Indiana University-Purdue University Indianapolis (IUPUI) / Signal Transducer and Activator of Transcription 4 (STAT4) is an important transcription factor activated by IL-12 signaling. Activated STAT4 is essential for Th1 cell differentiation, a process characterized by increased potential for interferon (IFN)-γ production. Defective IFN-γ production due to STAT4 deficiency occurs after autologous stem cell transplantation for lymphoma. We have investigated the mechanisms of post-transplant STAT4 deficiency. The tumor-bearing state is ruled out to be the cause because STAT4 levels were not significantly different in peripheral blood mononuclear cells (PBMCs) obtained from lymphoma patients prior to treatment and healthy control subjects. The magnitude of the decrease in STAT4 levels corresponded with increasing intensity of chemotherapeutic treatment in vivo. Furthermore, treatment of normal PBMC cultures or a natural killer (NK) cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and reduced IL-12-induced IFN-γ production. Chemotherapy drugs are shown to have no impact on the stability of STAT4 mRNA, while steady-state levels of STAT4 transcripts are decreased in lymphoma patients. Our findings demonstrated that chemotherapeutic drugs up-regulate the ubiquitination rates of the STAT4 protein, which in turn promotes its degradation via the proteasome-mediated pathway. Treatment with the proteasome inhibitor bortezomib largely reversed the chemotherapy-induced STAT4 deficiency. Thus, acquired STAT4 deficiency in lymphoma patients is a consequence of treatment with chemotherapy. These results have important implications for design of optimal immunotherapy for lymphoma.

No description available.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL). The current standard of care is the combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but this only results in a 60% over-all 5-year survival rate, thus highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics that is being clinically evaluated for combination therapy. Rational selection of companion therapeutics for HDACi is difficult due to their poorly understood, cell-type specific mechanisms of action. To understand these mechanisms better, we developed a pre-clinical model system of response to the HDACi belinostat. Using this model system, we identified two major responses. Resistance, consisting of a reversible G1 cell cycle arrest with little induction of apoptosis; or sensitivity, consisting of mitotic arrest and high levels of apoptosis. In this dissertation, we determine that the induction of G1 cell cycle arrest is due to the increased expression of cyclin dependent kinase inhibitors (CDKi) that bind to and inhibit the cyclin E/CDK2 complex thereby blocking the final repressive phosphorylation steps of Rb protein. Repression of transcriptional elongation blocked CDKi upregulation and prevented G1 cell cycle arrest in belinostat-resistant cells. Additionally, we identified that belinostat arrests sensitive cells prior to metaphase and belinostat-resistant cells slow-down in mitosis but complete the process prior to arresting in G1. The combination of belinostat with the microtubule-targeting agent, vincristine resulted in strong synergistic induction of apoptosis by targeting mitotic progression. Furthermore, this combination prevents polyploidy, a key mechanism of resistance to microtubule targeting agents. Finally, we utilized selective class one HDAC inhibitors to identify the individual contributions of HDACs in the eliciting the responses observed with belinostat treatment. HDAC1&2 inhibition recapitulated the belinostat-resistant phenotype of G1 cell cycle arrest with little apoptosis, in both belinostat-resistant and sensitive cell lines. HDAC3 inhibition resulted in the induction of DNA damage, increased S phase and the induction of apoptosis in belinostat-resistant cells. Belinostat-resistant cells did not have observable effects to HDAC3 inhibitor alone but when combined with vincristine had significantly increased G2/M population at early time points. This suggests that HDAC3 maintains roles in DNA replication and also in mitotic progression. HDAC3 inhibition combined with vincristine resulted in a significant increase in polyploidy, suggesting that HDAC3 might not regulate the expression of apoptotic regulating factors as belinostat does.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Plasmablastic lymphoma (PBL) was originally described in 1997 as an AIDS associated tumour although cases have been described in individuals not infected with HIV. Due to the high number of people living with HIV in South Africa, a substantial number of cases are diagnosed annually and 45 cases were included in this study. This represented the largest cohort of PBL affecting the oral mucosa published to date. Three main aspects of PBL were investigated: pathological features, viral status and certain genetic characteristics. The results from the genetic studies were the most important and interesting. These included rearrangements of the IGH gene in 63% and MYC- rearrangements in 62% of PBL’s. Seven of 43 cases (16%) showed rearrangement of both the IGH gene alleles, a finding never described before. New genetic findings also included increased CCND1 gene copy numbers in 17/41 (42%) and increased IGH gene copy numbers in 6/41 (15%) of cases. The exact role of MYC-rearrangements in the development of PBL is unclear. Many factors may be responsible for MYC deregulation but in the case of PBL of the oral cavity the possible role of Epstein Barr Virus (EBV) infection was considered. All but one of the patients with known HIV-status (32/45) was HIV positive and I supported the proposal that the diagnosis of PBL should serve as a sign of immunodeficiency, either as diagnostic thereof or as a predictor of a progressive state of immunodeficiency in patients with known HIV/AIDS status. The HIV-negative patient in this study was the only one that presented with an EBV-negative PBL on in situ hybridisation. The clinico-pathological features of the current study therefore strongly suggested an association between EBV, PBL and HIV/AIDS although the exact nature thereof remains uncertain. Routine genetic evaluation of tumours diagnosed as PBL should be introduced, as this may have prognostic and eventually treatment implications in the future. The exact panel of genes to be evaluated with a possible diagnosis of PBL should still be determined but examination of IGH and MYC for rearrangements should be included. This study proved the histomorphological features including the degree of plasmacytic differentiation not to have any diagnostic role although its prognostic value should be determined. The results of the immunohistochemical investigations performed in this study confirmed PBL always to be negative for CD20 but proved PBL not to be a morphological or immunohistochemical diagnosis by any means. In conclusion, it became clear that PBL should never be diagnosed without thorough clinical, systemic, pathological and genetic investigations, especially in the backdrop of HIV/AIDS. No pathologist should make the diagnosis of PBL and no clinician should accept such a diagnosis or decide on the treatment modality for the patient involved unless all other possibilities of systemic plasma cell disease have been excluded. / Thesis (PhD)--University of Pretoria, 2011. / Oral Pathology and Oral Biology / unrestricted

Orientador: Carmino Antonio de Souza / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T12:06:26Z (GMT). No. of bitstreams: 1 Beltrame_LuizPaulo_D.pdf: 1273755 bytes, checksum: a809e73238738768c971673f3daef900 (MD5) Previous issue date: 2006 / Resumo: As elevadas taxas de mortalidade após transplante alogênico de medula óssea (TMO) com regime de condicionamento pré-transplante mieloablativo, levou-nos a iniciar a realização destes procedimentos utilizando-se regime de condicionamento pré-transplante não-mieloablativo, para pacientes considerados de maior risco. Esta modadlidade de tratamento passou a ser oferecida para pacientes com neoplasias hematológicas que devido à idade mais avançada, e/ou presença de comorbidades, eram inelegíveis para serem submetidos a um TMO convencional, e também para aqueles que estavam sendo submetidos a um segundo TMO. Entre julho de 2001 e outubro de 2005, 26 pacientes (leucemia mielóide aguda, n=1; leucemia mielóide crônica, n=1; Linfoma de Hodgkin, n=4; Linfoma não-Hodgkin agressivo, n=6; mieloma múltiplo, n=14) receberam TMO de um doador relacionado HLA-idêntico com células progenitoras periféricas (CPP), após um condicionamento pré-TMO não-mieloablativo. O regime de condicionamento consistia de fludarabina, 30 mg/m2/dia por 3 dias, e 2 Gy de irradiação corporal total. A profilaxia da doença do enxerto-contra-hospedeiro foi feita com ciclosporina-A por 56 dias, e micofenolato mofetil por 28 dias. Dos 26 pacientes, 23 (88%) encontravam-se em progressão de doença, e 24 (92%) estavam sendo submetidos ao segundo TMO. O seguimento mediano global foi de 436 dias (3-1397 dias), e o seguimento mediano dos pacientes vivos ao término deste estudo foi de 640 dias (135-1397 dias). São apresentados também, sem qualquer finalidade comparativa, os resultados de 47 pacientes que no mesmo período e na mesma unidade, foram submetidos ao TMO com CPP após um regime de condicionamento mieloablativo. Nos pacientes que receberam TMO com regime de condicionamento não-mieloablativo, a toxicidade não-hematológica foi branda e a recuperação rápida. Infecção bacteriana foi observada em 11 pacientes (44%). O tempo mediano com contagem de neutrófilos menor que 500 células por ml de sangue foi de 6 dias, e apenas 3 pacientes (12%) atingiram contagem plaquetária abaixo de 20.000. Quimerismo hematopoiético completo foi atingido em 25 pacientes (95%), e infusão de linfócitos do doador foi necessária em 6 indivíduos, sendo em 3 devido ao estado de quimerismo misto, e em 3 devido à progressão de doença. A doença do enxerto-contra-hospedeiro (DECH) aguda graus II ou maior ocorreu em 9 pacientes (37%) e a DECH crônica extensa ocorreu em 15 (60%). Houve 12 óbitos (46%), 7 relacionados a complicações do procedimento e 5 devido a progressão de doença. A sobrevida global, sobrevida livre de progressão e tempo para progressão nestes pacientes foram respectivamente 39% (95% IC, 15-63%), 33% (95% IC, 11-55%) e 64% (95% IC, 32-96%), considerando-se um tempo de seguimento mediano de 436 dias, com variação de 3 a 1397. O TMO com regime de condicionamento pré-transplante não-mieloablativo mostrou-se factível e seguro, com redução da toxicidade e mortalidade relacionadas ao procedimento, mesmo para pacientes com neoplasias hematológicas de alto risco / Abstract: Background and Objectives. High mortality rate after allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning prompted us to offer HSCT with non-myeloablative conditioning (NST). Design and Methods. Between July, 2001 and October, 2005, 26 patients [acute myeloid leukemia, n=1; chronic myeloid leukemia, n=1; Hodgkin¿s lymphoma, n=4; aggressive non-Hodgkin¿s lymphoma n=6; multiple myeloma (MM), n=14], received peripheral NST from HLA-identical siblings. Conditioning regimen consisted of fludarabine plus 2 Gy of TBI, and GVHD prophylaxis with cyclosporine-A plus micofenolate mofetil. Eighty-eight percent were in progression of disease (PD) and 92% were undergoing their second HSCT. Results. Non-hematologic toxicities were mild and transient. Bacterial infection occurred in 44%. Median time to granulocyte recovery was six days and only 12% achieved platelets count lower than 20 x 109/L. Full donor chimerism was established in 95%. Donor lymphocyte infusion was required in 6 patients, 3 because of mixed chimerism and 3 because of PD. A-GVHD grade II or higher was observed in 37%, and extensive c-GVHD in 60%. There were 12 deaths (46%), 7 transplant related mortality and 5 related to PD. OS, PFS and time to progression (TTP) were respectively 39% (95% CI, 15-63%), 33% (95% CI, 11-55%) and 64% (95% CI, 32-96%) for the whole group. MM patients had OS, PFS and TTP of 27% (CI 95%, 0-67%), 42% (95% CI, 8-76%) and 86% (95% CI, 60-100%), respectively. Interpretation and Conclusion. This approach showed feasible and safe with reduction in transplant related toxicities, even for these high risk hematopoietic malignancies / Doutorado / Clinica Medica / Doutor em Clínica Médica

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-07-24T14:40:58Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) LINFOMAS RELACIONADOS AO HIV EM ADULTOS ATENDIDOS NA REDE PÚ.pdf: 3190389 bytes, checksum: 7bff194ffad1d460a15b68dc1d8121ef (MD5) / Made available in DSpace on 2017-07-24T14:40:58Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) LINFOMAS RELACIONADOS AO HIV EM ADULTOS ATENDIDOS NA REDE PÚ.pdf: 3190389 bytes, checksum: 7bff194ffad1d460a15b68dc1d8121ef (MD5) Previous issue date: 2016-08-31 / O presente estudo descreveu os linfomas associados ao vírus da imunodeficiência humana (HIV) e identificou o perfil histológico e imuno-histoquímico predominante, bem como as características clínicas gerais da população, estadiamento inicial do linfoma, terapia realizada suas complicações e o desfecho do tratamento. A pesquisa foi retrospectiva, tipo série de casos. Realizada através da coleta de dados de prontuários médicos nos serviços de arquivo de oncohematologia dos seguintes hospitais: Hospital das Clínicas da Universidade Federal de Pernambuco (HC-UFPE), Hospital de Câncer de Pernambuco (HCP), e Hospital Universitário Oswaldo Cruz (HUOC). Foram analisados 18 prontuários de pacientes infectados com HIV e/ou com aids diagnosticados com linfoma. Foram excluídos aqueles pacientes que não apresentaram estudo imuno-histoquímico do linfoma. Os dados foram alocados em tabelas próprias, que contemplaram todas as variáveis a serem estudadas. Dos 18 pacientes incluídos no estudo, 61,1% eram do sexo masculino, com idade média de 41 anos. Metade dos pacientes tiveram seu diagnóstico de infecção pelo HIV posterior ao diagnóstico do linfoma. Quanto ao estudo anatomopatológico, os tipos mais frequentes foram o linfoma não Hodgkin de células B, somando 8 casos (44,4%), e o Linfoma de Burkitt 5 (27,8%) casos. O estadiamento de Ann Arbor com modificações de Cotswolds em 14 (77,7%) pacientes estava entre III e IV. Sintomas B estiveram presentes em 11 (61,1%) pacientes, doença Bulky também em 11 (61,1%) pacientes, e comprometimento extra linfonodal em metade dos casos. Sobre o tratamento, quatro pacientes foram a óbito já na primeira linha de tratamento e dois foram refratários, enquanto que seis pacientes tiveram resposta parcial e apenas um obteve resposta completa. Entre os pacientes acompanhados na segunda linha de tratamento um foi a óbito. Dentre os que seguiram para a terceira linha de tratamento dois foram a óbito, e o único paciente que se submeteu ao quarto tratamento também evoluiu para o óbito. Em acordo com a literatura, observamos que os pacientes com diagnóstico de linfoma associado ao HIV apresentaram um estadiamento clínico inicial avançado, e evoluíram com baixas taxas de resposta à quimioterapia o que pode estar relacionado com as frequentes complicações infecciosas relacionadas ao tratamento, à não utilização do anticorpo monoclonal anti-CD20 no tratamento, ao retardo do diagnóstico, tanto do linfoma como do HIV e às baixas condições de saúde básica e de vida da população em estudo, reforçando a necessidade de melhores condições de acesso à saúde. / The present study described lymphomas associated with human immunodeficiency virus (HIV) and identified the predominant histological and immunohistochemical profile, as well as the general clinical characteristics of the population, initial lymphoma staging, therapy performed, its complications and treatment outcome. The research was of a retrospective, case series type. This was done through the collection of data from medical records in the onco-hematology archive services of the following hospitals: Clinical Hospital of the Federal University of Pernambuco (HC-UFPE), Pernambuco Cancer Hospital (HCP), and Oswaldo Cruz University Hospital (HUOC). The medical records of 18 patients were analyzed who had been infected with HIV and/or AIDS and diagnosed with lymphoma. Patients who did not present an immunohistochemical study of lymphoma were excluded. The data were allocated to separate tables, which included all the variables to be studied. Of the 18 patients included in the study, 61.1% were male, with a mean age of 41 years. Half of the patients had their diagnosis of HIV infection following the diagnosis of lymphoma. As for the anatomical and pathological study, the most frequent types were B-cell non-Hodgkin’s lymphoma, adding up to 8 cases (44.4%), and Burkitt’s lymphoma, 5 cases (27.8%). The Ann Arbor staging with Cotswolds modifications in 14 (77.7%) patients was between III and IV. B symptoms were present in 11 (61.1%) patients, bulky disease also in 11 (61.1%) patients, and extra-lymph node involvement in half of the cases. Concerning treatment, four patients died during the first line of treatment and two were refractory, while six patients had partial response and only one had a complete response. Among the patients followed in the second-line treatment, one died. Among those who went to the third-line treatment, two died, and the only patient who underwent the fourthline treatment also died. According to the literature, we observed that patients diagnosed with HIV-associated lymphoma presented an advanced initial clinical staging, and evolved with low rates of response to chemotherapy which may be related to frequent infectious complications related to treatment, non-use of the anti-CD20 monoclonal antibody in the treatment, delayed diagnosis of both lymphoma and HIV, and low basic health and life conditions of the study population, reinforcing the need for better living conditions and access to health care.

Marginal zone (MZ) lymphomas (MZLs) represent a group of lymphomas originating from B lymphocytes of the “marginal zone” which is the external part of the secondary lymphoid follicles. The WHO classifies MZL into 3 entities; extranodal MZL, splenic MZL and nodal MZL. Extranodal marginal zone lymphoma (EMZL) can arise in different tissues, including the stomach, salivary gland, lung, small bowel, thyroid, ocular adnexa and skin. We present a 25 years old female with a history of angioedema and chronic cutaneous eczema who developed an unusual EMZL. Patient presented with a history of rapidly enlarging skin nodule on her left elbow that had been present for almost one year. Over a period of 2-3 weeks she felt the nodule rapidly changed in size and shape. Excisional biopsy of the mass revealed a lymphoid infiltrate based in the reticular dermis and focally extending into the subcutaneous adipose tissue with formation of disrupted lymphoid follicles positive for CD20, CD23 and BCL2 but negative for CD10, Cyclin D1 and SOX11. Diagnosis was consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Patient on presentation did not have any B symptoms other cutaneous lesions, lymphadenopathy or hepatosplenomegaly. PET scan revealed no evidence of abnormal uptake leading to a final Stage IE definition. Patient initiated definitive radiation therapy. EMZL accounts for 5 -10 % of non-Hodgkin lymphoma. It has been described often in organs that are normally devoid of germinal centers. It may arise in reactive lymphoid tissue induced by chronic inflammation in extranodal sites. Primary cutaneous marginal zone lymphoma (PCMZL) is associated with infectious etiologies such as Borrelia burgdorferi and less commonly with viral infections or in relation to autoimmune disorders. Autoimmune disorders, specifically Sjögren's syndrome is associated with a 30-fold increased risk of marginal zone lymphoma. Localized disease can be treated by local radiotherapy, intralesional injections or excision. Widespread skin disease is usually treated with a CD20 directed monoclonal antibody-Rituximab. Patients with PCMZL usually have an indolent clinical course. Extracutaneous dissemination of MALT Lymphoma is uncommon and happens in 6-8 % of patients. The 5 years overall survival is between 98-100%. Family physicians and dermatologists should have a high index of suspicion for this rare lymphoma subtype especially in patients with inflammatory chronic skin conditions and atopy.

Mantle cell lymphoma (MCL) represents a heterogenous subtype of non-Hodgkin lymphoma (NHL), which can present in three distinct clinicopathologic variants: indolent type MCL, classic type MCL and blastoid type MCL. Despite the different variations, MCL, in general, is almost always associated with advanced-stage disease at diagnosis, with a strong predilection for significant extranodal involvement, usually to the bone marrow, CNS, peripheral blood and the gastrointestinal tract. However, the literature review reveals ocular involvement is a more rarely described extranodal site of involvement by MCL. Among the reported cases, the orbit was most commonly involved, followed by the eyelid and the lacrimal gland. We report a 63-year-old male who presented with a nine-month history of progressive symptoms of periorbital swelling and eyelid apraxia, causing bilateral visual disturbances. The patient was initially treated for presumed blepharospasm by his ophthalmologist with botulinum toxin injections; however, his periorbital edema continued to worsen, and he developed a discrete nodule in his right lower eyelid. Biopsy of the right eyelid nodule revealed classic type MCL with immunohistochemical testing positive for CD20, CD5, cyclin D1, SOX11 and Ki67 proliferative index of 40%. Fluorescence in situ hybridization (FISH) analysis detected (11;14) translocation. Mantle Cell Lymphoma International Prognostic Index Combined Biologic Index (MIPIb) score was calculated to be 6.5 points based on his age, ECOG performance status of 0-1, normal serum LDH, normal white blood cell count and elevated Ki67 proliferative index, stratifying patient into the high-risk group, with an estimated median overall survival of 37 months. Due to the bulky MCL involvement in the palpebral conjunctiva affecting his vision and eyelid function, he was immediately treated with radiation therapy to the bilateral orbits. PET-CT revealed adenopathy above and below the diaphragm. Bone marrow biopsy revealed focal involvement (5-10%) by MCL. Brain MRI revealed MCL infiltration in the bilateral orbits and lacrimal glands. Upper and lower endoscopy revealed multiple polyps positive for MCL. Given the advanced stage of the disease and his high-risk stratification, he was started on intensive induction chemotherapy with rituximab, dexamethasone, cytarabine, and carboplatin and received prophylactic intrathecal methotrexate. Systemic imaging after completion of four cycles of treatment revealed near resolution of the majority of the lymphadenopathy and all of the lymph nodes no longer demonstrated any significant metabolic activity. He completed two additional cycles of systemic chemotherapy and is currently being evaluated for autologous hematopoietic stem cell transplantation in complete remission-1 given his excellent response to treatment, his young age, high-risk disease at diagnosis, and good performance status. Despite the diffuse and extensive systemic disease, interestingly, our patient did not exhibit any constitutional or metastasis-associated symptoms and only presented with isolated periorbital swelling. Our case emphasizes the rare extranodal site of involvement by MCL and encourages all medical providers to remain cognizant of the varying ways in which MCL can present clinically.