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Published on : Feb 24, 2014
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Slide 1 - EBV positive DLBCL of the elderly 2013/04/01 住院總醫師 王智慧 報告 感謝 蕭樑材大夫 指導
Slide 2 - Am. J. Hematol. 86:663–667, 2011.
Slide 3 - diffuse large B-cell lymphoma (DLBCL)~ 31% of all non-Hodgkin lymphoma Burkitt , plasmablastic, NK/T-cell, angioimmunoblastic, Hodgkin, hydroa-like T-cell lymphoma and lymphomas associated with HIV infection, post-transplant lymphoproliferations, and after exposure to certain cytotoxic or immunomodulator agents.
Slide 4 - Patients and Methods January 2002-December 2009, all newly diagnosed DLBCL from the medical records CD20,CD10,bcl-6,MUM1/IRF4 (cutoff: 30%) EBER in ≧20% of malignant cells
Slide 5 - EBV-positive DLBCL of the elderly were defined: (1) age ≧ 50 years, (2) no clinical and/or laboratory evidence of immunodeficiency, (3) diffuse large cell morphology with positive expression of CD20, (4) EBV-encoded RNA positivity in the tumor cells.
Slide 6 - -exclusion- Transformed and primary cutaneous variants of DLBCL coinfection by HIV, hepatitis B, hepatitis C, or human T-lymphotrophic virus-1 clinical suspicion of immunodeficiency such as chronic infections, chronic diarrhea, and chronic eczema chronic disease associated with leucopenia or lymphopenia, or low immunoglobulin levels
Slide 7 - ppt slide no 7 content not found
Slide 8 - AWOD: alive without disease, AWD: alive with disease, NR: no response Oyama score includes age≧ 70 years and presence of B symptoms as adverse risk factors three risk groups, low (0 factors), intermediate (1 factor), and high risk (2 factors).
Slide 9 - Multivariate survival analyses were not attempted due to the small number of cases.
Slide 10 - Results A total of 199 new cases of DLBCL were identified, 28 patients met the criteria, incidence rate of 14% . Median age at diagnosis: 75 years (51~95) . 17 men, 11 women (61% and 39%) 1.5:1. Hb <10 g/dL, platelets <150 x 10^9/L, lymphocytes <1.0x 10^9/L in 61%, 21%, and 37% of the patients, respectively. ECOG >1  18 patients (64%), LDH levels elevated in 11 (41%),
Slide 11 - advanced clinical stages (Stage III or IV) in 14 (50%). N=14 (50%) presented exclusively with nodal disease, n=11 (39%) had nodal and extranodal involvement, n=3 (11%) had primary extranodal disease, involving the stomach in all cases.
Slide 12 - extranodal sites of involvement were GI tract (n=6), lung (n=3), oropharynx (n=3), bone marrow (n =2), adrenals (n=1), skin (n=1), bone (n=1). B symptoms in 12 cases (43%) IPI scores >2 in 16 cases (57%). Low, intermediate, high Oyama scores in 5 (18%), 12 (43%), and 11 (39%) patients
Slide 13 - ppt slide no 13 content not found
Slide 14 - Histology diffuse pattern, large cells (68%) Monomorphic with a centroblastic or immunoblastic morphology, frequent mitoses, usually necrosis (32%) polymorphic large neoplastic cells with immunoblastic morphology admixed with variable amounts of small lymphocytes and histiocytes. All cases showed scattered RS- like cells.
Slide 15 - 19 patients (68%) had a non-germinal center (NGC) and 9 (32%) had a germinal center (GC)-like phenotype.
Slide 16 - Blood. 2004;103:275-282
Slide 17 - Blood. 2004;103:275-282
Slide 18 - ppt slide no 18 content not found
Slide 19 - Therapy
Slide 20 - median follow up of 32 months, 18 patients (64%) have died; 83% from lymphoma progression. OS for the entire group was 5 months and 3-year OS was 33%
Slide 21 - Worse OS age ≥70 years (n= 14; P= 0.002), advanced clinical stage (n= 9; P= 0.02), ALC <1.0x10^9/L (n= 4; P= 0.004). ECOG performance status > 1, hemoglobin <10 g/dL , platelets <200x 10^9/L, elevated LDH levels showed a trend
Slide 22 - 64 mos 5 mos
Slide 23 - 64 mos 8 mos
Slide 24 - Discussion age >70, advanced stage and ALC <1.0 3 109/L ~ a worse OS rate, R-CHOP may derive better CR and OS rates than CHOP Asian studies, incidence 5 ~11% in Western populations, incidence < 5%
Slide 25 - Immunosenescence characterized by decreased number and function of T-cells in peripheral blood and lymph nodes, apoptosis dysregulation, and elevation of levels of proinflammatory molecules Park et al. showed that EBER-positive DLBCL patients showed poorer clinical response and worse OS rates than EBER-negative patients
Slide 26 - In a prior study from our group, the presence of EBER in DLBCL patients was also independently associated with a worse prognosis these studies did not include patients treated with rituximab-containing regimens
Slide 27 - Clin Cancer Res 2007;13:5124–5132.
Slide 28 - Materials and Methods Diagnosis. when more than 50% of the proliferating, often neoplastic appearing cells showed both of the expression of one or more pan–B cell antigens (CD20/CD79a) and/or light-chain restriction and positive signal for in situ hybridization using EBV-encoded small nuclear early region (EBER) oligonucleotides on paraffin section for patients more than 40 y/o without predisposing immunodeficiency
Slide 29 - Among 149 cases fulfilling these criteria, 96 cases with available clinical data set were enrolled For the control group, 107 patients aged over 40 years with EBV-negative DLBCL treated consecutively at Aichi Cancer Center between 1993 and 2000.
Slide 30 - ppt slide no 30 content not found
Slide 31 - Sites of extranodal involvement N= 17 (20%), limited to extranodal sites. N= 27 (31%) had only lymphadenopathies without extranodal involvement, N= 43 (49%) had lymphadenopathies with extranodal involvement.
Slide 32 - polymorphic subtype scattered distribution of Hodgkin and Reed-Sternberg - like giant cells CD 20 (+) EBNA2 stain
Slide 33 - Histologic features diffuse and polymorphic proliferation of large lymphoid cells with a varing degree of reactive components such as small lymphocytes, plasma cells, histocytes, and epithelioid cells ,sometimes accompanied by necrosis and an angiocentric pattern. Often featured by a broad range of B-cell maturation, containing morphologic centroblasts, immunoblasts, and Hodgkin and Reed-Sternberg (HRS)–like giant cells with distinct nucleoli
Slide 34 - morphologically divided into two subtypes: large cell lymphoma (LCL): n=34, having notably dominant areas where large lymphoid cells with relatively monomorphic appearance. polymorphic LPD subtypes: n=62, scattered distribution of large cells in the polymorphous composition.
Slide 35 - The histology was frequently varied from area to area, indicating a continuous spectrum no significant difference in any clinical characteristics and immunophenotype between these two groups
Slide 36 - Phenotypic features LMP1 was positive on the large atypical cells in 67 (94%) out of 71 tested cases. EBNA2 was detected in the nuclei of 16 (28%) of 57 tested cases CD30 was stained more common in age-related EBVpositive B-cell LPDs than in EBV-negative DLBCL (75% vs 13%, P < 0.0001).
Slide 37 - CD10 expression (18% vs 38%, P = 0.015)
Slide 38 - Response to treatment and Kaplan-Meier survival estimates chemoregimens containing anthracycline for 62 patients (79%) and without anthracycline for 7 patients (9%)~EBV+ 40 (63%) of 64 evaluable patients with achieved a CR with initial therapy~EBV+ 95 (91%) of 104 evaluable cases with DLBCL achieved a CR (P < 0.0001).
Slide 39 - 57 deaths in 96 cases of age-related EBV-positive B-cell LPDs , 34 deaths in 107 cases of DLBCL. causes of death available for 47 cases for age-related EBV-positive B-cell LPDs and 29 for DLBCL.
Slide 40 - Deaths (PD and complications such as infections) in 38 and 9 cases, in age-related EBV-positive B-cell LPDs, 23 and 6 cases in EBVDLBCL. The observed differences between two disease groups were not significant (P = 0.870). more than 70 y/o- not significant (P = 0.747).
Slide 41 - 24 mos A significant difference was still found even when accounting for age
Slide 42 - H-I/High IPI
Slide 43 - Low/L-I IPI
Slide 44 - ppt slide no 44 content not found
Slide 45 - score of 0 (n = 18), no adverse factors 56.3 mos score of 1 (n = 39), one factor25.2 mos score of 2 (n = 21) , two factors 8.5 mos Oyama score
Slide 46 - ppt slide no 46 content not found
Slide 47 - 56 mos 25 mos 8.5 mos
Slide 48 - Switzerland, Austria, Italy 8/258 (3.1%)
Slide 49 - OS: 5.5 mos (EBNA2+): 103 mos (DLBCL > 50 y/o) EBV-positive DLBCL of the elderly in the Asian population seems to be more frequent at extranodal sites, e.g. up to 80% Median age: 67.5 y/o no correlation between age and prevalence of EBV in any of the studied DLBCL collectives