This study examines the influence social support has on delay of treatment among African-American lymphoma patients. One hundred nineteen (119) social work assessments were collected from medical records utilizing non-probability sampling. Data were extracted from the social work assessments of lymphoma patients considered for or having had bone marrow transplantation. The measurement tool was designed based on survey information from the Supportive Care Needs Survey, Social Support Behaviors Scale and the Social Support Survey Instrument. The findings of the study indicated that, overall, social support did not significantly influence delay of treatment. However, there were statistically significant relationships among social worker support and delay, gender and delay, and type of lymphoma diagnosis and delay for bone marrow transplantation. A large percentage of the patient population who may have been considered for bone marrow transplantation did not receive social work assessments and could have experienced delay associated with limited social support. Further research should be conducted on why this population did not receive social work assessments and comparisons should be made to the population that did in order to examine group differences

名古屋大学博士学位論文 学位の種類 : 博士(医学)(課程) 学位授与年月日:平成25年3月25日 水野紘樹氏の博士論文として提出された

Resumo: O Linfoma de Hodgkin (LH) é uma neoplasia linfóide histologicamente caracterizada pela presença de escassas células neoplásicas peculiares, denominadas células de Hodgkin/Reed-Sternberg (H-RS), em meio a infiltrado inflamatório não-neoplásico. Seu curso clínico está diretamente relacionado ao estadiamento, subtipo histológico e presença de alguns fatores prognósticos adversos já estabelecidos. Sintomas constitucionais como febre, perda de peso e sudoreses noturna, associados a um aparente desbalanço da resposta imune celular, são características comuns ao diagnóstico e denotam anormalidade da resposta imunológica desses pacientes, provavelmente causada pela produção de diferentes citocinas, tanto pelas células H-RS como pelo infiltrado inflamatório de permeio. Na maior parte dos casos de LH, há produção aumentada de citocinas de padrão Th2. No presente estudo, foram determinadas, por ELISA, as concentrações séricas de IL-6, IL-10 e IL-13 de 28 pacientes com LH clássico, antes e depois do tratamento anti-neoplásico, e de 26 voluntários saudáveis que compuseram grupo-controle. Dosagens de IL-6 e IL-10 pré-tratamento foram significativamente maiores nos pacientes em relação ao grupo-controle. Todos os pacientes apresentaram redução do nível sérico de IL-6 e IL-10 após o tratamento antineoplásico. Ao diagnóstico, níveis elevados de IL-6 foram associados à presença de linfonodomegalia abdominal, hepatomegalia, sintomas B e anemia. O estudo da regressão linear múltipla mostrou que sintomas B e linfocitopenia são bons preditores de níveis séricos pré-tratamento de IL-6. Níveis elevados de IL-10 foram relacionados à hipoalbuminemia e hepatomegalia. Nenhum paciente apresentou dosagem Resumo 52 sérica detectável de IL-13. Os resultados demonstram que níveis séricos elevados de IL-6 e IL-10 ao diagnóstico estão... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Hodgkin's lymphoma (HL) is a malignant lymphoid neoplasia characterized by abnormal immune response. Part of this disturbance is attributable to the activity of cytokines produced by the malignant Hodgkin/Reed-Sternbergh cells and reactive inflammatory cells. IL-6, IL-10 and IL-13 seem to play an important role in the pathogenesis of HL. Although some features of the disease have been associated with the production of these interleukins, there is insufficient data about changes in its serum levels at diagnosis and after the treatment, as well as its potencial use as biomarkers of HL course. Design and Methods. Serum levels pre and post treatment of IL-6, IL-10 and IL-13 in 28 patients with HL were determined by ELISA. Results were evaluated against clinical and laboratory parameters, as well as response to treatment and presence of infection by the Epstein-Barr virus (EBV), assessed by in situ hybridization with biotinylated probe directed to the viral transcript EBER-1. Serum samples from 26 healthy blood-donors volunteers were evaluated as a control group. Results. IL-6 and IL-10 serum levels before treatment of HL were significantly higher in patients compared to healthy individuals (p<0,001), and a significant reduction after treatment of the disease was observed (p<0,001). Serum levels of IL-13 were indetectable both in patients (before and after treatment) and controls. Serum levels of IL-6 before treatment were higher in patients with abdominal involvement by HL (p=0,03), hepatomegaly (p=0,04), B-symptoms (p=0,01), and anemia (p=0,02). On the other hand, IL-10 pre-treatment levels were higher in patients with hypoalbuminemia (p=0,04) and hepatomegaly (p=0,01). Multivariate analysis Abstract 54 revealed that lymphocytopenia and B-symptoms were good predictors of IL-6 levels in serum before treatment of patients... (Complete abstract click electronic access below) / Orientador: Deilson Elgui de Oliveira / Coorientador: Lígia Niéro-Melo / Banca: José Salvador Rodrigues de Oliveira / Banca: Maria Claudia Nogueira Zerbini / Mestre

Despite improved treatments for Non-Hodgkin’s Lymphoma (NHL) and Multiple Myeloma (MM), most patients eventually relapse and these diseases remain largely incurable. This has precipitated recent research into more clinically relevant in vitro models to enable development of more effective therapies. We have validated and standardised two in vitro primary culture models using tumour samples derived from patients with NHL, Chronic Lymphocytic Leukaemia (CLL) and MM. Several novel findings have been demonstrated. In vitro sensitivity of primary NHL cells cocultured in a CD40L model predicted clinical response to bortezomib in patients receiving the drug in a phase II trial. In vitro sensitivity correlated with CD40 expression, identifying a potential surrogate biomarker for response to bortezomib. The novel HDAC inhibitor, UCL67022 was 10-fold more potent than vorinostat in NHL and produced synergy when combined with bortezomib. UCL67022 maintained its potency in primary MM samples grown in an HS-5 stromal model. It modulated cytokine secretion resulting in downregulation of cytokine-induced signalling pathways (JAK/STAT3). A novel Hsp90 inhibitor, KW-2478 maintained activity in the HS-5 model and enhanced the activity of bortezomib and melphalan. Hsp70 was identified as a potential surrogate biomarker to monitor the combinatorial effect in future clinical trials. A highly synergistic and schedule-dependent cytotoxic effect occurred when primary MM cells were pre-treated with melphalan followed by bortezomib, with important implications for future clinical trial design. IL-6, IL-8 and VEGF levels correlated with resistance to bortezomib and melphalan and were associated with activation of JAK/STAT, MAPK and PI3K/Akt signalling pathways. Antibody neutralization of IL-6, IL-8 and VEGF resulted in restoration of drug sensitivity. We have therefore demonstrated the ability of primary culture models to predict response to chemotherapy, to identify therapeutically beneficial novel agents and to enable study of tumour microenvironmental interactions responsible for drug resistance in patients with haematological malignancies.

Mantle Cell Lymphoma (MCL) is a rare but aggressive Non-Hodgkin Lymphoma (NHL). Although t(11;14) is a hallmark of MCL, it is insufficient for lymphomagenesis. The phosphoinositide-3 kinase (PI3K) pathway is thought to play an important role in MCL pathogenesis and the PI3K p110δ isoform is enriched in leucocytes making it an attractive target. Early phase trials evaluating the p110δ selective inhibitor GS-1101 however demonstrate inferior responses in MCL compared to chronic lymphocytic leukaemia and indolent NHL. The relative contribution of the class Ia PI3K isoforms p110α (PIK3CA), p110β (PIK3CB) and p110δ (PIK3CD) was therefore evaluated in MCL. Immunohistochemistry on MCL tissue microarrays revealed that while p110δ was highly expressed, p110α showed wide variation and p110β expression was the weakest. A significant increase in p110α expression was found with disease progression. Although GS-1101 was sufficient to abolish B-cell receptor mediated PI3K activation, additional p110α inhibition was necessary to abolish constitutive PI3K activation in MCL exhibiting high p110α expression. Compared to GS-1101, GDC-0941 (p110α and p110δ inhibitor) had greater in vitro toxicity and a high PIK3CA/PIK3CD mRNA ratio (> twice ratio in healthy B-cells) was able to identify primary MCL samples that were resistant to GS-1101 but significantly more sensitive to GDC—0941. This ratio also increased with disease progression. No PIK3CA or PIK3R1 activating mutations were found. In summary, blockade of both p110α and p110δ appears to be necessary for effective PI3K inhibition in MCL, particularly with relapse. The PIK3CA/PIK3CD mRNA ratio may help identify those patients that are most likely to respond. Finally, a disseminated xenograft model of human primary MCL was established in NSG mice. Engraftment of primary MCL was demonstrated by peripheral blood flow cytometry, tissue immunohistochemistry and FISH for t(11;14). This model is potentially valuable for pre-clinical in vivo testing of novel drugs for this incurable disease.

No description available.

Idarubicin, a new analogue of daunorubicin, was administered intravenously at a dose of 15 mg/m2 to 31 patients with previously treated patients with unfavorable non-Hodgkin's lymphoma. Clinical characteristics included median age 69 years, performance status 1, and prior chemotherapeutic regimens 1. Twenty of the patients were relapsing after prior therapy and 11 were refractory; 29 had received prior anthracycline or anthracenedione. Responses were observed in 43% of patient (3 CR and 10 PR) with a median duration of 10 + months (2-29+ months). Idarubicin was well tolerated with non-hematologic toxicities (nausea/vomiting, mucositis, and anorexia) seen in <50% of patients. Median hematologic values during the first cycle for this dosage included WBC 1300/mm3 platelets 129,000/mm3, and hemoglobin 10.9 mg/dl. With dose escalation, hematologic toxicity was dose-limiting. Symptomatic cardiac toxicity was observed in one patient who had received maximum dose doxorubicin and radiotherapy. Median values for the cardiac ejection fraction during the full course of therapy for the entire group of patients were 0.62 (initial) and 0.60 (final). Idarubicin in intravenous form is an active drug in previously treated patients with unfavorable non-Hodgkin's lymphoma. Further studies employing idarubicin in non-Hodgkin's lymphoma should be considered. Cardiac function should be followed in trials utilizing anthracycline-type chemotherapeutic agents.

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare and unique subtype of Hodgkin's lymphoma (HL), accounting for approximately 5% of HL. On histology, NLPHL presents with “popcorn cells” composed of lymphocytic and histiocytic cells that express CD20 and CD45, unlike the pathognomonic Reed-Sternberg cells in classic HL (cHL) that express CD15 and CD30. Such differences in histopathology may require alternative treatment approaches. We present a rare case of NLPHL with atypical features at presentation with excellent response to treatment regimen used in Non Hodgkin’s Lymphoma (NHL). A 36-year-old male presented with acute onset back pain. He also noted multiple gradually enlarging lumps in his neck, axilla, and anterior chest wall for a few months. He mentioned significant constitutional symptoms including fatigue, weight loss, and drenching night sweats. No evidence of end-organ damage was present, except significant hypercalcemia suggestive of hypercalcemia of malignancy. An excisional biopsy of his axillary lymph node confirmed the diagnosis of NLPHL with immuno-stains that were positive for CD20, CD45 and negative for CD15 and CD30. PET scan demonstrated extensive tumor burden in the skeletal system, including the sternum, and multi-stationary lymphadenopathy. Splenomegaly with lymphomatous infiltration was also present. He was assigned stage IV based on the Ann Arbor staging system. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was initiated with a goal of 6 cycles, differing from ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen that is used for cHL. Interval PET scan post 4 cycles of R-CHOP showed no evidence of residual disease. PET scan after 6 cycles demonstrated a complete response (CR), including resolution of hypermetabolic uptake in the spleen, lymph nodes and bones. NLPHL is often considered indolent in clinical courses but with a tendency for multiple late relapses compared to cHL. It still maintains a favorable prognosis. In contrast to cHL, NLPHL less frequently presents with constitutional symptoms, increased tumor burden, or at an advanced stage, which is associated with a worse prognosis. Our patient had multiple features that are unusual in NLPHL such as hypercalcemia, extensive bony involvement with hypermetabolic lytic lesions and significant constitutional symptoms. The clinical conundrum with this rare subtype is whether to treat with HL vs NHL regimens. Literature and the guidelines recommend a conservative approach for low stage NLPHL with observation vs radiation vs single agent rituximab (used in NHL!). Advanced stages require multi-agent regimens ranging from one end of the spectrum with ABVD (used in cHL) to the other end with R-CHOP and its variants (used in NHL). Our patient with a rare subtype of HL had a very unusual and aggressive presentation with CR to R-CHOP demonstrating that rituximab based regimens should be the mainstay of treatment.

No description available.

Marek’s disease (MD) of chickens is an economically important, contagious, neoplastic disease caused by Gallid herpesvirus type 2. All chicken are susceptible to MDV infection and neoplastic transformation, but, only susceptible genotypes develop gross lymphomas. Lymphomas regress in resistant genotypes from 21 days post infection (dpi). The central aims of this study were to understand the mechanisms of non-MHC associated genetic resistance and the molecular pathways of neoplastic transformation. We hypothesized that, a) in resistant chickens at 21 dpi the tissue microenvironment is compatible with cell mediated immunity but in susceptible lines antagonistic to cell mediated immunity, b) resistant genotypes present immunogenic peptides on their MHC class I which while the peptides presented by susceptible genotypes do not induce CTL immunity resulting in tumor progression. We used inbred, MHC homozygous MD resistant (L6) and susceptible (L7) chickens and reductionist methods to test our hypotheses. Our results indicated that the tumor microenvironment is pro T-regulatory in both resistant and susceptible genotypes, and, the host immune response (pro Th-1 in resistant and pro Th-2/T-reg in susceptible) influences the tumor regression or progression. Statistical analysis of MHC class I bound peptides from resistant and susceptible genotypes confirmed that they present the same peptides and perhaps genes outside the MHC locus play an important role in determining resistance. Next, using Systems Biology tools like genomics, proteomics, Gene Ontology modeling and pathway analysis we compared the transcriptome and proteome of neoplastically transformed cells (CD30hi) and non-neoplastically transformed cells (CD30lo) which are the two components of tumor microenvironment. We demonstrated that: a) in situ, CD30lo cells are pre-neoplastic and the proteome involved in transformation and potential mechanisms that may be controlled by MDV oncogene Meq; b) Meq can drive a feed forward loop that induces CD30 transcription and overexpression, increased CD30 signaling, which then activates NFêB and, in turn, increases Meq transcription; c) Meq transcriptional repression or activation from the CD30 promoter generally correlates with a polymorphism in the CD30 promoter between MD-resistant and -susceptible chicken genotypes and so a herpesvirus has evolved to utilize NFêB as a direct transcriptional activator for its oncogene.