ten. Twenty years later (2008), she complained of inflammatory arthralgia with acute dyspnea. She was diagnosed with SLE (according to ACR criteria) and Hashimoto disease with positive IgG anti-cardiolipin and IgA anti-beta2 glycoprotein. In 2018, she presented a left segmental pulmonary embolism. Antiphospholipid syndrome was retained. She was treated with steroids, hydroxychloroquine, anticoagulation therapy and levothyroxine. Her SLE treatment was re-enforced by cyclophosphamide because of corticosteroid dependence and recurrent hemolytic crises.

Mutations are responsible for familial cancer syndromes which account for approximately 5–10 % of all types of cancers. Familial cancers are often caused by genetic alterations occurring either in tumor suppressor or genomic stability genes such as TP53. In this study, we have analyzed the TP53 gene by direct sequencing approach, in a panel of 18 Tunisian familial hematological malignancies cases including several forms of leukemia, lymphoma and myeloid syndrome and 22 cases of sporadic acute leukemia. In one familial case diagnosed with acute lymphoblastic leukemia, we reported an intronic substitution 559+1 G>A which may disrupt the splice site and impact the normal protein function. Most of the deleterious mutations (Arg158His; Pro282Trp; Thr312Ser) as classified by IARC data base, were commonly reported in ALL cases studied here. The cosegregation of the two variants rs1042522 and rs1642785 was observed in most patients which may be in favor of the presence of linkage disequilibrium. The most defined TP53 mutations found here were identified in acute lymphoblastic leukemia context whereas only 3 % of mutations have been in previous studies. The cosegregation of the two recurrent variant rs1042522 and rs1642785 should be further confirmed.

Isocitrate dehydrogenase IDH 1 and IDH 2 mutations were reported in several cancer forms, especially in hematological malignancies, but were never been investigated in familial aggregation. The aim of this study is to determine whether germline isocitrate dehydrogenase genes mutations are involved. We targeted IDH1 and IDH2 genes in 104 familial cases belonging to Tunisian and French populations, including several forms of hematological malignancies and cosegregated solid tumors. We report one IDH1 variant: c.315 G>T, p.Gly105Gly in 15 % of cases, which was assigned to the worst outcome in several studies. Three IDH2 variants were found, among them, one intronic substitution c.543+45 G>A (rs142033117) and two new variants not previously described: c.389 A>T, p.Lys130Met and c.414 T>C, p.Thr138Thr. The p.Lys130Met was found in one case diagnosed with Waldenstrom’s disease with familial history of cancer. The enrolled in silico analysis, the functional study, and the absence of this variant in control population strengthen the hypothesis of its deleterious effect. From an extended number of candidate genes analyzed in familial hematological malignancies, IDH2 might be considerably involved since we reported a potential damaging effect.

Familial aggregation of hematological malignancies has been reported highlighting inherited genetic predisposition. In this study, we targeted four candidate genes: JAK2 and RUNX1 genes assuring a prominent function in hematological process and CBL and NPM1 as proto-oncogenes. Their disruption was described in several sporadic hematological malignancies. The aim of this study is to determine whether JAK2, CBL, RUNX1, and NPM1 germline genes mutations are involved in familial hematological malignancies. Using direct sequencing, we analyzed JAK2 (exons 12 and 14); CBL (exons 7, 8 and 9); NPM1 (exon 12) and the entire RUNX1 in 88 independent families belonging to Tunisian and French populations. Twenty-one sporadic acute leukemias were included in this study. We reported a heterozygous intronic c.1641 + 6 T > C JAK2 variant (rs182123615) found in two independent familial cases diagnosed with gastric lymphoma and Hodgkin lymphoma. The in silico analysis suggested a potential impact on splicing, but the functional splicing minigene reporter assay on rs182123615 variant showed no aberrant transcripts. In one sporadic acute myeloblastic leukemia, we reported an insertion 846 in. TGTT in exon 12 of NPM1 gene that may impact the normal reading frame. The rs182123615 JAK2 variant was described in several contexts including myeloproliferative neoplasms and congenital erythrocytosis and was supposed to be pathogenic. Through this current study, we established the assessment of pathogenicity of rs182123615 and we classified it rather as rare polymorphism.

International audience; Data are limited in developing countries regarding the clinicopathologic features and response to therapy of chronic myeloid leukemia (CML) in the era of imatinib (IM). The objective of this study is to report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400 mg daily as frontline therapy, and to determine imatinib's efficacy and safety. From October 2002 to December 2014, 410 CML patients were treated with IM in six Tunisian departments of hematology. Response (hematologic, cytogenetic, and molecular responses) and outcome-overall survival (OS), event-free survival (EFS), and progression-free survival (PFS)-were evaluated. The following prognostic factors were analyzed for their impact on the European leukemia net (ELN) response, OS, EFS, and PFS at 5 years: age, sex, leukocyte count, Sokal score, European Treatment and Outcome Study (EUTOS) score, CML phase, time to starting IM, and impact of adverse events. The median age was 45 years (3-85 years). Two hundred ten (51.2%) patients were male. Splenomegaly was present in 322 of the 410 (79%). Additional cytogenetic abnormalities were encountered in 25 (6.3%) patients. At diagnosis, 379 (92.4%) patients were in CP, 31 (7.6%) were in AP. The Sokal risk was low in 87 (22.5%), intermediate in 138 (35.7%), and high in 164 patients (41.9%). The EUTOS risk was low in 217 (74%), and high in 77 (26%) patients. The rates of cumulative complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4/5 log (MR4.5) in CP/AP-CML patients were 72, 68.4, and 46.4%, respectively. The median time to reach CCyR, MMR, and MR4.5 was 6 months (3-51), 18 months (3-72), and 24 months (3-100), respectively. According to the ELN criteria, optimal, suboptimal response, and failure were noted in 206 (51.8%), 61 (15.3%), and 125 (31.4%) patients, respectively. Five-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) were 81, 90, and 90%, respectively. By multivariate analysis, AP, high EUTOS risk, and baseline WBC ≥ 150G/l remained independent predictive factors of non-optimal response to IM. The adverse events (AE) of IM were moderate and tolerable. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The frontline use of second-generation tyrosine kinase inhibitor (TKI) is expected to improve the results of the first-line treatment of these high-risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries.

The study was carried out to investigate the effects of inhaled Mg alone and associated with F in the treatment of bronchial hyperresponsiveness. 43 male Wistar rats were randomly divided into four groups and exposed to inhaled NaCl 0.9%, MeCh, MgSO4 and MgF2. Pulmonary changes were assessed by means of functional tests and quantitative histological examination of lungs and trachea. Results revealed that delivery of inhaled Mg associated with F led to a significant decrease of total lung resistance better than inhaled Mg alone (p < 0.05). Histological examinations illustrated that inhaled Mg associated with F markedly suppressed muscular hypertrophy (p = 0.034) and bronchoconstriction (p = 0.006) in MeCh treated rats better than inhaled Mg alone. No histological changes were found in the trachea. This study showed that inhaled Mg asso- ciated with F attenuated the main principle of the central components of changes in MeCh pro- voked experimental asthma better than inhaled Mg alone, potentially providing a new therapeutic approach against asthma.

Case We describe a 55-year-old woman suffering from Sezary syndrome, had undergone chemotherapy consisting of cycles of cyclophosphamide and prednisone. 10 months later, she noticed a progressively increasing reticulated generalised pigmentation in the face, trunk and the extremities. Cylophosphamide was withdrawn. The hyperpigmentation began to clear slowly and gradually after 7 months. One year after cyclophosphamide withdrawal and facing the relapse of the disease, and its transformation to a large T cell lymphoma a mini CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) protocol was held, leading to a remarkable aggravation of the pigmentation. Conclusion This adverse drug reaction to cyclophosphamide is peculiar by its localization and distribution and should be known in order not to confuse with other dermatosis.

We report four cases of non-Hodgkin lymphoma involving the nasopharynx. Clinical, radiological, histological and treatment modalities are described. The four patients were male and aged 20, 42, 71 and 77 years. The symptoms were nasal obstruction with epistaxis in three cases and a cervical node in the fourth case. The histological type was a non-Hodgkin lymphoma of phenotype B with large cells CD20+ in the four cases. The treatment consisted in radiotherapy and chemotherapy.

Although light is accepted as the dominant zeitgeber for entrainment of the human circadian system, reports that some totally blind individuals appear entrained to the 24-h day have suggested that non-photic stimuli may also be effective circadian synchronizers in humans. We investigated the sleep and rest–activity patterns of 22 blind subjects (17 teenagers and 5 adults) in their natural environmental conditions. Sleep disorder was assessed using three questionnaires and daily activity was monitored using the actiwatch activity monitoring system. Blind adults showed a significantly decreased “actual sleep time” and “sleep efficiency”. In the blind adult and control adult groups the actigraphic estimates of “sleep latency” and “fragmentation index” increased significantly. The interdaily stability was similar in the four age groups, while blind and control adults showed a significant decrease in relative amplitude. The present study suggests that age might have more effects in the alteration of sleep–wake...

From January 1997 to December 2005, 337 patients with aggressive non Hodgkin's lymphoma were treated with one of the two successive multicentric non randomized protocols established in Tunisia. The mean age was 53 years. Most patients had diffuse large cell lymphoma with B phenotype in 86% and T in 14%. The performance status was 2 or 3 in 34% of cases. The LDH were elevated in 74% of cases. Advanced disease (III or IV stage) was noted in 59% of cases and 10% had a tumoral mass greater than 10 cm. According to the international prognostic index (IPI) adjusted to age, we distinguish four groups: group 1 (0 factor and age 70 years). The patients of group 1 (N = 47) received 3 courses of CHOP regimen followed by irradiation. The patients of group 2 (N = 160) received 4 courses of ACVBP regimen (+ rituximab for 21 patients) followed by consolidation (N = 92) or peripheral blood progenitor cell transplantation (N = 20). The patients of group 3 (N = 61) received 8 courses of CHOP regimen (+ rituximab for 20 patients). The patients of group 4 (N = 69) received 6 courses of mini-CEOP regimen (N = 48) or 6 courses CVP regimen (N = 21). The 4-year overall survival was 56% and the 4-year event free survival was 49%.

The mechanisms for the formation of variant Philadelphia (Ph) translocations that occur in 5-10% of patients with chronic myeloid leukemia (CML) are not fully characterized. Studies on the prognosis of these variant translocations have yielded conflicting results, especially regarding imatinib outcome and the status of deletions on the derivative chromosome 9. To shed light on these controversial subjects, we sought to analyze all variant translocation cases presented at diagnosis and identified in our institution between the years 2001 and 2008. Of 336 CML patients who presented at diagnosis and were studied by conventional cytogenetics and fluorescence in situ hybridization (FISH), 25 patients (7.44%) exhibited variant Ph-rearrangements. All chromosomes could be implicated in variant Ph rearrangements, with 32 breakpoints defined. Their distribution was located preferentially in the CG-richest regions of the genome. Deletions on der(9) were observed in 15 of the 25 cases (60%), a greater proportion in typical Ph translocations (12-15%). Both one- and two-step mechanisms were encountered in our series, as well as multiple-step mechanisms, which originate more complex rearrangements. Higher prevalence was observed for the two-step mechanism (56%). Proper assessment of the prognostic significance of variant translocations requires better categorization of these translocations based on their mechanisms of genesis and 9q34 deletion status.

Cytogenetic analysis was performed on 224 bone marrow (BM) of Tunisian patients with de novo myelodysplastic syndrome (MDS) at our institution from January 1993 to December 2006. According to French-American-British (FAB) criteria, there were 36% of patients with refractory anaemia (RA), 26% with refractory anaemia with excess of blasts (RAEB), 10% with refractory anaemia with ringed sideroblasts (RARS), 12% with chronic myelomonocytic leukaemia (CMML), 9% refractory anaemia with excess of blasts in transformation (RAEB-t) and 7% of unclassified MDS. A clonal chromosomal abnormality was observed in 51% of the patients. The most frequent karyotypic change was 5q- in 30 cases (13%), followed by -7/7q- in 17 cases (8%), del(12p) in 8 cases (4%), del(20q) and trisomy 8 in 7 cases each (3%), i(17q) in 2 cases (1%) and -y in only one case (0.4%). This is the first large comparative series of MDS from an Arab country, with cytogenetic analysis showing haematological and cytogenetic features similar to those of MDS population of European or mixed European-subsaharian African origin (like Brazil), but different from those seen in Eastern populations.

Background Diffuse large B-cell lymphoma (DLBCL) exhibits heterogeneous clinical features and a marked variable response to treatment. Patients and methods We investigated the prognostic significance of the methylation status of DAPK, GSTP1, P14, P15, P16, P33, RB1, SHP1, CDH1, APC, BLU, VHL, TIMP3, and RASSF1A genes in 46 DLBCL specimens from Tunisian patients. Methylation status of each gene was correlated with clinicopathological parameters including the International Prognostic Index (IPI), the germinal center immunophenotype, and response to treatment and survival. Overall survival (OS) and disease-free survival (DFS) rates were calculated by the Kaplan–Meier method and differences were compared with the log-rank test. Results Hypermethylation of SHP1 was associated with elevated lactate dehydrogenase level (P = 0.031). P16 and VHL were frequently hypermethylated in patients with high IPI scores (P = 0.006 and 0.004) and a performance status of two or more (P = 0.007 and 0.047). In addition, hypermethylation of P16 was significantly associated with advanced clinical stages and B symptoms (P = 0.041 and 0.012). Interestingly, hypermethylation of DAPK was significantly correlated with resistance to treatment (P = 0.023). With regard to survival rates, promoter hypermethylation of DAPK, P16, and VHL were significantly associated with shortened OS (P = 0.003, 0.001, and 0.017, respectively) and DFS (P = 0.006, 0.003, and 0.046, respectively). In multivariate analysis, hypermethylation of DAPK remains an independent prognostic factor in predicting shortened OS (P = 0.001) and DFS (P = 0.024), as well as the IPI and the germinal center status. Conclusions This study demonstrates that DLBCLs with hypermethylated P16, VHL, DAPK, and SHP1 commonly show a biologically aggressive phenotype and worse prognosis. Interestingly, hypermethylation of DAPK was found to be an independent prognostic factor that may be used in conjunction with the conventional prognostic factors such as the IPI and the germinal center status.

Cytogenetic studies were performed on 117 Tunisian patients with de novo myelodysplastic syndromes (MDS). According to the French–American–British (FAB) criteria 40 patients presented with refractory anaemia (RA, 34%), eight with refractory anaemia with ringed sideroblasts (RARAS, 7%), 19 with refractory anaemia with excess of blasts (RAEB, 16%), 16 with refractory anaemia with excess of blasts in transformation (RAEB-t, 14%), 18 had chronic myelomonocytic leukaemia (CMML, 15%) and 16 unclassifiable MDS (14%). Seventy-five were men and forty-two were women. Five were children and 112 were adults with a median age of 58 years. Fifty-five per cent of the patients presented clonal chromosome abnormalities. Rates of abnormality varied from one FAB subtype to the other: 55% in RA, 75% in RARAS, 63% in RAEB, 75% in RAEB-t and 28% in CMML. The most frequent chromosome abnormalities were del(5q) (22 cases), monosomy 7 (12 cases), del(12p) (6 cases), and trisomy 8 (5 cases). Rare abnormalities were also found: ring of chromosome 12 and trisomy 15. Conventional cytogenetics remains the basic technique in identifying chromosomal abnormalities associated with MDS.

Background: High dose Melphalan (HDM) and autologous stem cell transplantation (ASCT) is a standard care for Myeloma ≤ 65 years. Studies have demonstrated that depth of response prior to ASCT does not impact outcome post ASCT, e.g. solely depth of response post ASCT matters. However, with improving induction regimens, the questions remains whether patients achieving a deeper response at completion of induction would not perform better post ASCT. ASCT can only be performed in Tunisia if newly diagnosed Multiple Myeloma (NDMM) achieves at least PR; we therefore sought to report the national Tunisian experience. Patients and Methods: NDMM aged ≤65 years received three cycles of Thalidomide (200mg daily) and Dexamethasone, followed by HDM and ASCT.52% received maintenance therapy for 12 months with Thalidomide, from 3 months post transplantation. Non responders to TD induction were salvaged with Lenalidomide or Bortezomib-based regimen. The response was assessed based on IMWG response criteria. The study is performed in ITT. Results: 202 consecutive pts were included between April 2012 and December 2014. The median age was 56 yrs (range, 25-65), sex ratio was 1.R-ISS stage was 3 in 27.5%. 21% had high risk cytogenetic (by Conventional karyotyping and FISH). Renal failure was observed in 17%. ORR after induction was 71% with 12% CR, 17% VGPR. 22% failed to obtain PR following TD induction, and 51% of whom received salvage induction therapy (ST) with 72% that further reached ≥PR after ST. Overall, 141 pts (70%) underwent ASCT, 121 of whom had evidence of chemo-sensitive MM at completion of induction. 16% were transplanted in CR, 22% in VGPR and 62% in PR. At 3 months post-ASCT, the ORR in induction chemo-sensitive MM was 89%: 36% CR, 20% VGPR, and 33% PR. With a median follow-up post-ASCT of 27 months, the OS, PFS and EFS at 27 months were 82%, 60.5% and 56%, respectively. Maintenance treatment was significantly associated with longer PFS only in MM who did not achieve CR (29 versus 9 months, p=0.004). MM with improved response post-ASCT had a significantly longer PFS (39 versus 21 months, p=0.003) and EFS (39 versus 20 months, p=0.002). Importantly, achieving CR before (p=0.03) and after ASCT (p In multivariate analysis, ISS stage 3 was the sole independent predictor of induction failure (p=0.003). Importantly, predictive factors of achievement of CR post-ASCT comprised absence of delay farther to 4 months from completion of induction (p=0.006; OR = 4.54) and achievement of at least VGPR status before transplant (p=0,001; OR = 4.09). Conclusion: Achievement of at least VGPR at completion of induction improved response after ASCT and consequently influenced the post-ASCT outcome. Therefore, depth of response matters before and after ASCT, and validates in some extent the concept of induction salvage therapy prior to ASCT for patient not reaching response. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

Background: Diffuse Large B Cell Lymphoma (DLBCL) is the most common form of aggressive non-Hodgkin's lymphoma (NHL) accounting for approximately 40 % of all NHL cases. The aim of our study is to carry out an epidemiologic description and to compute the incidence of DLBCL in 2North African countries, Algeria and Tunisia. Patients and methods: This is a multicenter retrospective and descriptive study, covering a period of 5 years (January 2010 - December 2014), carried out in 17 centers in Algeria and 5 centers in Tunisia. Patients aged less than 15 years were excluded. We used the classification of World Health Organization. We used Epi info 6 software to analyze the data. Results: 1432 cases were identified, 1175 in Algeria and 257 in Tunisia. The sex distribution of DLBCL was as follows: males 837 (58.4 %), females 591 (41.6 %), male-to-female ratio 1.40. The age of patients ranged from 16 to 96 years (median 52 years) and 64.2 % of the patients are less than 60. The incidence estimates for the years 2012 and 2013 are respectively 0.86 and 0.87 for 100,000 inhabitants. The most frequent occupation of the cases is farmworker (11.5%). The average time between the date of diagnosis and clinical examination is 31 days. The average delay between the first clinical sign and the date of diagnosis is 133 days. A familial history of cancer is found in 10% of the cases. The lymph node biopsy was undertaken in 30.7% of the cases in the cervical area and in 15% of cases in the mediastinal area. A reexamination of the slides was undertaken in 20% of cases while 61.6% of them were found to be advanced clinical stages (III + IV). Splenomegaly was found in 16% of the cases and hepatomegaly in 7%. ORL damage was found in 16% of the cases and marrow infiltration in 10.2%. A Prognostic Score IPI ≥ 2 is found in 38% of the patients. Comments: On a previous Algerian study concerning all lymphomas diagnosed over a period of 6 years (2007-2012) (Journal of Hematology No. 10-11, 2015), 485 new cases of lymphoma were diagnosed on average per year. In the present study, the average number of new cases of DLBCL was 235 and the average proportion was 48% of all lymphomas. It should be emphasized that all cases underwent an immunohistochemical study and that lymphatic cases were excluded (digestive, bone, skin). The national incidence rate is low compared to that of international studies, a fact that is probably due to difficulties in the diagnosis including lack of implementation of immunohistochemistry techniques in our region. Disclosures No relevant conflicts of interest to declare.

The aims of this study are to investigate the frequency of derivative chromosome 9 (der (9)) deletion in Tunisian patients with chronic myeloid leukemia (CML) and to assess the correlation between this deletion and the cytogenetic response for patients treated with hydroxyurea (HU) or imatinib (IM). Karyotype analysis of 336 patients with CML was performed with R-banding technique. Fluorescence in situ hybridization (FISH) was carried using home-brew probes 17L7 and 248J22 for detecting, respectively, adjacent 5′ABL and 3′BCR deletions on der(9). Cytogenetic study demonstrated typical t(9;22)(q34;q11) translocation in 89.6% and variant translocation in 10.4% of patients. Interphase FISH studies showed deletion of der(9) in 59 (17.6%) of the 336 patients, 23 (39%) of them had variant rearrangements. There are 19 patients with solely 5′ABL deletion and 40 with concomitant 5′ABL and 3′BCR deletions. Cytogenetic response was evaluated during 18 months with HU or IM therapy. Our results demonstrate that (a) 3′BCR deletion is associated with 5′ABL deletion in all patients with der(9) deletions, (b) the 5′ABL and 3′BCR deletions arise simultaneously with t(9;22), (c) deletions on der(9) chromosome were frequently encountered in older patients and in patients presenting variant rearrangements, (d) both 5′ABL and 3′BCR deletions were associated with cytogenetic response failure in patients treated with HU, however, patients treated with IM and carrying der(9) deletions presented better cytogenetic response.

Extrahematologic manifestations, such as symptoms of rheumatic disease, have been recorded in association with myelodysplastic syndromes, including chronic myelomonocytic leukemia (CMML). We report the case of a 51-year-old woman with tumoral infiltration of the Achilles tendons bilaterally, indicating CMML. This diagnosis was confirmed at postmortem examination.

Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in the PRF1 coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutated PRF1 in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein.

The precision of immunological characterization of leukemias was improved by a certain number of technical innovations, particularly hybridoma production and standardization, resulting in monoclonal antibodies and definition of recognised cellular antigens (designated by CD: Cluster of Differentiation).The aim of this work was to determine the immunophenotyping profile of patients with leukemia, by means of a flow cytometric method: 66 blood samples coming from leukemic persons in the Sahel region were studied by flow cytometry, using about thirty monoclonal antibodies all marked with a fluorochrome, in one or two colour systems to assess their distribution according to type (lymphoid B or T / myeloid) and age, and to search for possible co-expressions of markers of different lineages.The marked preponderance of childhood B-ALL in our series is, at least partly, attributable to the age distribution of the Tunisian population. In agreement with studies from other countries, the majority of AML cases occurred among adults. A high proportion of AML cases in our series co-expressed markers of other lineages. Overall, accurate classification of acute leukemias was possible from a simple peripheral blood sample in 62 of 66 cases (93.9%).

Previously we have reported the presence of simian virus 40 DNA in 56% of diffuse large B-cell lymphomas in Tunisia. Here, we investigated the relationship between the status of simian virus 40 and t(14;18) translocation, germinal center status, and P53 and BCL2 expression to assess the clinical and biological relevance of simian virus 40 presence in diffuse large B-cell lymphomas. Therefore, we evaluated by immunohistochemistry the expression patterns of CD10, BCL6, MUM1, BCL2, and P53 in 86 diffuse large B-cell lymphomas (48 simian virus 40-positive and 38 simian virus 40-negative cases). The t(14;18) translocation was investigated by polymerase chain reaction. Immunostaining patterns for CD10, BCL6, and MUM1 were used to subclassify diffuse large B-cell lymphoma cases as germinal center or non-germinal center phenotypes. Germinal center phenotype, t(14;18), P53, and BCL2 expression were found in 71, 30, 55, and 65% of cases, respectively. Interestingly, germinal center phenotype, t(14;18), and P53 accumulation were found to be more frequent in simian virus 40-positive cases than in simian virus 40-negative ones (81, 44, 69 vs 58, 13, 37%; P=0.018, 0.002, and 0.003, respectively). However, there were no correlations between the presence of simian virus 40 and the expression of CD10, BCL6, MUM1 and BCL2, patient's age and gender, clinical stage, or the International Prognosis Index. Multivariate logistic regression analyses revealed that the germinal center phenotype, P53 accumulation, and t(14;18) were independent factors for simian virus 40 association (P=0.029, 0.006, and 0.014, respectively). There were no significant differences in overall survival regarding P53, BCL2, or t(14;18) status. However, patients with germinal center phenotype or low International Prognosis Index scores displayed a significantly better survival than those with non-germinal center phenotype or high International Prognosis Index scores (P=0.003 and 0.0001, respectively). These two prognosis factors remain independent in multivariate analyses (P=0.001 and0.0001, respectively). Interestingly, among patients with germinal center phenotype, simian virus 40-positive subgroup displayed a significantly shorter survival than simian virus 40-negative subgroup (P=0.034). In summary, these findings support a role of simian virus 40 in the pathogenesis of diffuse large B-cell lymphomas. On other hand, they suggest that a significant proportion of diffuse large B-cell lymphoma cases with germinal center phenotype may result from early transformation by simian virus 40, mainly those harboring the t(14;18). Modern Pathology (2008) 21, 282-296; doi:10.1038/modpathol.3800993; published online 28 December 2007.

The simian virus SV40 (SV40), a potent DNA oncogenic polyomavirus, has been detected in several human tumors including lymphomas, mainly in diffuse large B-cell type (DLBCL). However, a causative role for this virus has not been convincingly established. Hypermethylation in promoter regions is a frequent process of silencing tumor suppressor genes (TSGs) in cancers, which may be induced by oncogenic viruses. In this study, we investigated the relationship between the presence of SV40 DNA sequences and the methylation status of 13 TSGs in 108 DLBCLs and 60 nontumoral samples from Tunisia. SV40 DNA presence was investigated by PCR assays targeting the large T-antigen, the regulatory and the VP1 regions. Hypermethylation was carried out by methylation-specific PCR. SV40 DNA was detected in 63/108 (56%) of DLBCL and in 4/60 (6%) of nontumoral samples. Hypermethylation frequencies for the tested TSGs were 74% for DAPK, 70% for CDH1, SHP1, and GSTP1, 58% for p16, 54% for APC, 50% for p14, 39% for p15, 19% for RB1, 15% for BLU, 3% for p53, and 0% for p300 and MGMT. No hypermethylation was observed in nontumoral samples. Hypermethylation of SHP1, DAPK, CDH1, GSTP1 and p16 genes were significantly higher in SV40-positive than in SV40-negative DLBCL samples (p values ranging from 0.0006 to

The tumor necrosis factor (TNF) is a pro-inflammatory cytokine involved in the severity of different immune-regulated diseases including autoimmune, infectious, and malignant diseases. Chronic immune system stimulation could be a potential etiologic factor in these diseases. Given the determining role of TNF acting early in the immune response, we investigated the effect of an inherited genetic polymorphism at TNF promoter (-308A/G) on a predisposition to non-Hodgkin's lymphoma (NHL). The genotype distribution was determined in 194 patients with NHL and 160 age- and sex-matched population-based controls. The comparison of the -308TNF genotypes between the NHL patients and the controls showed a significant excess of A/A genotype that is previously associated with higher TNF production. Indeed, the A/A genotype is present in 7.7% of the cases, but in only 2.5% of the controls. This genotype is associated with a significant increased risk of NHL (odds ratio = 3.63, P = 0.028). These results indicate that the genetic polymorphism which could lead to an increased TNF production or a neighboring gene within the MHC region may influence the susceptibility to NHL in Tunisian population. Other epidemiologic studies carried out in both the Tunisian population and elsewhere are needed to confirm this finding.

Granulocytic sarcoma is a rare orbital complication of acute leukemia. It concerns primarily children under 10 years of age suffering from primitive acute myeloid leukemia. The diagnosis is made by clinical examination, computed tomography and confirmed by haematological investigations. The treatment approach is based on chemotherapy associated with intravenous steroid therapy. We report the case of a 6-year-old girl who presented with bilateral proptosis revealing acute myeloid leukemia. The patient was treated by a combination of chemotherapeutic drugs in two phases, associated with intravenous steroids. After a follow-up period of 24 months, the patient was in complete remission. The diagnosis of granulocytic sarcoma should be considered in any orbital mass of uncertain origin, particularly if it is bilateral. Special stains and immunohistochemistry play an important role in the diagnosis.

Objective: The aim of this study was to evaluate the effects of pulmonary rehabilitation on oxidative stress biomarker (Thiobarbituric acid substances "TBARS") and antioxidant enzymes activities (superoxide dismutase "SOD", glutathione peroxidise "GPx" and catalase "CAT") in patients with chronic obstructive pulmonary disease (COPD) compared to healthy subjects. Material and Methods: The study included 26 patients with COPD and 12 healthy subjects. The patients were divided into 2 groups (16 trained and 10 untrained). Trained groups performed 45 min individualized exercise training enrolled to an 8 weeks pulmonary rehabilitation program 3 times a week. Prior to and after the programme, exercise testing and pulmonary function were evaluated. Antioxidant enzymes activities were measured by spectrophotometry and spectrofluorimetry was used for plasma levels of thiobarbituric acid substances. Results: After the program, exercise capacity improved significantly in trained groups. At baseline, plasma TBARS were significantly increased in patients with COPD compared to the healthy subjects (p

Granulocytic sarcoma is an uncommon and localized extramedullary tumor composed of immature granulocytic cells. It may present in association with acute myeloid leukaemia, myelodysplastic syndrome and chronic myelogenous leukaemia. Granulocytic sarcoma may occur in any anatomical site but involvement of the gastrointestinal tract is rare, especially in the rectum. We report on the case of a 17 year old female who presented with rectal bleeding, abdominal pain and weight loss one mo prior to admission. Rectosigmoidoscopy revealed a rectal polypoid and ulcerated mass. The histological examination of the mass showed granulocytic sarcoma. Bone marrow examination was compatible with acute promyelocytic leukaemia (FAB type M3). This case report is a reminder of this peculiar sign of tumoral syndrome in acute myeloid leukaemia. We also discuss diagnostic methods and analyze the disease course.

International audience; Fanconi anemia (FA) is a rare autosomal recessive disease characterized by progressive pancytopenia, congenital malformations, and predisposition to acute myeloid leukemia. Fanconi anemia is genetically heterogeneous, with at least eight distinct complementation groups of FA (A, B, C, D1, D2, E, F, and G) having been defined by somatic cell fusion studies. Six genes (FANCA, FANCC, FANCD2, FANCE, FANCG, and FANCF) have been cloned. Mutations of the seventh Fanconi anemia gene, BRCA2, have been shown to lead to FAD1 and probably FAB groups. In order to characterize the molecular defects underlying FA in Tunisia, 39 families were genotyped with microsatellite markers linked to known FA gene. Haplotype analysis and homozygosity mapping assigned 43 patients belonging to 34 families to the FAA group, whereas one family was probably not linked to the FANCA gene or to any known FA genes. For patients belonging to the FAA group, screening for mutations revealed four novel mutations: two small homozygous deletions 1693delT and 1751-1754del, which occurred in exon 17 and exon 19, respectively, and two transitions, viz., 513G−\textgreaterA in exon 5 and A−\textgreaterG at position 166 (IVS24+166A−\textgreaterG) of intron 24. Two new polymorphisms were also identified in intron 24 (IVS24-5G/A and IVS24-6C/G).