Primary gastrointestinal lymphoma is the most common type of extra-nodal lymphoma, representing about 30%-50% of all extra-nodal involvement. The stomach is the most common site, with the colon and rectum accounting for a minority of occurrences. Primary colorectal lymphoma is uncommon, representing only 0.3% of all large intestinal malignancies and approximately 3% of gastrointestinal (GI) lymphomas, with the majority of these being B-cell non-Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) being the most common subtype. We present a case of an 85-year-old male who presented with symptoms suggestive of bowel obstruction, who, after further evaluation, was diagnosed with primary non-Hodgkin lymphoma of the colon, DLBCL subtype.

Lymphomas are malignant tumours arising from cells in the lymphatic system. They are classified as B-cell lymphomas, T-cell lymphomas and Hodgkin lymphoma (HL). Of the B-cell lymphomas, one of the most common is diffuse large B-cell lymphoma (DLBCL). Many patients with lymphomas can be successfully treated however patients who relapse or are refractory have a poor prognosis, warranting further investigations to identify potential targets and develop novel drugs. Picropodophyllin (PPP), a potent and selective inhibitor of IGF-1R, inhibits malignant cell growth with low or no toxicity on normal cells in preclinical models. In paper I, we investigated the potential benefits of using PPP against DLBCL and found that the anti-tumor effects of PPP might possibly be explained by IGF-1R-unrelated mechanism(s). However, the inhibitory effects of PPP on lymphoma cells together with its low toxicity in vivo makes it a promising drug candidate for treatment. Melflufen, a derivative of melphalan, is currently being evaluated in a clinical phase I/II trial in relapsed or refractory multiple myeloma. In paper II, we confirmed previous reports of superior potency of melflufen over melphalan. Being active in cell lines and primary cultures of lymphoma cells as well as in a xenograft model in mice, melflufen considered being a candidate for further evaluation in treatment. bAP-15, a novel inhibitor of proteasome activity, inhibits ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase L5 (UCHL5). In paper III, we investigated the activity of b-AP15 in DLBCL and HL cell lines and compared the results to standard drugs used in treatment. Results showed inhibition of the proteasome and growth inhibition/cytotoxicity with IC50-values in the micromolar range. Treatment failure and lack of clinical benefit of proteasome inhibitors like bortezomib in DLBCL patients inspired us investigating for possible new targets, with major focus on proteasome inhibitors in DLBCL. In paper IV, we suggested that UCHL5 and/or USP14, as new targets for proteasome inhibitors in DLBCL, be further evaluated. The findings in this thesis suggest that PPP, Melflufen and b-AP15 are potential candidates for clinical drug development and UCHL5 and/or USP14 are new potential targets for proteasome inhibitors in DLBCL.

Purpose: To investigate if apparent diffusion coefficient (ADC) values within primary central nervous system lymphoma correlate with cellularity and proliferative activity in corresponding histological samples. Materials and Methods: Echo-planar diffusion-weighted magnetic resonance images obtained from 21 patients with primary central nervous system lymphoma were reviewed retrospectively. Regions of interest were drawn on ADC maps corresponding to the contrast enhancing parts of the tumors. Biopsies from all 21 patients were histologically analyzed. Nuclei count, total nuclei area and average nuclei area were measured. The proliferation index was estimated as Ki-67 positive nuclei divided by total number of nuclei. Correlations of ADC values and histopathologic parameters were determined statistically. Results: Ki-67 staining revealed a statistically significant correlation with ADCmin (r = -0.454, p = 0.038), ADCmean (r = -0.546, p = 0.010) and ADCmax (r = -0.515, p = 0.017). Furthermore, ADCmean correlated in a statistically significant manner with total nucleic area (r = -0.500, p = 0.021). Conclusion: Low ADCmin, ADCmean and ADCmax values reflect a high proliferative activity of primary cental nervous system lymphoma. Low ADCmean values—in concordance with several previously published studies—indicate an increased cellularity within the tumor.

Orientador: Maria Aparecida Custódio Domingues / Resumo: O linfoma difuso de grandes células B (LDGCB) integra o grupo das neoplasias malignas hematopoiéticas classificado como linfomas não-Hodgkin e representa o subtipo mais prevalente no Brasil e no mundo. Ao seu diagnóstico, segue-se um estadiamento clínico denominado Classificação de Ann-Arbor/Lugano, visando estimar o tratamento. Neste estadiamento, além de exames laboratoriais, parâmetros clínicos e imagens radiológicas, faz-se avaliação da medula óssea (MO) para pesquisa de infiltração neoplásica. O presente estudo comparou a análise unicamente morfológica da MO em relação à combinação da morfologia com imunoistoquímica (IHQ) na detecção de infiltração neoplásica medular em pacientes com LDGCB. Para isso, realizou-se levantamento retrospectivo de 113 pacientes diagnosticados com LDGCB submetidos a biópsia/aspirado de MO para estadiamento. Informações clínicas foram levantadas nos prontuários médicos e as lâminas histológicas de biópsias e coágulos de MO foram revisadas quanto a seus aspectos morfológicos. Procedeu-se estudo IHQ com os marcadores CD20 e CD3, sendo este o padrão ouro. A sensibilidade da análise morfológica isolada foi de 42,9%, considerada baixa se considerarmos que esta serviria como um exame de triagem. A quantidade de acúmulos linfoides (AcL) na MO e o aumento de trama reticulínica no acúmulo linfoide mostraram p-valor respectivamente de 0,02, para uma mediana de 2 acúmulos, e 0,01 para uma mediana de trama reticulínica de II, mostrando assim existir uma re... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Diffuse Large B Cell Lymphoma (DLBCL) belongs to a group of hematopoietic malignancies called Non-Hodgkin's Lymphomas, being the most prevalent in Brazil. After the diagnosis is followed a staging, called Ann-Arbor/Lugano classification, aiming to estimate the treatment. This staging, in addition to laboratory exams, clinical parameters and radiological images, includes the histological evaluation of bone marrow (BM) for the investigation of neoplastic infiltration. The present study compared BM morphological analysis only and morphology combined with immunohistochemistry (IHC) to detect BM infiltration in patients with DLBCL. For this, a retrospective survey was performed on 113 patients diagnosed with LDGCB submitted to biopsy / aspiration for BM staging. Clinical information was reviewed from medical records and histological biopsy and clots were reviewed for morphological aspects. The IHQ study was performed with CD20 and CD3 markers. The sensitivity of the isolated morphological analysis was 42.9%, considered low if we remember that this evaluation would serve as a screening test. The amount of lymphoid agreggates in BM and the increase in reticulin stain into the lymphoid agreggates showed p-value respectively of 0.02 and a median of 2 agreggates and 0.01 for a grade II reticulin, thus showing a relation of these two morphological parameters with BM infiltration. After this, we can conclude that the isolated morphological analysis is not recommended, and should always b... (Complete abstract click electronic access below) / Mestre

No description available.

1 ABSTRACT B-cell non-Hodgkin lymphomas (B-NHL) represent the most common mature lymphoproliferative diseases. B-NHL arise at different stages of B-cell development and represent their malignant counterpart. Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are aggressive types of B-NHLs. Deregulation of cell cycle control, inhibition of apoptosis or abnormal DNA damage response play a key role in the pathogenesis of DLBCL and MCL. Aberrant activation of several signaling pathways that further promote survival, cell proliferation or affect the tumor microenvironment have been recently recognized. Increased understanding of the oncogenic mechanisms implicated in pathogenesis of B-NHL lead to development of novel agents that target the oncogenic drivers of distinct lymphoma subtypes. MCL is an aggressive subtype of B-NHL associated with poor prognosis. In vivo models of human MCL for experimental therapy are however scarce. We established and characterized several mouse models of human MCL by xenotransplantation of either primary cells or established cell lines into immunodeficient mice (publication no 1). We demonstrated that engrafted MCL cells displayed complex changes of gene expression profile, phenotype and sensitivity to cytotoxic agents compared to the original in vitro growing...

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O linfoma difuso de grandes cÃlulas B (LDGCB) corresponde a 50 % dos casos de linfoma nÃo-Hodgkin (LNH). Seu tratamento de escolha à a quimioterapia de associaÃÃo, em especial o esquema CHOP (ciclofosfamida, doxorrubicina, vincristina e prednisona), considerado o tratamento inicial padrÃo dos LDGCB. VariaÃÃes deste esquema, como o protocolo CHOP-Bleo (ciclofosfamida, doxorrubicina, vincristina, prednisona e bleomicina) tem sido utilizadas com a intenÃÃo de se obter maiores taxas de remissÃo completa pelos pacientes. No Brasil, pouco se conhece a respeito da incidÃncia, do comportamento clÃnico, da resposta Ãs terapÃuticas utilizadas e da sobrevida de pacientes com LDGCB. Este estudo teve como objetivos traÃar o perfil epidemiolÃgico dos pacientes portadores de linfoma difuso de grandes cÃlulas B, atendidos no Hospital UniversitÃrio Walter CantÃdio (HUWC), com data de primeiro atendimento de janeiro de 1989 a dezembro de 2003, e que fizeram uso dos esquemas quimioterÃpicos CHOP e/ou CHOP-Bleo; avaliar a eficÃcia e seguranÃa terapÃutica dos esquemas propostos atravÃs da anÃlise do tipo de resposta terapÃutica, achados clÃnicos e laboratoriais destes pacientes. A coleta dos dados foi realizada a partir dos prontuÃrios mÃdicos dos 31 pacientes analisados. Destes, 21 (67,74%) eram do sexo masculino e 10 (32,26%) do feminino, com idade mÃdia de 45,81  16,3 anos. A ocupaÃÃo trabalhador agrÃcola representou 25,82% (8/31). O estÃdio III da classificaÃÃo de Ann Arbor foi o mais freqÃente (32,26%), mas apenas 45% dos pacientes apresentaram sintomas B. A lactato desidrogenase (LDH) sÃrica de 49% dos pacientes encontrava-se elevada à Ãpoca do diagnÃstico, sendo que outros 16% dos pacientes nÃo apresentavam resultado desta enzima em seus prontuÃrios. Quanto ao IPI, 71% foram classificados como de risco baixo e intermediÃrio, 13% de alto risco intermediÃrio, nenhum dos pacientes do estudo apresentou IPI compatÃvel com de alto risco e em 16% dos pacientes nÃo foi possÃvel estabelecer a classificaÃÃo devido à ausÃncia de dados nos prontuÃrios. Quanto à utilizaÃÃo dos protocolos quimioterÃpicos, 58% (18/31) dos pacientes fizeram uso do esquema CHOP, 36% (11/31) utilizaram CHOP-Bleo e 6% (2/31) utilizaram os dois esquemas quimioterÃpicos. Entre os pacientes que utilizaram o esquema CHOP, 78% atingiram a remissÃo completa (RC), 17% apresentaram recidiva da doenÃa e apenas 5 % foram a Ãbito. No grupo que utilizou o esquema CHOP-Bleo, 63% atingiram a RC, 18% apresentaram recidiva da doenÃa e 19% foram a Ãbito. Os 2 pacientes que utilizaram os dois esquemas como tratamento apresentaram recidiva da doenÃa. Os valores de LDH dos pacientes apÃs a quimioterapia apresentam-se reduzidos tanto em pacientes que atingiram a remissÃo completa como naqueles que tiveram recidiva. Verificamos que a sobrevida global (SG) e a sobrevida livre de doenÃa (SLD) nÃo foram influenciadas pelo estÃdio clÃnico e LDH inicial dos pacientes. A regressÃo logÃstica nÃo mostrou significÃncia estatÃstica quando analisou a remissÃo completa dos pacientes a partir dos resultados das variÃveis em estudo pÃs QT, com exceÃÃo da proporÃÃo de reduÃÃo da LDH e a resposta ao tratamento. Os resultados mostraram a eficÃcia e seguranÃa dos esquemas terapÃuticos CHOP e CHOP-Bleo em nossa populaÃÃo de estudo. Os resultados demonstram ainda que se faz necessÃrio o estudo epidemiolÃgico de diferentes populaÃÃes com LDGCB para que haja seguranÃa na escolha de esquemas quimioterÃpicos, bem como a uniformidade em descrever e classificar os linfomas e os seus fatores prognÃstico por parte dos patologistas e oncologistas. / Diffuse Large B-Cell Lymphomas (DLBCL) corresponds to 50% of non-Hodgkinâs lymphomas (LNH). Their treatment of choice is the association chemotherapy, in special the CHOP therapy (cyclophosphamide, doxorubicin, vincristine and prednisone) considered the standard treatment initial of the DLBCL. Variations of this therapy, with the CHOP-Bleo protocol (cyclophosphamide, doxorubicin, vincristine, prednisone and bleomycin) have been used with the intention of obtaining complete response rates for the patients. In Brazil, little is known about the incidence, clinical behavior, response to therapy and survival of the patients with DLBCL. This study aimed to set out the epidemiological profile of patients with diffuse large B-Cell lymphomas, who received medical care at Hospital UniversitÃrio Walter CantÃdio (HUWC), outline in Cearà state, with the first attendment from January 1989 to December 2003, who the used the CHOP and/or CHOP-Bleo therapy; Evaluating the security and efficiency of the protocols proposed by analysis of the kind of therapeutical response, clinical and laboratorial outcomes of these patients. The data collection was performed from medical recording of the 31 patients analyzed. These, 21 (67,74%) were the men and 10 (32,26%) women. The average age was 45,81  16,3 anos. Agriculturists represented 25,82% (8/31) of all patients. The stage III the Ann Arbor classification were the most frequent (32,26%), but only 45% of the patients had B symptoms. The values of lactate dehydrogenises (LDH) enzyme were elevated in 49% of the patients at diagnosis, but in 16% of the patients these values at diagnosis were unknown. As much as the IPI, 71% were classified as an IPI low and intermediate risk, 13% as an IPI intermediate-high risk, none of the study patients showed as an IPI high risk and 16% there is not possible the classification to establish due to the data is unknown. As much as the chemotherapy protocols used, 58% (18/31) of the patients was received CHOP chemotherapy, 36% (11/31) CHOP-Bleo chemotherapy and 6% (2/31) received CHOP associated with CHOP-Bleo chemotherapy. Among the patients who used CHOP chemotherapy, 78% was achieving complete response (CR), 17% was achieving relapse of the disease and only 5% were the death. In the group who used CHOP-Bleo chemotherapy, 63% was achieving RC, 18% was achieving relapse of the disease and 19% died. The 2 patients who used CHOP and CHOP-Bleo chemotherapy were achieving relapse of the disease. The values of the LDH after chemotherapy showed decreased in patients with RC as much as the relapsed patients. We verified that the overall survival (OS) and disease-free survival (DFS) were not influenced by the clinic stage and initial values of the LDH patients. The logistic regression did not show statistical differences when the complete response was analyzed comparing to outcomes the studied variables after QT, except for the proportion of reduction of LDH levels and response to the treatment. The results stress the security and efficiency of the protocols CHOP e CHOP-Bleo in our study population. The data obtained also the need epidemiological studies in different DLBCL populations for the security in the choice chemotherapy, well as standardized the classification and description of the DLBCL and prognoses factures by pathologists and oncologists.

Orientador: Oslei Paes de Almeida / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-23T09:15:14Z (GMT). No. of bitstreams: 1 ToralRizo_VictorHugo_D.pdf: 3216317 bytes, checksum: f10b9daa311d7ae2e304dc1ea8925abf (MD5) Previous issue date: 2013 / Resumo: O linfoma difuso de grandes células B (LDGCB) é o linfoma da cavidade bucal mais comum. Alguns dos LDGCB podem apresentar células grandes morfologicamente similares às células Hodgkin e Reed/Sternberg (HRS) dos linfomas de Hodgkin clássico (LHC). O objetivo deste estudo foi comparar os LDGCB bucal que apresentem células HRS-like (LDGCB-HRS) com o linfoma de Hodgkin primário nodal, considerando os aspectos histológicos e imunoistoquímicos (IQs), angiogênese, índice de mastócitos e células dendríticas (CD), por meio de um amplo painel IQ. Quize casos foram estudados, nos quais sete eram LDGCB-HRS like e oito eram LHC nodal. Para a análise dos aspectos histológicos e IQs foram utilizados os seguintes anticorpos: CD3, CD15, CD20, CD30, CD43, LCA, CD45RO, CD79a, CD83, EMA, MUM-1, PAX-5, perforina, granzyme B, FASN, Ki-67, LMP-1; e EBER1/2. Já para a análise da angiogênese foram utilizados os anticorpos CD34, CD31, D2-40, CD105, vWF e VEGF; e para o índice de mastócitos utilizou-se o mast cell triptase. Finalmente, para avaliar a expressão IQ das CD os anticorpos CD1a, CD83, CD123, CD207, S-100 e FXIIIa foram utilizados. Todas as lâminas foram escaneadas e as células HRS-like, mastócitos e CD imunopositivas foram analisados, assim como os parâmetros morfométricos da angiogênese. Os resultados mostraram que a imunoexpressão foi postiva em 100% de casos de LHC e em 57% dos casos de LDGCB de boca, enquanto que LCA, CD20 e CD79a foram exclusivos para todos os LDGCB, e apenas CD15 foi exclusivo para os LHC. Angiogênese e o índice de mastócitos estavam aumentados em ambas as lesões, e entre elas, o LHC obteve maiores valores que o LDGCB da cavidade bucal em todos os anticorpos analisados. Por fim, o índice de CDs foram estatisticamente significante entre os grupos, exceto para CD83, que não mostrou nenhuma diferença estatística. A distribuição de CD foi reconhecida principalmente na área tumoral e ao redor das células neoplásicas em ambas as entidades. Foi possível concluir que os LDGCB com células HRS-like da cavidade bucal devem ser incluídos no diagnóstico diferencial de LHC da cavidade bucal. Quando da avaliação destes casos, a analise morfológica detalhada assim como o uso de um amplo painel de IQ são recomendados para realizar o diagnóstico correto. A angiogênese é essencial para o desenvolvimento de LDGCB da cavidade bucal, e quaisquer dos anticorpos CD34, CD31 e vWF podem ser utilizados para avaliar os parâmetros morfométricos. A presença significativa de CD nestes linfomas provavelmente desempenha um papel patologicamente relevante nos linfomas. Nossos resultados sugerem que o aumento no número de CD parece ser um fator contribuinte para a resposta imune estimulada pelo crescimento tumoral / Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common oral lymphoma. Some DLBCLs can present large cells morphologically similar to Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). The objective of this study was to compare oral DLBCL presenting HRS-like cells (DLBCL-HRS like) with primary nodal cHL, considering the following aspects: histological and immunohistochemical (IHC), angiogenesis, index of mast cells and dendritic cells (DCs); through a broad immunohistochemical panel. Fifteen cases were studied, of which, seven were DLBCL-HRS like and eight were nodal cHL. For histological and IHC aspects, immunoexpression of CD3, CD15, CD20, CD30, CD43, LCA, CD45RO, CD79a, CD83, EMA, MUM-1, PAX-5, perforin, granzyme B, FASN, Ki-67, LMP-1; and EBER1/2, were assessed. As for angiogenesis analysis, the antibodies used were CD34, CD31, D2-40, CD105, vWF and VEGF; and for the index of mast cell were used the mast cell tryptase. Finally, for IHC expression of DCs, the antibodies used were CD1a, CD83, CD123, CD207, S-100, and FXIIIa. All slides were scanned and positive immunoreactive cells HRS-like, mast cell and DCs were analyzed, as well as morphometric parameters of angiogenesis. The results showed that the immunoexpression of CD30 was 100% positive in cHL and 57% in oral DLBCL HRS-like, while LCA, CD20 and CD79a were exclusive for all oral DLBCL, and only CD15 was exclusive for cHL. Angiogenesis and mast cell index values were increased in both lesions and between them, cHL was greater than oral DLBCL with all antibodies studied. Finally, DC subsets were statistically significant between groups, except CD83, which did not show statistical significance. The distribution of DCs was mainly in the tumor area, around neoplastic cells in both entities. It was possible to conclude that DLBCL-HRS should be included in the differential diagnosis of oral cHL. When evaluating these cases, a detailed morphologic and a broad IHC analyses for the correct diagnosis are recommended. Angiogenesis is essential to the development of DLBCL of the oral cavity and any of the antibodies CD34, CD31 and vWF could be used to evaluate morphometric parameters. The presence of significantly higher numbers of DCs in these lymphomas could suggest that these cells are likely to play a pathological relevant role in lymphomas. Our findings suggest that increased number of DCs in lymphomas appears to be a factor contributing to the immune response against tumor growth / Doutorado / Patologia / Doutor em Estomatopatologia

Abstract In the present study, some of the difficulties in the treatment of the most common malignant lymphoma, diffuse large B-cell lymphoma (DLBCL), were evaluated. Some patients develop local or central nervous system (CNS) relapse after first-line treatment. The treatment of relapsed disease is challenging and despite all efforts, some patients die of the disease. Chemoresistant disease also remains challenging because some patients suffer from refractory disease of a progressive nature. The antioxidant enzymes peroxiredoxins (Prxs) and thioredoxin-1 (Trx) were evaluated as prognostic and predictive markers of DLBCL. High cytoplasmic expression of Prx VI was found to correlate with poor prognosis in patients with DLBCL. Trx knockdown in lymphoma cell culture revealed a possible predictive role of Trx. Trx knockdown sensitized cells to doxorubicin, a widely used chemotherapeutic agent in treatment schemas of DLBCL. Etoposide, another widely used chemotherapeutic agent, on the other hand, killed more native DLBCL cells than did doxorubicin. Patients with high Trx expression at the diagnostic stage of the disease benefitted from etoposide-containing high-dose chemotherapy and autologous stem cell transplantation and did not develop post-transplantation relapses which Trx-negative patients did. Antithrombin III (AT III) in cerebrospinal fluid has been suggested to be a biomarker in previous studies of CNS lymphoma. In the present study, AT III was evaluated in patients with CNS lymphoma and with neurological diseases. High concentrations of AT III in cerebrospinal fluid reflected the magnitude of blood-brain barrier leakage and because of this, AT III should not be used as a biomarker in clinical practice. / Tiivistelmä Tutkimuksessa arvioitiin osaa yleisimmän pahanlaatuisen imukudossyövän eli lymfooman, diffuusin suurisoluisen B-solulymfooman, hoidon haasteista. Osa potilaista saa ensilinjan hoidon jälkeen joko paikallisen tai aivoston alueen taudin uusiutuman. Uusiutuneen taudin hoito on haasteellista, ja hoitoyrityksistä huolimatta osa potilaista kuolee tautiinsa. Solunsalpaajille resistentti tauti on myös yksi haastavista hoitotilanteista, ja osa potilaista kärsiikin hoitojen läpi etenevästä taudista. Antioksidatiivisia entsyymejä, kuten peroksiredoksiineja ja tioredoksiinia, arvioitiin ennusteellisina ja ennakoivina merkkiaineina diffuusissa suurisoluisessa B-solulymfoomassa. Peroksiredoksiini VI:n korkea sytosolinen ilmaantuvuus korreloi tavallista huonompaan diffuusin suurisoluisen B-solulymfooman ennusteeseen. Tioredoksiinin hiljentäminen lymfoomasoluviljelyssä paljasti sen mahdollisen ennakoivan merkityksen hoitoon liittyvässä päätöksenteossa. Solut herkistyivät tiodredoksiinin hiljentämisen vuoksi doksorubisiinille, jota käytetään laajalti diffuusin suurisoluisen B-solulymfooman solunsalpaajahoidoissa. Etoposidi, joka on huomattavasti myrkyllisempi solunsalpaaja, päinvastoin tappoi enemmän tavallisia diffuusia suurisoluisia B-solulymfoomaa edustavia soluja kuin doksorubisiini. Potilaat, joilla oli korkea tioredoksiinin määrä taudin diagnostisessa vaiheessa, hyötyivät etoposidia sisältävästä korkea-annoshoidosta sekä autologisesta kantasolusiirrosta. Näille potilaille ei kehittynyt kantasolusiirron jälkeisiä taudin uusiutumia kuin taas niitä kehittyi potilaille, joilla oli tioredoksiini negatiivinen. Antitrombiini III:a on ehdotettu soveltuvaksi aikaisempien tutkimusten perusteella aivoston lymfooman merkkiaineeksi aivo-selkäydinnesteestä. Tässä tutkimuksessa antitrombiini III:n määrää mitattiin potilailta, joilla oli aivoston lymfooma tai neurologinen sairaus. Korkeat konsentraatiot antitrombiini III:a aivo-selkäydinnesteessä kuitenkin vain heijastivat veri-aivoesteen vuotamisen määrää, ja näin ollen antitrombiini III:a ei tulisi käyttää kliinisessä käytössä.

Introdução: O linfoma difuso de grandes células B é o mais freqüente grupo de linfoma não- Hodgkin, perfazendo quase 50% dos casos no serviço de hematologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e Instituto do Câncer do Estado de São Paulo. Possui heterogeneidade clínica e biológica traduzida em mais de vinte subtipos na Organização Mundial da Saúde. Sua terapêutica se baseia na associação do anticorpo monoclonal anti-CD20 e quimioterapia com antracíclico, esquema que resulta em 43,5% de sobrevida global em 10 anos. Determinantes de prognóstico clínico como o Índice Internacional de Prognóstico e o Índice Internacional de Prognóstico Revisado carecem de acurácia, pois até 20% dos pacientes de baixo risco falecerão da doença e 60% dos pacientes de alto risco estarão vivos em quatro anos. Essas discrepâncias podem, em parte, ser atribuídas a fatores genéticos. A assinatura gênica do linfoma difuso de grandes células B tipo centro germinativo apresenta sobrevida global superior ao tipo células B ativadas (76% versus 16%, p=0,01), contudo o perfil de expressão gênica por microarray ainda não está disponível na prática clínica. Entretanto, o escore preditivo de mortalidade para linfoma difuso de grandes células B baseado no valor prognóstico da expressão dos genes BCL2, BCL6, CCND2, FN1, LMO2 e SCYA3 por PCR em tempo real quantitativa mostrou-se independente do Índice Internacional de Prognóstico na era pré-rituximabe. Mas não foi significante em pacientes de alto risco clínico tratados com R-CHOP. Os genes BCL2, CCND2 e SCYA3 integram a assinatura de células B ativadas, BCL6 e LMO2 a do centro germinativo e FN1 a linfonodal. Objetivo: Avaliar o impacto da expressão absoluta dos genes BCL2, BCL6, CCND2, FN1, LMO2 e SCYA3 em população brasileira com linfoma difuso de grandes células B tratada com R-CHOP em relação à resposta global, sobrevida livre de doença, sobrevida livre de progressão e sobrevida global. Métodos: A expressão gênica foi analisada por PCR em tempo real quantitativa de RNA extraído de amostras parafinadas de 63 pacientes, porém foi avaliável em 42. Seus valores foram normatizados pelo gene endógeno ABL e transformados em escala logarítmica na base 2 para posterior correlação com variáveis clínicas e de desfecho. Resultados: Com mediana de seguimento de 29 meses, as sobrevidas global, livre de doença e livre de progressão foram, respectivamente, 82,8%, 97,14% e 87,53%, enquanto a resposta completa foi 82,5%. A expressão de LMO2>3logs e BCL6>3,5logs definiu um grupo de maior sobrevida global (91% versus 64,3%, p=0,040) e sobrevida livre de doença (95,5% versus 70,7%, p=0,03), independentemente do Índice Internacional de Prognóstico (p=0,010 e p=0,042) e com significativa hiperexpressão do SCYA3 (p=0,046). Não se observou associação entre escore preditivo de mortalidade baseado nos seis genes e prognóstico. Assim, foi criado novo escore genético prognóstico baseado no poder da expressão concomitante de LMO2 e CCND2, definindo-se grupos de baixo risco (<2,5) e alto risco (>=2,5) com distintas sobrevidas global (92,4% versus 57,1%, p=0,011) e livre de progressão (96,2% versus 66,7%, p=0,013), independentes do IPI. Conclusão: Em pacientes com linfoma difuso de grandes células B tratados com R-CHOP, a hiperexpressão de BCL6, LMO2 e SCYA3 correlacionou-se com melhor prognóstico. O novo escore genético prognóstico definido por LMO2 e CCND2 estratificou grupos de risco de prognósticos distintos independentes do Índice Internacional de Prognóstico / Introduction: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma; which accounts for almost 50% of the cases at the Hematology Department of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo. Its clinical and biological heterogeneity results in more than twenty subtypes according to the World Health Organization classification. Its treatment is based on a combination of anti-CD20 monoclonal antibody and antracycline-based chemotherapy, with a 10-year overall survival of 43.5%. Clinical prognostic determinants such as the International Prognostic Index and the Revised International Prognostic Index lack accuracy, since up to 20% of low-risk patients will die from the disease and up to 60% of high-risk patients will be alive within four years. Such discrepancies can partially be attributed to genetic factors. Diffuse large B-cell lymphoma germinal center gene signature shows superior overall survival compared to activated B-cell signature (76% versus 16%, p=0.01), however microarray gene expression profile is not yet available in clinical practice. Nonetheless, the Mortality Predictor Score for diffuse large B-cell lymphoma based on the prognostic value of BCL2, BCL6, CCND2, FN1, LMO2 and SCYA3 gene expression by quantitative real-time PCR has proved to be independent from the International Prognostic Index in the pre-rituximab era. But it was not significant in high clinical risk patients treated with R-CHOP. The genes BCL2, CCND2 and SCYA3 compose activated B-cell signature, whereas BCL6 and LMO2 compose the germinal center signature and FN1 the lymph-node signature. Objective: Evaluate the impact of BCL2, BCL6, CCND2, FN1, LMO2 and SCYA3 absolute gene expression in Brazilian population diagnosed with diffuse large B-cell lymphoma and treated with R-CHOP, with respect to overall response, disease free survival, progression free survival and overall survival. Methods: Gene expression was analyzed by quantitative real-time PCR of RNA extracted from paraffin-embedded samples of 63 patients, although evaluable in 42. Their values were normalized by endogenous gene ABL and log- transformed on a base 2 scale for subsequent correlation with clinical and outcome variables. Results: With a median follow-up of 29 months, overall survival, disease free survival and progression free survival accounted for 82.8%, 97.14% and 87.53% respectively, while complete response was 82.5%. The expression of LMO2>3logs and BCL6>3.5logs defined a group with higher overall survival (91% versus 64.3%, p=0.040) and progression free survival (95.5% versus 70.7%, p=0.03), independent of International Prognostic Index (p=0.010 and p=0.042) and with significant overexpression of SCYA3 (p=0.046). It was not identified any association between six gene Mortality Predictor Score and prognosis. As a result, we developed the New Genetic Prognostic Score based on the power of concomitant expression of LMO2 and CCND2, defining low-risk (<2.5) and high-risk (>=2.5) groups with distinct overall survival (92.4% versus 57.1%, p=0.011) and progression free survival (96.2% versus 66.7%, p=0.013), independent of International Prognostic Index. Conclusion: In patients with diffuse large B-cell lymphoma treated with R-CHOP, hyperexpression of BCL6, LMO2 and SCYA3 was correlated with a better prognosis. The New Genetic Prognostic Score, defined by LMO2 and CCND2, stratified risk groups with different prognosis, independent of International Prognostic Index