The efficacy of therapeutic modalities for non-Hodgkin’s lymphoma have been tested and improved throughout the 19th century through various series of drug trials aimed at eliminating cellular malignancies, first through chemotherapy treatment, and more recently through immunotherapy. While to an extent successful in eliminating cancerous lesions and affected cells, chemotherapy treatments have shown to influence the induction of new malignancies, through genetic mutation, as well as unwanted toxic effects of systemic poisoning. The purpose of this thesis is to compare treatment methods in terms of their biomolecular activity, precision of intended results, and possible drawbacks, as well as their application to specific populations of Non-Hodgkin lymphoma diagnoses, including Follicular and Diffuse Large B-Cell lymphomas. In the following sections on contributing factors specific to Diffuse Large B-Cell lymphomas and Follicular lymphoma, elements of disease prognosis will be analyzed from a molecular and clinical point of view. This includes a focus on the impact of genetic mutation, the immunohistochemical evidence these changes present, as well as the variances in immune cell functionality, and finally a description of symptoms with direction to specific underlying causes. An analysis of standard of care chemotherapy, and monoclonal antibody treatments will then be provided for each occurrence. The second segment will discuss novel techniques being developed for the treatment of lymphoma including but not limited to new monoclonal antibodies, synthetic lethality modulation, inhibition of selected chemokine receptors, DNA vector immunization for production of internal host antibodies, concepts of cell mediated bispecific antibody induced destruction, and new generations of Immunomodulatory drugs. With the recent development of cost effective sequencing technology, included is a discussion of the shift towards personalized medicine treatments, targeting appropriate phenotypic specific populations for optimal results, as it relates to therapies for Diffuse Large B-Cell lymphoma and Follicular lymphoma.

Case Report: Diffuse Large B Cell Lymphoma (DLBCL) is an aggressive tumor of B cells that can arise almost anywhere in the body. It is the most common type of non-Hodgkin lymphoma in adults. We report a case of double hit lymphoma, a rare subtype that has an abnormal MYC and BCL2 gene translocation and occurs in about 5% of DLBCLs. A 58-year-old male with a 15-year smoking history presented with abdominal pain accompanied by weight loss of 20 lbs, night sweats, poor appetite, and fatigue. CT angiogram showed posterior mediastinal mass 3.5x5.6x12.8 cm, massive lymphadenopathy in the retroperitoneum surrounding aorta 10.5x5.2x11cm and a large left upper quadrant mesenteric mass measuring 7.2x10.2x13.6 cm. Left abdominal mass was biopsied and pathology showed DLBCL. FISH showed double hit lymphoma. Bone marrow biopsy and aspiration was negative for involvement. LV EF was 61% per ECHO. Patient underwent PET/CT, which showed extensive adenopathy in the inferior neck, chest, and abdomen, as well as a retroperitoneal mass extending into T10-11 extradural space. International Prognostic Index (IPI) for DLBCL categorized the patient as having a poor prognosis and in the high-intermediate risk group with a 4 year overall survival of 55% and 4 year progression-free survival of 53%. The PET scan results showing multiple extranodal sites was a factor in calculating his prognosis. MRI T spine with contrast showed direct invasion of T9, 10, 11, and 12. Urgent chemotherapy was started with DA-R-EPOCH. Our case demonstrates how imaging predicts the aggressiveness of DLBCL biology. The PET scan is very important in determining the extent of disease and the stage to allow for risk stratification of patients with DLBCL.

A dissertation submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in the branch of Anatomical Pathology. 21 July 2017. / Aims and objectives The study design aimed to assess and validate various laboratory techniques in the detection of EBV in HIV positive patients with diffuse large B cell lymphoma. The sensitivity and specificity of each technique was determined, as was the presence of an asymptomatic (latent) or lytic phase infection and the viral strain. DLBL samples occurring in HIV seropositive patients were used as a vehicle for these laboratory procedures which included chromogenic in situ hybridisation (EBER), immunohistochemistry (EBNA 2, LMP 1), real time PCR, (EBNA 1, LMP 2 and BZLF 1) and nested PCR (EBNA 2). Materials and Methods 46 cases of previously diagnosed DLBL from HIV positive individuals were identified and retrieved from the archives of the Department of Anatomical Pathology of the University of Witwatersrand and NHLS. All in-situ hybridisation, immunohistochemical and PCR laboratory procedures were carried out in accordance with the Standard Operating Procedures of the Anatomical Pathology Molecular Laboratory, using appropriate negative and positive controls throughout. Ethical clearance was obtained (M140273). Results/Conclusion A 20% frequency of EBV in HIV positive DLBL cases was established. All EBV infections were found to be in the lytic phase, with an almost equal distribution of latency patterns II and III and an equal distribution of EBV strains 1 and 2. EBER in situ hybridisation was confirmed to be the most sensitive and reliable method of viral detection, and the presence of the BZLF 1 gene determined by real time PCR was found to be a reliable indicator of a lytic infection. / LG2018

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.

No description available.

Thesis (M.A.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / High dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) who are chemosensitive to salvage therapy. There is now evidence that the achievement of complete remission by PET scan (PET-CR) after salvage therapy is a favorable determinant of ASCT outcome, implying that PET response should be part of the prognostic assessment for patients considering ASCT. However, it is unclear whether other prognostic factors are still relevant in patients getting post-salvage PET scanning. Moreover, while ASCT is often also used for patients with R/R transformed indolent lymphoma (TIL), there are no data on whether prognostic factors that are important for DLBCL patients, especially PET response to salvage, are similarly prognostic in this population. We conducted a retrospective study of 143 patients with R/R DLBCL and TIL who were transplanted in the last decade and had a post-salvage PET scan prior to ASCT. We examined prognostic factors in both groups, and constructed a prognostic score for DLBCL patients. For patients with DLBCL, post-salvage PET response was an important prognostic factor. Advanced age and symptomatic relapse were also significantly associated with inferior outcome. A simple score could stratify patients into 3 risk groups with 4-year post-ASCT overall survival of 84%, 59%, and 10%, and 4-year progression-free survival of 67%, 41% and 0% (p<0.0001 for both). However, none of those factors (including PET response to salvage) could be demonstrated for TIL, likely because of the limited sample size. Our novel prognostic score for DLBCL patients undergoing ASCT may be useful for prognostication, for stratification in clinical trials, and to motivate the design of new strategies for patients in the highrisk group, who may not derive benefit from standard ASCT. Those factors, however, do not apply to patients with TIL, which has important implications for their treatment and inclusion in ASCT clinical trials with larger sample sizes. / 2031-01-01

<p>Difuzni krupnoćelijski B limfom je najče&scaron;ći limfom na svetu i obuhvata do 30% non Hodgkin limfoma u zapadnim zemljama i veći procenat u zemljama u razvoju i nerazvijenim zemljama. Obično nastaje de novo ali može nastati sekundarno kao rezultat progresije manje agresivnih limfoma. U većini slučajeva počinje u limfnim čvorovima. Histolo&scaron;ka slika nije uniformna kod svih podtipova DLBCL, zbog morfolo&scaron;kog diverziteta tumorskih ćelija i zbog pratećih neneoplastičnih procesa. Na&scaron;e istraživanje obuhvata 92 bolesnika koji su dijagnostikovani i lečeni na Institutu za onkologiju Vojvodine od 2003. do 2011. godine, od kojih je 66 imalo kompletna imunohistohemijska ispitivanja. Svi su lečeni standardnim protokolom koji uključuje rituksimab. Ispitivali smo morfolo&scaron;ki i imunohistohemijski podtip, ekspresiju imunohistohemijskih markera, pol, starost, stadijum, nodalno/ekstranodalno ishodi&scaron;te i preživljavanje. CD20 je bio pozitivan u svim dostupnim uzorcima. MUM1 u 62,07%, CD10 u 20,23%, BCL6 u 51,72%, CD30 u 10,81%, CD5 u 8,05%, Ki-67 u 30-92%, BCL2 u 39,33%, BAFFR u 46,15%, TACI u 43,94%, BCMA u 10,61%, VEGF u 27,7%, COX2 u 63,64%, CD43 u 18,52%, EBV LMP u 37,88%. Među obolelim ženama je statistički značajno veći procenat MUM1 pozitivnih i BAFFR pozitivnih bolesnika nego među obolelim mu&scaron;karcima. Kod starijih ispitanika je statistički signifikantno ređa ekspresija CD30, COX2, TACI i BCMA. Kod ekstranodalnih limfoma ekspresija TACI je če&scaron;ća nego kod nodalnih limfoma. Ispitanici sa pozitivnom ekspresijom COX2 i ispitanici sa pozitivnom ekspresijom TACI imaju značajno izraženiju ekspresiju Ki-67. Bolesnici sa negativnom ekspresijom BCL2 imaju statistički značajnu korelaciju sa negativnom ekspresijom CD5 i negativnom ekspresijom CD43. Bolesnici sa pozitivnom ekspresijom CD30 imaju statistički značajnu pozitivnu korelaciju sa ekspresijom BCMA. Ispitanici sa pozitivnom ekspresijom COX2 imaju statistički značajnu pozitivnu korelaciju sa ekpresijom TACI. Markeri aktivacije i diferencijacije limfocita nemaju statistički značajnu pozitivnu korelaciju sa boljom prognozom. Markeri signalnih puteva angiogeneze i inflamacije nemaju statistički značajnu pozitivnu korelaciju sa lo&scaron;ijom prognozom. Izgleda da treba biti racionalan i upotrebiti samo osnovna antitela za određivanje imunohistohemijskog podtipa i antitela potrebna za diferencijalnu dijagnozu. Čini se da je prognostički značaj imunohistohemijskih antitela (osim CD20) danas kada se u terapiji koristi Rituximab minimalan.</p> / <p>Diffuse large B-cell lymphoma is the most common lymphoma in the world and represents up to 30% of all NHL in western countries and more in developing and undeveloped countries. It is usually a primary disease but also it can develop secondary as a result of progression of low grade lymphomas. In most cases the disease begins in lymph nodes. Histological features are not uniform in all subtypes of DLBCL due to morphological diversity and following non-neoplastic processes. Our research includes 92 patients whom are diagnosed and treated at the Institute for Oncology of Vojvodina since 2003. to 2011. and 66 among them have complete immunohistochemical findings. All of them are treated with standard protocols including Rituximab. We have examined morphological and immunohistochemical subtype, expression of immunohistochemical markers, sex, age, stadium, nodal / extranodal origin and survival. CD20 was positive in all available samples. MUM1 in 62,07%, CD10 in 20,23%, BCL6 in 51,72%, CD30 in 10,81%, CD5 in 8,05%, Ki-67 in 30-92%, BCL2 in 39,33%, BAFFR in 46,15%, TACI in 43,94%, BCMA in 10,61%, VEGF in 27,7%, COX2 in 63,64%, CD43 in 18,52%, EBV LMP in 37,88%. Female patients have significantly more often MUM1 and BAFFR expression compared to male patients. Older patients have significantly less often CD30, COX2, TACI and BCMA expression. Extranodal lymphomas have more frequent TACI expression then nodal ones. Patients with COX2 expression and patients with TACI expression have significantly higher Ki-67 expression. Patients without BCL2 expression have a significant correlation with CD5 negative expression and CD43 negative expression. Patients with CD30 expression have significant correlation with BCMA expression. Patients with COX2 expression have significant correlation with TACI expression. Markers of activation and differentiation of lymphocytes do not have significant correlation with better prognosis. Markers of signaling pathways for angiogenesis and inflammation do not have a significant correlation with worst prognosis. It seems that we should be rational and use only basic antibodies for determination if immunohistochemical subtype and antibodies necessary for differential diagnosis. It seems that prognostic significance of immunohistochemical antibodies (except CD20) is minimal today in Rituximab era.</p>

Philosophiae Doctor - PhD / The incidence of Diffuse large B cell Lymphoma has been increasing lately at an alarming rate especially, in developing countries like Sudan. The standard therapy in Sudan is based solely on the R-CHOP chemotherapy regimen, yet it has been noticed that Diffuse Large B cell Lymphoma prognosis remains unfavorable. The late diagnosis and the consequent side-effects of the therapy directly affected the disease’s poor outcome. There is a scarcity of scientific publications regarding DLBCL in Sudan, but the increased burden necessitates the need for further research.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20260号 / 医博第4219号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 前川 平, 教授 木原 正博, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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 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.