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1
Ikeda, Tomoka, Yuka Gion, Yoshito Nishimura, Midori Filiz Nishimura, Tadashi Yoshino, and Yasuharu Sato. "Epstein–Barr Virus-Positive Mucocutaneous Ulcer: A Unique and Curious Disease Entity." International Journal of Molecular Sciences 22, no. 3 (January 21, 2021): 1053. http://dx.doi.org/10.3390/ijms22031053.
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Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in 2010. EBVMCU is a unifocal mucosal or cutaneous ulcer that often occurs after local trauma in patients with immunosuppression; the patients generally have a good prognosis. It is histologically characterized by proliferating EBV-positive atypical B cells accompanied by ulcers. On the basis of conventional pathologic criteria, EBVMCU may be misdiagnosed as EBV-positive diffuse large B-cell lymphoma or other lymphomas. However, its prognosis differs from that of EBV-associated lymphomas, in that patients with EBVMCU frequently show spontaneous regression or complete remission without chemotherapy. Therefore, EBVMCU is now recognized as a low-grade malignancy or a pseudo-malignant lesion. Avoiding unnecessary chemotherapy by distinguishing EBVMCU from other EBV-associated lymphomas will reduce the burden and unnecessary harm on patients. On the basis of these facts, EBVMCU was first described as a new clinicopathological entity by the World Health Organization in 2017. In this review, we discuss the clinicopathological characteristics of previously reported EBVMCU cases, while focusing on up-to-date clinical, pathological, and genetic aspects.
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Lachar, Whitney A., Imran Shahab, and A. Joe Saad. "Accuracy and Cost-Effectiveness of Core Needle Biopsy in the Evaluation of Suspected Lymphoma: A Study of 101 Cases." Archives of Pathology & Laboratory Medicine 131, no. 7 (July 1, 2007): 1033–39. http://dx.doi.org/10.5858/2007-131-1033-aacocn.
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Abstract Context.—Lymphomas have traditionally been diagnosed on excisional biopsies of lymph nodes in order to evaluate tissue architecture and cytomorphology. Recent lymphoma classification schemes emphasize immunophenotypic, genetic, and molecular aspects in addition to morphology as diagnostic features. Core needle biopsies are increasingly being used to obtain tissue for diagnosis in patients with lymphadenopathy and a clinical suspicion of lymphoma. These procedures are rapid, minimally invasive, well tolerated, and may provide some architectural framework (unlike fine-needle aspirations), as well as material for ancillary studies. Objective.—To explore the accuracy, utility, and cost-effectiveness of this technique. Design.—Core needle biopsies of 101 consecutive patients from 2 large community hospitals who were suspected of having primary or recurrent lymphomas were retrospectively reviewed. All patients had hematoxylin-eosin–stained sections of needle cores. Specimens morphologically suspicious for lymphoma were subjected to ancillary studies, including immunohistochemistry, flow cytometry, and/or molecular studies. Core needle biopsy diagnoses were correlated with subsequent excisional biopsies, if performed. Results.—Core needle biopsies established a definitive pathologic diagnosis for the vast majority of cases. A diagnosis was considered sufficient to begin treatment for primary and recurrent lymphomas in most cases. Compared with an open biopsy, there is a cost savings of greater than 75%. Conclusion.—The accuracy of this technique, along with the cost savings and decreased morbidity, suggest that this method may be used safely and reliably as a first-line diagnostic technique.
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Christie, Amanda L., Samuel Y. Ng, Raphael Koch, Alexandra N. Christodoulou, Tiffany DeSouza, Mark A. Murakami, Moony Tseng, et al. "T-Cell Lymphoma Patient-Derived Xenografts and Newly Developed Cell Lines Recapitulate Aspects of Disease Biology and Represent Novel Tools for Preclinical Drug Development." Blood 128, no. 22 (December 2, 2016): 3015. http://dx.doi.org/10.1182/blood.v128.22.3015.3015.
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Abstract Lymphomas represent nearly 70 distinct diseases with unique clinical presentations, therapeutic responses and underlying biology. There is a pressing shortage of publically available cell line and in vivo models of nearly all of these diseases; T-cell lymphoma models are particularly under-represented compared to B-cell lymphomas, which has severely hampered efforts to understand and target their biology. The majority ofin vivo models of T-cell lymphomas are genetically-engineered mouse models, which often don't faithfully recapitulate human disease. To address this issue, we have established a repository of patient-derived xenografts (PDX) of lymphomas by engrafting human tumors into immunodeficient NOD/Scid/IL2rgnull mice with or without an MHC Class 1 deficiency (to prevent graft versus host disease). Blood and bone marrow specimens involved with tumor were injected by tail vein injection. Lymph node and extranodal biopsy specimens were implanted under the renal capsule as a 1x1x2mm tumor seed, which maintains the in situ microarchitecture. A description of T-cell lymphoma PDXs is included in the Table. PDXs have been extensively characterized by immunohistochemistry (IHC), flow cytometry, transcriptome sequencing and targeted DNA sequencing. These studies have demonstrated retention of key architectural, cellular, and molecular features of the primary tumors. Flow cytometric analysis of patient tumors and their respective xenografts revealed highly concordant patterns of surface marker expression. IHC of murine tissues confirmed retention of tumor immunophenotypes, architecture, and even tissue tropism in the PDXs. For example, blood from a patient with Sézary Syndrome manifested in the skin of recipient mice when injected into the lateral tail vein. A breast implant-associated ALK-negative anaplastic large cell lymphoma (ALCL) implanted under the renal capsule metastasized to the liver and spleen while uniformly retaining CD30 positivity. A peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) specimen implanted under the renal capsule engrafted in the spleen, with the notable admixture of nonmalignant T cells and scattered EBV-positive B cells in first passage. T-cell receptor gene rearrangement PCR performed on this PTCL-NOS demonstrated an identical rearrangement pattern in the primary tumor and the PDX. An angioimmunoblastic T-cell lymphoma (AITL) specimen engrafted in spleen, lymph node and bone marrow within 6 weeks and serially transplanted through three generations in an orthotopic manner while maintaining a CD3+CD4+PD1+CD30partial immunophenotype. The genetic characterization of the PDX models using a targeted DNA sequencing approach showed a mutational profile that clearly matched primary T-cell lymphoma samples and significantly expands the current repertoire of available pre-clinical models. For example, a PDX model of AITL showed mutations of TET2 and ARID1B; a model of an ALK-negative ALCL harbored mutations of STAT3 and STAT5. This massively extends the spectrum of clinically representative model systems that can be used to explore novel therapeutic strategies for T-cell lymphomas. Several early-passage PDXs have been used to generate T-cell lymphoma cells lines, including three cell lines from AITL PDX models. One of these AITL cell lines has proliferated through 30 passages and was validated by immunophenotype and molecular confirmation of bi-allelic TET2 mutations with loss of 6q, 7q, and 10q confirmed using Sanger and TruSeq Custom Amplicon Sequencings. To our knowledge, there have been no reports of an AITL cell line in the literature. Additional peripheral T-cell lymphoma cell lines are currently under development. These lymphomas, along with a spectrum of PDXs of other hematologic malignancies, are available to collaborators through the online portal PRoXe (Public Repository of Xenografts) at www.proxe.org. These models represent a unique opportunity to interrogate biology and perform preclinical studies with in vivo models. Table 1 Table 1. Disclosures Jacobson: Kite: Membership on an entity's Board of Directors or advisory committees. Armand:Pfizer: Research Funding; Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding; Roche: Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Shipp:Bristol-Myers Squibb: Consultancy, Research Funding; Cell Signaling: Honoraria; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Bayer: Research Funding. Fisher:Pharmacyclics: Consultancy. Weinstock:Novartis: Consultancy, Research Funding.
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Konopleva, Maria V., Maxim S. Belenikin, Andrei V. Shanko, Alexey I. Bazhenov, Sergei A. Kiryanov, Tatyana A. Tupoleva, Maria V. Sokolova, Alexander V. Pronin, Tatyana A. Semenenko, and Anatoly P. Suslov. "Detection of S-HBsAg Mutations in Patients with Hematologic Malignancies." Diagnostics 11, no. 6 (May 27, 2021): 969. http://dx.doi.org/10.3390/diagnostics11060969.
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Multiple studies of hepatitis B virus (HBV) genetic variability and its relationship with the disease pathogenesis are currently ongoing, stemming from growing evidence of the clinical significance of HBV mutations. It is becoming increasingly evident that patients with hematologic malignancies may be particularly prone to a higher frequency of such mutations. The present report is the first extensive study of the prevalence of escape mutations in S-HBsAg, performed using isolates from 59 patients from hospital hematology departments with diagnoses of leukemia (n = 32), lymphoma (n = 20), multiple myeloma (n = 3), and non-tumor blood diseases (n = 4). The isolates were serologically examined for the presence of HBV markers and sequenced using either next-generation sequencing (NGS) or Sanger sequencing. Occult hepatitis B was found in 5.1% of cases. Genetic analysis of the region corresponding to S-HBsAg demonstrated an exceptionally high mutation frequency in patients with leukemias (93.4%) and lymphomas (85.0%), along with the prominent mutation heterogeneity. Additionally, more than 15 mutations in one sample were found in patients with leukemias (6.3% of cases) and lymphomas (5.0% of cases). Most of the mutations were clinically significant. The study analyzes the mutation profile of HBV in different oncohematological diseases and the frequency of individual mutations. The data strongly suggest that the NGS method, capable of detecting minor populations of HBV mutations, provides a diagnostic advantage, lays the foundation for the development of screening methods, and allows for the study of the virological and pathogenetic aspects of hepatitis B.
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Hildebrand, Joanne M., Zhenghua Luo, Michelle Manske, Steven Ziesmer, Tammy Price-troska, Wai Lin, Bruce Hostager, et al. "A BAFF-R Mutation Associated with Non-Hodgkin Lymphoma Exhibits Altered TRAF Binding and Reveals New Insights Into Proximal BAFF-R Signaling." Blood 116, no. 21 (November 19, 2010): 468. http://dx.doi.org/10.1182/blood.v116.21.468.468.
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Abstract Abstract 468 The requirement for BAFF and BAFF-R in normal human and murine B cells is well studied, but there is also significant evidence to suggest that BAFF plays an important role in malignant B cell proliferation and survival. Serum BAFF levels are elevated in patients with non-Hodgkin lymphoma (NHL) and high BAFF levels correlate with aggressive disease and a poor response to therapy. There is also increasing genetic evidence suggesting an association between the development of human disease and genetic variation in genes encoding BAFF and its receptors. Mutations in TNFRSF13B (TACI) were identified in patients with familial common variable immunodeficiency (CVID) and IgA deficiency and we have found that single nucleotide polymorphisms (SNP) in TNFSF13B (BAFF) are associated with elevated BAFF levels and risk for developing NHL. To build upon these findings we sequenced BAFF and its receptors; TNFSF13B, TNFRSF13B, TNFRSF17(BCMA), and TNFRSF13C (BAFF-R) in NHL patients to identify novel genetic variants that may be associated with NHL risk. Among 40 individual samples (20 controls and 20 follicular lymphoma (FL) cases) that were bi-directionally sequenced we identified a heterozygous cytosine to thymidine transition in 1 patient specimen at position 475 (C475T) of TNFRSF13C. The C475T transition encodes a missense substitution of tyrosine for histidine in codon 159 (H159Y) in the highly conserved cytoplasmic tail of BAFF-R, adjacent to the TRAF3 binding motif PVPAT. We next expanded our analysis of BAFF-R H159Y and analyzed NHL tumor biopsies for the presence of the mutation. 4/41 (10%) follicular lymphomas (FL), 2/42 (5%) diffuse large B cell lymphomas, 1/22 (5%) lymphoplasmacytic lymphomas (LPL), and 1/24 (4%) mucosal associate lymphoid tissue lymphomas carried the heterozygous mutation. The BAFF-R H159Y mutation was not detected in any of the normal control DNA from healthy donors (n=100). Given its close proximity to the TRAF3 binding site in the cytoplasmic domain of BAFF-R we first wanted to determine if the H159Y mutation altered BAFF induced signaling. We generated cell lines that express HA-tagged wildtype BAFF-R, BAFF-R with the H159Y mutation, or BAFF-R with an ablated TRAF3 binding site as a negative control. Analysis of cells expressing H159Y BAFF-R demonstrates that this mutation results in increased BAFF-R-mediated NFκB1 and NF-κB2 activation. The enhanced signal activated by BAFF-R H159Y is coupled with a several fold increase in TRAF3, TRAF2, and TRAF6 recruitment to BAFF-R and increased IgM production. We further demonstrate that recruitment of TRAF6 to BAFF-R is not unique to the mutant H159Y BAFF-R, but is also an important and necessary feature of BAFF-R signaling in normal B cells. Collectively, our data identify a novel lymphoma-associated mutation in BAFF-R and describe exciting new aspects of BAFF-R signaling that are important for understanding normal B cell homeostasis and function, as well as pathogenic BAFF-R contributions to human disease. Disclosures: No relevant conflicts of interest to declare.
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Braziel, Rita M., Margaret A. Shipp, Andrew L. Feldman, Virginia Espina, Mary Winters, Elaine S. Jaffe, Emanuel F. Petricoin, and Lance A. Liotta. "Molecular Diagnostics." Hematology 2003, no. 1 (January 1, 2003): 279–93. http://dx.doi.org/10.1182/asheducation-2003.1.279.
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Abstract It is increasingly evident that molecular diagnostics, that is, the use of diagnostic testing to understand the molecular mechanisms of an individual patient’s disease, will be pivotal in the delivery of safe and effective therapy for many diseases in the future. A huge body of new information on the genetic, genomic and proteomic profiles of different hematopoietic diseases is accumulating. This chapter focuses on new technologies and advancements in understanding the molecular basis of hematologic disorders, providing an overview of new information and its significance to patient care. In Section I, Dr. Braziel discusses the impact of new genetic information and research technologies on the actual practice of diagnostic molecular hematopathology. Recent and projected changes in methodologies and analytical strategies used by clinical molecular diagnostics laboratories for the evaluation of hematologic disorders will be discussed, and some of the challenges to clinical implementation of new molecular information and techniques will be highlighted. In Section II, Dr. Shipp provides an update on current scientific knowledge in the genomic profiling of malignant lymphomas, and describes some of the technical aspects of gene expression profiling. Analysis methods and the actual and potential clinical and therapeutic applications of information obtained from genomic profiling of malignant lymphomas are discussed. In Section III, Dr. Liotta presents an update on proteomic analysis, a new and very active area of research in hematopoietic malignancies. He describes new technologies for rapid identification of different important proteins and protein networks, and the potential therapeutic and prognostic value of the elucidation of these proteins and protein pathways in the clinical care of patients with malignant lymphomas.
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Turbatu, Andrei, Andrei Coliţă, Marilena Stoian, Ana-Maria Bordea, Mădălina Oprea, Cecilia Ghimici, Ionel Gelatu, et al. "How Epstein-Barr Virus “Manipulates” The Tumoral Microenvironment in Hodgkin Lymphoma?" Internal Medicine 16, no. 2 (April 1, 2019): 47–52. http://dx.doi.org/10.2478/inmed-2019-0059.
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AbstractThe Epstein-Barr virus (EBV) is a gamma-herpesvirus that colonizes the B-cell system of its human host, allowing it to persist asymptomatically in the majority of the world’s adult population. In most people primary infection goes unnoticed, whereas in a minority of individuals, primary infection results in infectious mononucleosis (IM), a benign condition that almost always resolves after several weeks or months. However, EBV is also causally linked with a number of malignancies, including B-cell lymphomas, such as classical Hodgkin lymphoma (cHL).A proportion of patients with cHL harbor EBV within their tumor cells. Emerging evidence suggests that while EBV is able to subvert cellular processes to promote the growth and survival of HRS cells or their progenitors, mutations in key cell signalization pathways are probably required to do this when EBV is absent. The challenge is to unravel exactly how EBV and its latent genes contribute to the pathogenesis of cHL particularly with respect to how the virus co-operates with cellular genetic and epigenetic changes to drive transformation. It is hoped that the development of better in vitro and in vivo models of disease will reveal more fundamental aspects of EBV’s role in Hodgkin lymphoma pathogenesis and pave the way for targeted therapies for patients with EBV-positive cHL.
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Macintyre, Elizabeth, Dennis Willerford, and Stephan W. Morris. "Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma." Hematology 2000, no. 1 (January 1, 2000): 180–204. http://dx.doi.org/10.1182/asheducation.v2000.1.180.180.
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Abstract The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL. In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly. In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues. In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel “proto-oncogenes” involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcγRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.
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Macintyre, Elizabeth, Dennis Willerford, and Stephan W. Morris. "Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma." Hematology 2000, no. 1 (January 1, 2000): 180–204. http://dx.doi.org/10.1182/asheducation.v2000.1.180.20000180.
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The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL. In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly. In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues. In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel “proto-oncogenes” involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcγRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.
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Cordoba, Raul, María Socorro Rodriguez-Pinilla, Narvaez Javier, Fina Climent, Joaquin Sanchez, Carlos Perez Seoane, Javier Lopez Jimenez, et al. "Peripheral T-Cell Lymphomas in Spain: Profiling Clinical, Phenotypic and Genetic Characteristics in Spanish Population." Blood 132, Supplement 1 (November 29, 2018): 2938. http://dx.doi.org/10.1182/blood-2018-99-116562.
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Abstract Purpose The objective of this study was to investigate clinicopathologic features and prognostic factors of patients diagnosed with PTCL in 13 sites across Spain. Patients and Methods A multicenter, retrospective study was carried out between September 2015-November 2017.Medical charts of patients diagnosed with PTCLs between January 2008 and December 2013 that have signed the approved informed consent form were reviewed. PTCLs were then classified according to the 2016 revision of the WHO classification of lymphoid neoplasms. Clinical characteristics,history, standard immunohistochemistry (IHC) data, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (TCL) (PIT) were also assessed. Medians (range), mean (standard deviation) and frequency as the number of patients (n) and percentages (%) with confidence intervals at 95% (CI95%) were calculated. Overall Survival (OS) and Progression Free Survival (PFS) were analyzed using the Kaplan Meier method. Results 175 (88.4%) patients were successfully analyzed, the male/female ratio was 1.7:1.0, and the median age was 67.2 years (range: 24.8 years -95.8 years). ECOG performance status >1 was reported for 31.9% patients. Ann Arbor stages were III and IV 27.4% and 45.7%, respectively, and LDH levels were elevated to 92 patients (52.6%). Those with B symptoms accounted for 39.4%, while soft tissue was the most frequent location (23,7%) among the 76 patient with extranodal disease; bone marrow infiltration was confirmed in 18.3% patients. Relevant clinical antecedents related to immunological aspects were also frequently reported, including previous neoplasia (18.9%), autoimmune disease (16%), immunosuppressive treatments (7.3%) and previous viral diseases (HIV, HBV or HCV, 5.7%, 4.6% and 7.4%, respectively). Most patients presented with angioimmunoblastic TCL (31.4%); similar proportions of patients were observed among nodal PTCL with TFH phenotype (13.1%, PTCL not otherwise specified (12.0%) and extranodal NK/TCL nasal type (11.4%). CD30 expression and staining pattern (ranged 1-4) allowed the stratification of patients according CD30 intensity (n= 121; weak: 35, moderate: 57, and intense: 29); Patients were also classified based on CD30 expression considering the median value of quantitative CD30 in our sample (15%) the cut-off point: n=132; Negative <15%: 64; Positive, ≥15%: 68). First-line treatment with a CHOP/CHOP-like regimen was the most common finding (69.7%). Best response was observed after a median of 4 months since the start of first-line treatment (range 0.0 months - 65.2 months). Overall response rate after first-line treatment was 66.9%, with 61/151 patients reaching complete response (CR). Median PFS (n=157) and OS (n=175) of this series were 7.87 months (CI95%: 4.98 months-10.75months) and 15.77 months (CI95%: 10.23 months -21.30 months), respectively. Overall, IPI and PIT scores influenced the PFS and OS (p<0.001). A higher number of adverse factors was associated with a shorter survival. Reaching a CR was associated with a better PFS (CR: 62.6m; CI95%: 20.2 months -105.1 months) than the rest of patients (3.97m: CI95%: 3.08 months -4.85m; p<0.001). Response was also associated with OS; patients with CR showed an average OS of 67.01 months (CI95%: 58.2 months -75.9 months) that were significantly longer than that of patients with No-CR (median: 7.34 months; CI95%: 5.85 months -8.83 months; p<0.001). Conclusion This is the largest series of T cell Lymphoma reported in Spain and has allowed the description of distribution of PTCL subtypes, analyzed through central hematopathologists reanalysis and reclassification of samples from 175 PTCL patients, according to the WHO 2016 classification of lymphoid neoplasms. Our data confirm the poor prognosis of these patients, as well as the impact of prognostic indexes and the response to first line treatment on their outcome. Disclosures Rodriguez-Pinilla: Takeda: Honoraria. Piris:Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Kura: Honoraria. Ruiz-Zorrilla:Takeda: Employment. Montoto:Takeda: Employment.
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Liyanage, Marek, Zoë Weaver, Carrolee Barlow, Allen Coleman, Daniel G. Pankratz, Stacie Anderson, Anthony Wynshaw-Boris, and Thomas Ried. "Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice." Blood 96, no. 5 (September 1, 2000): 1940–46. http://dx.doi.org/10.1182/blood.v96.5.1940.
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Abstract Atm-deficient mice (Atm−/−) recapitulate many aspects of the ataxia telangiectasia (AT) syndrome, including the susceptibility to tumors of lymphoid origin. To investigate the mechanism of tumorigenesis, we have examined a panel of 8 thymic lymphomas from Atm−/− mice. AllAtm−/− tumors are of thymic lymphoblastoid origin, display an immature CD3− and CD4+/CD8+ phenotype, and arise coincident with V(D)J recombination. Cytogenetically, all tumors are diploid or near diploid but exhibit multiple chromosome aberrations with an average of 4 abnormal chromosomes per tumor. All the tumors revealed chromosome 14 rearrangements precisely at the T-cell receptorα/δ(Tcrα/δ) locus, suggesting the involvement of V(D)J recombination in these translocations. In addition, 11.5% ofAtm−/− peripheral T cells showed chromosome 14 translocations, suggesting that rearrangements at theTcrα/δ locus occur early during tumor development in the absence of ATM. However, additional genetic aberrations are required for tumorigenesis. For example, translocations involving chromosome 12, often with chromosome 14 (more than 60%), and partial or complete trisomy of chromosome 15, with copy number increases of the c-myc oncogene were frequently observed. These observations suggest that ATM is required for normal rearrangement of the Tcrα/δ locus but not for V(D)J recombination at other loci. The mechanisms that lead to tumorigenesis may be due to the involvement of ATM in monitoring double-stranded DNA breaks.
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Liyanage, Marek, Zoë Weaver, Carrolee Barlow, Allen Coleman, Daniel G. Pankratz, Stacie Anderson, Anthony Wynshaw-Boris, and Thomas Ried. "Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice." Blood 96, no. 5 (September 1, 2000): 1940–46. http://dx.doi.org/10.1182/blood.v96.5.1940.h8001940_1940_1946.
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Atm-deficient mice (Atm−/−) recapitulate many aspects of the ataxia telangiectasia (AT) syndrome, including the susceptibility to tumors of lymphoid origin. To investigate the mechanism of tumorigenesis, we have examined a panel of 8 thymic lymphomas from Atm−/− mice. AllAtm−/− tumors are of thymic lymphoblastoid origin, display an immature CD3− and CD4+/CD8+ phenotype, and arise coincident with V(D)J recombination. Cytogenetically, all tumors are diploid or near diploid but exhibit multiple chromosome aberrations with an average of 4 abnormal chromosomes per tumor. All the tumors revealed chromosome 14 rearrangements precisely at the T-cell receptorα/δ(Tcrα/δ) locus, suggesting the involvement of V(D)J recombination in these translocations. In addition, 11.5% ofAtm−/− peripheral T cells showed chromosome 14 translocations, suggesting that rearrangements at theTcrα/δ locus occur early during tumor development in the absence of ATM. However, additional genetic aberrations are required for tumorigenesis. For example, translocations involving chromosome 12, often with chromosome 14 (more than 60%), and partial or complete trisomy of chromosome 15, with copy number increases of the c-myc oncogene were frequently observed. These observations suggest that ATM is required for normal rearrangement of the Tcrα/δ locus but not for V(D)J recombination at other loci. The mechanisms that lead to tumorigenesis may be due to the involvement of ATM in monitoring double-stranded DNA breaks.
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Peker, Deniz, Yizhou Zhang, Young Yu, Zhigang Zhao, Yafei Wang, Hongliang Yang, Frank Glass, Lynn Moscinski, Lubomir Sokol, and Ling Zhang. "Clinicopathological Characteristics and Clinical Course of CD8 Expressing Primary Cutaneous Peripheral T-Cell Lymphomas (CTCL) - Retrospective Case Study." Blood 118, no. 21 (November 18, 2011): 5213. http://dx.doi.org/10.1182/blood.v118.21.5213.5213.
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Abstract Abstract 5213 Background: CD8-positive primary cutaneous T cell lymphomas (CTCL) are rare disorders and mainly include primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (AECTL) and CD8+ variant mycosis fungoides (MF). In contrast to primary cutaneous CD8+ AECTL, which frequently exhibits strikingly aggressive and unfavorable clinical behavior, CD8+ MF shows debatable clinical course, from an indolent to aggressive behavior. As previously reported, the indolent subtype CD8+ MF occur more frequently in pediatric group, while both clinical subtypes have been observed in adults. Albeit single case studies or small case series have been reported in the literature, it still lacks a large scale of study to enlighten the clinicopathological aspects of CD8+ primary CTCLs, in order to develop the appropriate therapeutic strategies. This study aims to retrospectively review these two entities to demonstrate their clinicopathologic characteristics and to correlate them with the clinical outcome. Design: The hematopathology files from H. Lee Moffitt Cancer Center & Research Institute (PATHNET) and Tianjian Cancer Research Institute were retrieved. The patients with a primary diagnosis of CD8 expressing primary CTCLs, diagnosed and treated between January 2004 and June 2011, were included. Cutaneous involvement by systemic peripheral T-cell lymphoma, primary cutanous gamma delta T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma were excluded. The corresponding patient demographics, laboratory datas, therapeutic strategies and the clinical outcomes were reviewed. All available histology slides, along with all of the ancillary study results were reviewed and correlated with the clinical outcome. Results: Total of 10 cases were included based on the confirmed histomorphological diagnosis. Cases were divided into two groups: 1) CD8+ MF (n=5) and 2) CD8+ non-MF (n=5) including 2 cases with definitive diagnosis of AECTL and 3 cases diagnosed as CD8-positive primary cutaneous T cell lymphoma, not further classifiable. Clinicopathological characteristics including patients' demographic data, diagnosis, site of involvement, treatment, duration of follow up and clinical outcomes are summarized in table 1. The overall survival time for CD8+CTCLs, non-MF type (excluding 1 patient with lost follow up) varied from 5 to 90 months (averaging 20.5 months) while it was shorter in CD8+ MF, 12.6 months (5 to 23 months). Of note, 1 patient with AECTL expired shortly after diagnosis, within 3 months, however; the other one received allogeneic hematopoietic stem cell transplant (allo-HSCT) and has been alive up to date. Conclusion: CD8-positive CTCLs remain a diagnostic challenge. CD8+ MF in adults exhibit dual growth patterns: localized or systemically disseminated disease. The latter could have a very short median overall survival regardless of the aggressive therapies. Allo-HSCT might be beneficial to those with AECTL. Larger series of CD8+ MF should be investigated for molecular gene profiling in order to establish genetic, molecular and phenotypic parameters not only to separate the indolent form from the aggressive subtype, but also to distinguish it from primary cutaneous CD8-positive AECTL. Disclosures: No relevant conflicts of interest to declare.
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Wienand, Kirsty, Bjoern Chapuy, Chip Stewart, Andrew Dunford, David Wu, Jaegil Kim, Atanas Kamburov, et al. "Comparative Genomic Analyses Defines Shared and Unique Features of cHL and PMBL and New Mechanisms of Sensitivity to PD-1 Blockade." Blood 134, Supplement_1 (November 13, 2019): 1493. http://dx.doi.org/10.1182/blood-2019-131904.
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Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (PMBL) are aggressive tumors with distinct cells of origin and pathomorphological features. However, these lymphomas share certain transcriptional signatures and aberrant signaling pathways. CHLs and PMBLs both exhibit constitutive activation of NF-κB and JAK/STAT signaling and genetic bases of PD-1 mediated immune evasion including frequent 9p24.1/PD-L1/PD-L2 copy gains. In both lymphomas, PD-1 blockade is a FDA-approved therapy for relapsed/refractory disease. To characterize genetic bases of response to PD-1 blockade and identify complementary treatment targets in cHL and PMBL, we defined the comprehensive genetic signatures of both diseases. First, we obtained flow cytometry-sorted Hodgkin Reed Sternberg (HRS) cells from 23 biopsies of newly diagnosed cHLs and intact tumor biopsy specimens from 37 newly diagnosed PMBLs. The isolated HRS cells and paired normal DNAs and PMBL biopsy specimens were subjected to whole exome sequencing using an optimized workflow for low input samples and an expanded bait set to capture structural variants (SVs), including translocations. We used newly developed and established analytical pipelines to analyze tumor samples without paired normals (PMBLs) and identify significantly mutated genes (candidate cancer genes [CCGs], MutSig2CV, CLUMPS), SCNAs (GISTIC2.0) and SVs(4 algorithms) in both cHL and PMBL. In cHL, we identified 15 CCGs, 13 recurrent SCNAs, SVs in ETV6 and CIITA, complementary alterations of JAK/STAT, NF-κB and PI3K signaling pathway components and a median number of 11 genetic drivers per tumor. Previously unappreciated aspects of the cHL genetic signature included the increased incidence of driver mutational events in cHLs with ARID1A alterations (p=0.012). Analyses of co-occurring genetic events in EBV+ and EBV- cHLs confirmed that EBV- cHLs were significantly more likely to exhibit alterations of specific NF-κB signaling intermediaries (such as TNFAIP3 mutation and/or focal copy loss, p=0.006) and perturbations of MHC class I antigen presentation pathway components (inactivating B2M mutations, HLA-B mutations or focal copy loss of 6p21.32/HLA-B, p=0.008). The latter findings provide genetic bases for the reported differences in cell surface expression of MHC class I in EBV+ and EBV- cHLs. In PMBL, we defined 15 CCGs and more selective perturbations of specific epigenetic modifiers (ZNF217 and EZH2), transcription factors (PAX5 and IRF2BP2) and TP53, in comparison with cHL. The majority of these alterations were clonal supporting their role as early drivers. We identified 18 SCNAs and additional SVs in CIITA and PD-1 ligands, recurrent alterations of JAK/STAT and NF-κB signaling pathway components and a median of 9 genetic drivers per PMBL. Antigen presentation pathways in PMBL were perturbed by multiple recurrent alterations, including B2M mutations, focal copy losses of B2M and the MHCI/II loci, SVs of CTIIA and EZH2 mutations. There was a significant correlation between genetic perturbations of MHC class I pathway components and absence of MHC class I expression in PMBL, as previously described in cHL. Recurrent cHL alterations including B2M, TNFAIP3, STAT6, GNA13 and XPO1 CCGs and 2p/2p15/2p16.1, 6p21.32, 6q23.2 and 9p/9p24.1 SCNAs were also identified in >20% of PMBLs, highlighting shared pathogenetic mechanisms in these diseases. These tumors of predominantly young adults (median age: cHL 26 yrs; PMBL 34 yrs) both had a high rate of spontaneous deamination of CpGs, a clock-like mutational signature that is typically associated with aging. CHLs and PMBLs both exhibited previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high mutational burdens, in comparison with other lymphoid and solid tumors. In particular, the mutational burden in EBV- cHLs was among the highest reported, similar to that in carcinogen-induced cancers (melanoma and NSCLC). Additionally, both cHLs and PMBLs had an increased incidence of microsatellite instability and APOBEC mutational signatures, features associated with a more favorable response to PD-1 blockade. Taken together, these data define genetic similarities and differences in cHL and PMBL and establish a framework to comprehensively assess molecular bases of response to PD-1 blockade and develop rational combination therapies in these diseases. Disclosures Armand: Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Infinity: Consultancy; Genentech: Research Funding; Tensha: Research Funding. Rodig:Merck: Research Funding; Affirmed: Research Funding; Kite, a Gilead Company: Research Funding; Bristol Myers Squib: Consultancy, Honoraria, Other: Travel Expenses, Speakers Bureau. Fromm:Merck, Inc.: Research Funding. Getz:Pharmacyclics: Research Funding; IBM: Research Funding; MuTect, ABSOLTUE, MutSig and POLYSOLVER: Patents & Royalties: MuTect, ABSOLTUE, MutSig and POLYSOLVER. Shipp:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Merck & Co.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Schwarzinger, Ilse, Markus Exner, Harald Esterbauer, Johannes Drach, Ulrich Jaeger, Andreas Chott, Oswald Wagner, and Berthold Streubel. "Microvessel Endothelial Cells of Hematological Malignancies Harbor Disease Specific Genetic Aberrations." Blood 104, no. 11 (November 16, 2004): 544. http://dx.doi.org/10.1182/blood.v104.11.544.544.
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Abstract The growth of most tumors depends on the formation of new blood vessels. In contrast to genetically unstable tumor cells, endothelial cells of tumor vessels are believed to be normal diploid cells that do not acquire mutations. We have recently observed that microvessel endothelial cells of patients with B-cell lymphomas carry lymphoma specific aberrations (NEJM351:250–9, 2004). The aim of this study was to determine whether hematological malignancies other than B-cell lymphomas also carry disease specific genetic aberrations. Using a combined immunohistochemical and fluorescence in situ hybridization assay, we investigated the endothelial cells of 5 multiple myelomas, 6 anaplastic large cell lymphomas, 1 angioimmunoblastic T-cell lymphoma, 4 chronic myeloid leukemias, 3 acute myeloid leukemias and 1 acute lymphoblastic leukemia for cytogenetic alterations that were known to be present in the malignant hematopoietic cells. We found that microvascular endothelial cells of all investigated cases harbored the disease-specific chromosomal aberrations. The percentages of genetically aberrant endothelial cells were highest in chronic myeloid leukemia (median 63%) and multiple myeloma (median 42%) and lowest in anaplastic large cell lymphoma (median 15%). Our findings suggest that the genetic relationship between tumor cells and their endothelium is a common phenomenon of hematological malignancies and reflect a novel aspect of tumor angiogenesis.
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Epstein, M. A. "Historical background." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1408 (April 29, 2001): 413–20. http://dx.doi.org/10.1098/rstb.2000.0774.
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The persisting ancient view of cancer as a contagious disease ended with 19th century scientific investigations which seemed to show it was not. The resulting dogma against an infectious cause for cancer produced great prejudice in the scientific community against the first report of an oncogenic virus by Rous early in the 20th century and, even in the 1950s, against Gross's finding of a murine leukaemia virus and a murine virus causing solid tumours. The Lucké frog renal carcinoma virus was the first cancer–associated herpesvirus. Intriguingly, an environmental factor, ambient temperature, determines virus genome expression in the poikilothermic frog cells. Although an α–herpesvirus, Marek's disease virus of chickens shares some aspects of biological behaviour with Epstein–Barr virus (EBV) of man. Very significantly, its lymphomas are the first naturally occurring malignancy to be controlled by an antiviral vaccine, with implications for human virus–associated cancers. The circumstances and climate of opinion in which successive γ–herpesviruses were discovered are described. The identification of EBV involved two unconventionalities: its finding in cultured Burkitt's lymphoma cells when no human lymphoid cell had ever been maintained in vitro , and its recognition in the absence of biological activity by the then new technique of electron microscopy. These factors engendered hostility to its acceptance as a new human tumour–associated virus. The EBV–like agents of Old World apes and monkeys and the T–lymphotropic γ–herpesviruses of New World monkeys were found at about the same time, not long after the discovery of EBV. For many years these were thought to be the only γ–herpesviruses of non–human primates; however, very recently B–lymphotropic EBV–like agents have been identified in New World species as well. Mouse herpesvirus 68 came to light by chance during a search for arboviruses and has become important as a laboratory model because of its close genetic relatedness to EBV and its comparable biological behaviour. The discovery of Kaposi's sarcoma–associated herpesvirus six years ago was made using unconventional new methods, but, unlike with EBV 30 years before, this did not hinder its acceptance. This contrast is discussed in the context of the great progress in human tumour virology which has been made in recent years.
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Andreea-Georgiana, Stoica, Tica Irina, Ciocodei Sabina-Livia, Mitroi Anca-Florentina, Brînzan Costel, Nicolau Antonela-Anca, Cozaru Georgeta Camelia, Aschie Mariana, and Ghinea Mihaela Maria. "Primary Pulmonary Small B-Cell Non-Hodgkin Lymphoma -Case Presentation-." ARS Medica Tomitana 26, no. 2 (May 1, 2020): 80–84. http://dx.doi.org/10.2478/arsm-2020-0016.
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Abstract Primary pulmonary non-Hodgkin lymphoma is a rare entity, accounting for 3-4% of extranodal non-Hodgkin lymphomas. Indolent primary pulmonary non-Hodgkin lymphomas are the most frequent types, with the MALT subtype representing majority of cases. Other indolent subtypes of B-cell primary pulmonary lymphomas are rare. We present the case of a 56-year-old patient, non-smoker, who presents for pain in the right hemithorax, worsened by deep inhales. Pulmonary X-ray showed a right paramediastinal superior and medial lobe homogenous opacity with faded contour. Thoracic computed tomography scan described a dense right superior mediastino-pulmonary tumoral mass, the absence of hilar or mediastinal adenopathies. In this context, an ultrasound-guided transbronchial needle aspiration was performed. Histopathology and immunohistochemistry confirmed the diagnosis of primary pulmonary small B-cell non-Hodgkin lymphoma. After 6 chemotherapy cycles, from a clinical and imagistic (thoracic CT scan) point of view, the response was favourable. Positron emission tomography (PET/CT) aspect indicated a complete metabolic response to treatment.
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Duy, Cihangir, Leandro Cerchietti, J. Jessica Yu, Weimin Ci, Srividya Swaminathan, Rahul R. Nahar, Soo-mi Kweon, et al. "BCL6-Dependent Negative Regulation of Cell Cycle Checkpoint Regulators Enables Drug-Resistance in Ph+ Acute Lymphoblastic Leukemia." Blood 114, no. 22 (November 20, 2009): 765. http://dx.doi.org/10.1182/blood.v114.22.765.765.
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Abstract Abstract 765 BCR-ABL1 tyrosine kinase inhibitors (TKI) are widely used for the treatment of patients with Ph+ ALL and CML. To elucidate mechanisms of TKI-resistance in Ph+ ALL, we studied gene expression changes of a set of 11 primary cases of Ph+ ALL in response to TKI-treatment (16 hours; 2 μmol/l Imatinib). Sorting genes based on the ratio of gene expression values in the presence vs the absence of TKI-treatment, the BCL6 gene consistently ranked #1 in this analysis. As confirmed by quantitative RT-PCR and Western blotting, BCL6 is upregulated by 60- to 90-fold in response to TKI-treatment of Ph+ ALL cells. The BCL6 transcription factor functions as a protooncogene in germinal center (GC)-derived B cell lymphomas. We focused our analysis on BCL6, because it functions a transcriptional repressor of p53 and other cell cycle check point regulators and thereby protects GC-derived B cell lymphoma cells from apoptosis. Of note, BCL6 protein levels in TKI-treated Ph+ ALL cells were as high as in GC-derived B cell lymphoma. We hypothesize that dramatic upregulation of the BCL6 gene in response to TKI-treatment represents a defense mechanism of Ph+ ALL to evade cell death induced by activation of p53 and cell cycle checkpoint regulators. We tested the role of BCL6 in Ph+ ALL in a genetic loss-of-function experiment: To this end, B cell precursors from bone marrow of BCL6+/+ and BCL6−/− mice were transformed with BCR-ABL1. Upon treatment with 1 mmol/l Imatinib for three days, viability of BCL6−/− BCR-ABL1 ALL cells (0.4% ± 0.2%) was lower by two log orders compared to BCL6+/+ leukemia cells (46.0% ± 8.2%; p=0.001). Consistent with our hypothesis that p53 and other cell cycle checkpoint regulators are transcriptional targets of BCL6 in Ph+ ALL, we observed in a comprehensive gene expression analysis that mRNA levels of p53, p21, Arf and p27 were significantly higher in BCL6−/− compared to BCL6+/+ and BCR-ABL1 ALL cells (confirmed by quantitative RT-PCR). To identify target genes of the BCL6 transcriptional repressor, we performed a ChIP-chip analysis for BCL6 both in Ph+ ALL and GC-derived B cell lymphoma. Among the 1,235 target genes of BCL6 in Ph+ ALL, 736 were shared targets with GC-derived B cell lymphoma and 499 were exclusive for Ph+ ALL. These findings suggest that the function of BCL6 in Ph+ ALL does not replicate all aspects of its function in GC-B cell lymphoma. Single locus ChIP analysis confirmed strong recruitment of BCL6 to the promoter regions of the p53, p21 (CDKN1A), Arf (CDKN2A) and p27 (CDKN1B) genes in human Ph+ ALL cells after TKI-treatment. In a genetic loss-of-function experiment, we tested whether transcriptional suppression of p53, p21, Arf and p27 represents a major function of BCL6-upregulation in response to TKI-treatment in Ph+ ALL. To this end, we measured sensitivity of wildtype and Arf−/−, p53−/−, p21−/− and p27−/− BCR-ABL1 ALL cells to either Imatinib alone or to a combination of Imatinib and a novel BCL6 peptide inhibitor (RI-BPI). TKI-treatment alone had approximately the same effect in wildtype BCR-ABL1 ALL cells compared to Arf−/−, p53−/−, p21−/− and p27−/− counterparts. However, when TKI-treatment was combined with BCL6 inhibition (5 μmol/l RI-BPI), the viability of Arf−/−, p53−/−, p21−/− and to lesser degree, p27−/−BCR-ABL1 ALL cells was significantly higher than survival of the respective wildtype control leukemia. These findings confirm that transcriptional suppression of Arf, p53 and p21 (to lesser extent p27) represents an important characteristic of BCL6-mediated drug-resistance in response to TKI-treatment. We next tested the potential therapeutic usefulness of concomitant TKI-treatment and BCL6 peptide inhibition: To this end, 2 × 106 BCR-ABL1 ALL cells were luciferase-labeled and injected into sublethally irradiated NOD/SCID mice. Mice were treated six times between days 7 and 21 after leukemia cell injection with either the BCR-ABL1 kinase inhibitor Nilotinib (75 mg/kg) alone or a combination of Nilotinib and RI-BPI (20 mg/kg). Addition of RI-BPI resulted in significantly prolonged median survival (29 days) compared to Nilotinib alone (22 days; 12 mice per group; p=0.004). We conclude that BCL6-mediated transcriptional repression of p53 and other cell cycle checkpoint regulators represents a novel and critical mechanism of drug-resistance in Ph+ ALL. Combination of TKI-treatment with BCL6 peptide inhibition represents a new promising approach to target drug-resistance in Ph+ ALL. Disclosures: No relevant conflicts of interest to declare.
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Tsuyama, Naoko, Kana Sakamoto, Seiji Sakata, Akito Dobashi, and Kengo Takeuchi. "Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects." Journal of Clinical and Experimental Hematopathology 57, no. 3 (2017): 120–42. http://dx.doi.org/10.3960/jslrt.17023.
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McCoyd, Matthew, and Gregory Gruener. "Neurologic Aspects of Lymphoma and Leukemias." CONTINUUM: Lifelong Learning in Neurology 17 (February 2011): 73–94. http://dx.doi.org/10.1212/01.con.0000394675.67372.5c.
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Ambinder, Alexander J., Pareen J. Shenoy, Neha Malik, Alison Maggioncalda, Loretta J. Nastoupil, and Christopher R. Flowers. "Exploring Risk Factors for Follicular Lymphoma." Advances in Hematology 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/626035.
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Follicular lymphoma (FL) is an indolent malignancy of germinal center B cells with varied incidence across racial groups and geographic regions. Improvements in the classification of non-Hodgkin lymphoma subtypes provide an opportunity to explore associations between environmental exposures and FL incidence. Our paper found that aspects of Western lifestyle including sedentary lifestyle, obesity, and diets high in meat and milk are associated with an increased risk of FL. Diets rich in fruits and vegetables, polyunsaturated fatty acids, vitamin D, and certain antioxidants are inversely associated with FL risk. A medical history of Sjogren's syndrome, influenza vaccination, and heart disease may be associated with FL incidence. Associations between FL and exposure to pesticides, industrial solvents, hair dyes, and alcohol/tobacco were inconsistent. Genetic risk factors include variants at the 6p21.32 region of the MHC II locus, polymorphisms of the DNA repair geneXRCC3, and UV exposure in individuals with certain polymorphisms of the vitamin D receptor. Increasing our understanding of risk factors for FL must involve integrating epidemiological studies of genetics and exposures to allow for the examination of risk factors and interactions between genes and environment.
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Takahara, Miki, Takumi Kumai, Kan Kishibe, Toshihiro Nagato, and Yasuaki Harabuchi. "Extranodal NK/T-Cell Lymphoma, Nasal Type: Genetic, Biologic, and Clinical Aspects with a Central Focus on Epstein–Barr Virus Relation." Microorganisms 9, no. 7 (June 25, 2021): 1381. http://dx.doi.org/10.3390/microorganisms9071381.
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Extranodal NK/T-Cell Lymphoma, nasal type (ENKTL-NT) has some salient aspects. The lymphoma is commonly seen in Eastern Asia, has progressive necrotic lesions in the nasal cavity, makes midfacial destructive lesions, and shows poor prognosis. The lymphoma cell is originated from either NK- or γδ T-cells, which express CD56. Since the authors first demonstrated the existence of Epstein–Barr virus (EBV) DNA and EBV oncogenic proteins in lymphoma cells, ENKTL-NT has been recognized as an EBV-associated malignancy. Because the angiocentric and polymorphous lymphoma cells are mixed with inflammatory cells on a necrotic background, the diagnosis of ENKTL-NT requires CD56 immunostaining and EBER in situ hybridization. In addition, serum the EBV DNA level is useful for the diagnosis and monitoring of ENKTL-NT. Although ENKTL-NT is refractory lymphoma, the prognosis is improved by the development of therapies such as concomitant chemoradiotherapy. The basic research reveals that a wide variety of intracellular/cell surface molecules, cytokines, chemokines, and micro RNAs are involved in lymphomagenesis, and some of them are related to EBV. Understanding lymphoma behavior introduces new therapeutic strategies, such as the usage of immune checkpoint inhibitors, peptide vaccines, and molecular targeting therapy. This review addresses recent advances in basic and clinical aspects of ENKTL-NT, especially its relation to EBV features.
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Choi, Sarah M., Bryan L. Betz, and Anamarija M. Perry. "Follicular Lymphoma Diagnostic Caveats and Updates." Archives of Pathology & Laboratory Medicine 142, no. 11 (September 17, 2018): 1330–40. http://dx.doi.org/10.5858/arpa.2018-0217-ra.
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Context.— Follicular lymphoma is a common small B-cell lymphoma, likely to be encountered by any practicing pathologist, regardless of specialty. Although the features of typical follicular lymphoma are well known and in most instances easily identifiable, there are lesser-appreciated morphologic appearances that can raise alternative diagnostic possibilities. The limited tissue available in core needle biopsies can make it additionally challenging to thoroughly evaluate those features in the context of architecture. Furthermore, ancillary testing including immunohistochemistry and molecular/genetic analysis do not always show classic findings and may pose additional challenges to interpretation. Objectives.— To review the morphologic features of follicular lymphoma with a discussion of morphologic variants and mimics; to discuss pitfalls of ancillary testing and provide the practicing pathologist with an appropriate context for interpretation of immunohistochemical and molecular/genetic studies when follicular lymphoma is part of the differential diagnosis; and to propose diagnostic strategies when there is limited tissue for evaluation. Data Sources.— We used examples of follicular lymphoma from our institution as well as a review of the literature, with a focus on the diagnostic aspects that are broadly relevant to a general pathology practice. Conclusions.— Follicular lymphoma can occasionally present with atypical morphologic, immunohistochemical, or molecular/genetic features. In particular, those findings can be difficult to interpret in the setting of a limited tissue sample. Awareness of those possibilities will help guide the pathologist to a more accurate and precise diagnosis.
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Couronné, Lucile, Christian Bastard, Philippe Gaulard, Olivier Hermine, and Olivier Bernard. "Aspects moléculaires des lymphomes T périphériques (2)." médecine/sciences 31, no. 11 (November 2015): 1023–33. http://dx.doi.org/10.1051/medsci/20153111017.
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McGee, Rose B., and Kim E. Nichols. "Introduction to cancer genetic susceptibility syndromes." Hematology 2016, no. 1 (December 2, 2016): 293–301. http://dx.doi.org/10.1182/asheducation-2016.1.293.
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AbstractThe last 30 years have witnessed tremendous advances in our understanding of the cancer genetic susceptibility syndromes, including those that predispose to hematopoietic malignancies. The identification and characterization of families affected by these syndromes is enhancing our knowledge of the oncologic and nononcologic manifestations associated with predisposing germ line mutations and providing insights into the underlying disease mechanisms. Here, we provide an overview of the cancer genetic susceptibility syndromes, focusing on aspects relevant to the evaluation of patients with leukemia and lymphoma. Guidance is provided to facilitate recognition of these syndromes by hematologists/oncologists, including descriptions of the family history features, tumor genotype, and physical or developmental findings that should raise concern for an underlying cancer genetic syndrome. The clinical implications and management challenges associated with cancer susceptibility syndromes are also discussed.
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Schultze, J. L., F. Fiore, and M. von Bergwelt-Baildon. "DCs in lymphoma — biology and therapeutic aspects." Cytotherapy 6, no. 2 (April 2004): 138–47. http://dx.doi.org/10.1080/14653240410006095.
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Nguyen, Lynh, Peter Papenhausen, and Haipeng Shao. "The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects." Genes 8, no. 4 (April 5, 2017): 116. http://dx.doi.org/10.3390/genes8040116.
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Dave, Sandeep S. "Host Factors for Risk and Survival in Lymphoma." Hematology 2010, no. 1 (December 4, 2010): 255–58. http://dx.doi.org/10.1182/asheducation-2010.1.255.
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Abstract All cancers arise from complex interactions between aspects of the patient (host) biology and the environment. Once tumors arise, they frequently remain dependent on interactions with their microenvironment for their growth and proliferation. In this review, we examine the contributions of the host genetics and environmental exposures to the development of lymphoma. We will further examine the interactions of the tumor and the microenvironment that influence tumor growth and proliferation.
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Naderi, Nadia, and David T. Yang. "Lymphoplasmacytic Lymphoma and Waldenström Macroglobulinemia." Archives of Pathology & Laboratory Medicine 137, no. 4 (April 1, 2013): 580–85. http://dx.doi.org/10.5858/arpa.2012-0034-rs.
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Lymphoplasmacytic lymphoma (LPL) is a low-grade, B-cell neoplasm composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that typically involve the bone marrow, and it is associated with an immunoglobulin M (IgM) gammopathy. The definition of Waldenström macroglobulinemia (WM) and its relationship to LPL has been confusing in the past. In addition, the diagnosis of LPL itself can be challenging because LPL lacks disease-specific morphologic, immunophenotypic, and genetic features to differentiate it from other mature B-cell neoplasms. Accurate diagnosis of LPL/WM rests on recognition of the differential diagnostic features between LPL and other diagnostic possibilities and the use of the recently refined definition of WM and its relationship with LPL: The presence of an IgM monoclonal gammopathy of any level in the setting of bone marrow involvement by LPL. This review summarizes the clinical, laboratory, and histologic features of LPL/WM, with particular emphasis on unique aspects of LPL/WM that may aid in accurate diagnosis.
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Clive, D., P. Glover, M. Applegate, and J. Hozier. "Molecular aspects of chemical mutagenesis in L5178Y/tk+/− mouse lymphoma cells." Mutagenesis 5, no. 2 (1990): 191–98. http://dx.doi.org/10.1093/mutage/5.2.191.
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Franchini, Genoveffa, Richard F. Ambinder, and Michèle Barry. "Viral Disease in Hematology." Hematology 2000, no. 1 (January 1, 2000): 409–23. http://dx.doi.org/10.1182/asheducation.v2000.1.409.20000409.
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As part of the international outreach of the American Society of Hematology, this review addresses some aspects of the genetics, biology, epidemiology, and clinical relevance of viruses that cause a variety of hematopoietic disorders in human populations. The viruses described here have a different pattern of geographical distribution, and the disease manifestations may vary according to environmental and/or genetic characteristics of the host. Epstein-Barr virus, a linear double-stranded DNA virus (herpesvirus), and the human T-cell leukemia virus, a retrovirus with a single-stranded diploid RNA genome, are associated among other diseases with lymphoma and leukemia/lymphoma, respectively. Both viruses cause a lifelong infection, but only a small percentage of infected individuals develop hematopoietic neoplasms. Epidemiological data suggest that the time of infection may be important in determining disease outcome in both HTLV-I and EBV infection. The pathogenic mechanisms used by these viruses are of most interest since they may recapitulate growth dysregulation steps also occurring in other hematopoietic malignancies.In Section I Dr. Franchini reviews the biology, genetics and diseases associated with HTLV-I and HTLV-II. In Section II, Dr. Ambinder reviews the biology of EBV infection and its relationship to the pathogenesis of Hodgkin's disease and other malignancies.In Section III, Dr. Barry reviews the viral hemorrhagic fevers caused by RNA viruses such as Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae, which can lead to acute syndromes that can be fatal. However, prompt diagnosis is key for patient management as well as for limiting their spread to others. These syndromes have become the focus of public concern and represent not only a clinical challenge, since in most cases no specific antiviral treatment is available, but also a challenge for future basic research on their biology and pathogenesis since little is known at present.
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Franchini, Genoveffa, Richard F. Ambinder, and Michèle Barry. "Viral Disease in Hematology." Hematology 2000, no. 1 (January 1, 2000): 409–23. http://dx.doi.org/10.1182/asheducation.v2000.1.409.409.
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Abstract As part of the international outreach of the American Society of Hematology, this review addresses some aspects of the genetics, biology, epidemiology, and clinical relevance of viruses that cause a variety of hematopoietic disorders in human populations. The viruses described here have a different pattern of geographical distribution, and the disease manifestations may vary according to environmental and/or genetic characteristics of the host. Epstein-Barr virus, a linear double-stranded DNA virus (herpesvirus), and the human T-cell leukemia virus, a retrovirus with a single-stranded diploid RNA genome, are associated among other diseases with lymphoma and leukemia/lymphoma, respectively. Both viruses cause a lifelong infection, but only a small percentage of infected individuals develop hematopoietic neoplasms. Epidemiological data suggest that the time of infection may be important in determining disease outcome in both HTLV-I and EBV infection. The pathogenic mechanisms used by these viruses are of most interest since they may recapitulate growth dysregulation steps also occurring in other hematopoietic malignancies. In Section I Dr. Franchini reviews the biology, genetics and diseases associated with HTLV-I and HTLV-II. In Section II, Dr. Ambinder reviews the biology of EBV infection and its relationship to the pathogenesis of Hodgkin's disease and other malignancies. In Section III, Dr. Barry reviews the viral hemorrhagic fevers caused by RNA viruses such as Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae, which can lead to acute syndromes that can be fatal. However, prompt diagnosis is key for patient management as well as for limiting their spread to others. These syndromes have become the focus of public concern and represent not only a clinical challenge, since in most cases no specific antiviral treatment is available, but also a challenge for future basic research on their biology and pathogenesis since little is known at present.
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Colafrancesco, Serena, Cinzia Ciccacci, Roberta Priori, Andrea Latini, Giovanna Picarelli, Francesca Arienzo, Giuseppe Novelli, Guido Valesini, Carlo Perricone, and Paola Borgiani. "STAT4, TRAF3IP2, IL10, and HCP5 Polymorphisms in Sjögren’s Syndrome: Association with Disease Susceptibility and Clinical Aspects." Journal of Immunology Research 2019 (February 10, 2019): 1–8. http://dx.doi.org/10.1155/2019/7682827.
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Sjögren’s syndrome (SS) is a chronic autoimmune condition characterized by autoantibody production, sicca syndrome, and periepithelial lymphocytic lesions in target tissues. A predisposing genetic background is likely, and, to date, several polymorphisms in non-HLA genes have been explored with interesting results. We investigated the association between the STAT4, TRAF3IP2, HCP5, and IL10 polymorphisms and SS susceptibility and their possible role in the modulation of clinical and laboratory features. 195 consecutive patients with SS were enrolled and clinical and laboratory data were collected. 248 age- and sex-matched healthy subjects were used as controls. Genotyping was performed by allelic discrimination assays. A case-control association study and a phenotype-genotype correlation analysis were performed. A genetic risk profile was developed considering the risk alleles. Both the variant alleles of rs7574865 in the STAT4 gene and rs3099844 in the HCP5 gene were significantly more prevalent in patients than in controls (OR=1.91 and OR=2.44, respectively). The variant allele of rs3024505 of IL10 resulted to be a susceptibility allele (OR=1.52), while the variant allele of rs1800872 seemed to confer a protective effect for the development of the disease (OR=0.65). A risk genetic profile showed a higher probability to develop the disease in subjects with at least three risk alleles; subjects with 4 risk alleles were not observed in the controls. HCP5 rs3099844 was associated with anti-SSA (P=0.006, OR=3.07) and anti-SSB (P=0.005, OR=2.66) antibodies, severity of focus score (P=0.03, OR=12), and lymphoma development (P=0.002, OR=7.23). Patients carrying the STAT4 rs7574965 variant allele had a higher risk of monoclonal component and leukopenia (P=0.002, OR=7.6; P=0.048, OR=2.01, respectively). We confirmed the association of SS with the STAT4 and IL10 genes and we describe a novel association with HCP5. In particular, we describe an association of this specific SNP of HCP5 not only with disease development but also with autoantibody production and focus score suggesting a potential contribution of this variant to a more severe phenotype.
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Kang, Jeong-Eun, In-Suk Kim, Nam-Hee Kim, and Min Kyoung Kim. "Genetic Variations In Immune Regulatory Genes and The Risk For Diffuse Large B-Cell Lymphoma." Blood 122, no. 21 (November 15, 2013): 4286. http://dx.doi.org/10.1182/blood.v122.21.4286.4286.
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Abstract Introduction There is growing evidence linking genetic variations of immune regulation genes to non-Hodgkin lymphoma (NHL) etiology. In a large consortial study, it has been recently reported that an increased risk for NHL, especially the major lymphoma subtype diffuse large B-cell lymphoma (DLBCL), with genetic variations in immune regulatory genes that mediate inflammation and autoimmunity. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 57 genetic variations of 7 candidate genes, and their relation to risk for DLBCL in Koreans. Methods The case-control series consisted of 192 de novo DLBCL treated at five hospitals throughout Korea from August 2001 through August 2009 and 192 individuals from the population with age and gender matched healthy volunteers. The DNA samples were genotyped using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (Sequenom, Inc., San Diego, CA). We genotyped 11 haplotype-tagging SNPs (htSNPs) of spleen tyrosine kinase (STK), 9 htSNPs of Fc fragment of IgG, low affinity IIa, receptor (FCGR2A), 3 htSNPs of Fc fragment of IgG, low affinity IIIa, receptor (FCGR3A), 15 htSNPs of interferon regulatory factor 4 (IRF4), 9 htSNPs of interleukin 7 receptor (IL7R), 7 htSNPs of interleukin 10 (IL10), and 3 htSNPs of tumor necrosis factor (TNF) genes. We used logistic regression to evaluate the association between genotypes and haplotypes with DLBCL. For DLBCL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the co-dominant model for each SNP. The haplotypes were reconstructed according to the genotyping data and the linkage disequilibrium status of these SNPs. Results We did not find significant associations between the htSNPs of FCGR2A, FCGR3A, IRF4, IL7R, and TNF genes and the risk of DLBCL. However, the minor allele heterozygotes of the rs3021094 htSNP of IL10 gene (P-trend = 0.028) and the rs2991216 htSNP of the SYK gene (P-trend = 0.035) showed an increased risk of DLBCL. On 10-million permutation testing, the haplotype including rs3021094 variant allele of IL10 gene was significantly associated with an increased risk of DLBCL (P = 0.001), however, the haplotype including rs2991216 variant allele of STK gene was statistically insignificant (P = 0.055). Conclusions This study presents several novel aspects of the genetic susceptibility to develop DLBCL. Although this study did not show statistically significant association between STK htSNPs and risk for DLBCL on 10-millinon permutation testing, we demonstrated that genetic variants and haplotypes of IL10 gene showed the significantly increased risk for DLBCL. Larger studies that focus on the role of the STK and IL10 genes will support to confirm causal variants to develop diffuse large B-cell lymphoma. Disclosures: No relevant conflicts of interest to declare.
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Saulite, Ieva, Wolfram Hoetzenecker, Stephan Weidinger, Antonio Cozzio, Emmanuella Guenova, and Ulrike Wehkamp. "Sézary Syndrome and Atopic Dermatitis: Comparison of Immunological Aspects and Targets." BioMed Research International 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/9717530.
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Sézary syndrome (SS), an aggressive form of erythrodermic pruritic cutaneous T cell lymphoma (CTCL), from an immunological perspective characterized by increased Th2 cytokine levels, elevated serum IgE and impaired cellular immunity. Not only the clinical appearance but also the hallmark immunological characteristics of SS often share striking similarities with acute flares of atopic dermatitis (AD), a common benign chronic inflammatory skin disease. Given the overlap of several immunological features, the application of similar or even identical therapeutic approaches in certain stages of both diseases may come into consideration. The aim of this review is to compare currently accepted immunological aspects and possible therapeutic targets in AD and SS.
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Fujiwara, Shigeyoshi, and Hiroyuki Nakamura. "Chronic Active Epstein–Barr Virus Infection: Is It Immunodeficiency, Malignancy, or Both?" Cancers 12, no. 11 (October 30, 2020): 3202. http://dx.doi.org/10.3390/cancers12113202.
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Chronic active Epstein–Barr virus (EBV) infection (CAEBV) is a rare syndrome characterized by prolonged infectious mononucleosis-like symptoms and elevated peripheral blood EBV DNA load in apparently immunocompetent persons. CAEBV has been primarily reported in East Asia and Latin America, suggesting a genetic predisposition in its pathogenesis. In most cases of CAEBV, EBV induces proliferation of its unusual host cells, T or natural killer (NK) cells. The clinical course of CAEBV is heterogeneous; some patients show an indolent course, remaining in a stable condition for years, whereas others show an aggressive course with a fatal outcome due to hemophagocytic lymphohistiocytosis, multiple organ failure, or progression to leukemia/lymphoma. The pathogenesis of CAEBV is unclear and clinicopathological investigations suggest that it has aspects of both malignant neoplasm and immunodeficiency. Recent genetic analyses of both viral and host genomes in CAEBV patients have led to discoveries that are improving our understanding of the nature of this syndrome. This article summarizes the latest findings on CAEBV and discusses critical unsolved questions regarding its pathogenesis and disease concept.
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Foieni, Fabrizio, Andrea Zanichelli, Anna Coerezza, Roberto Castelli, Lorena Maggioni, Chiara Suffritti, Erika Bonanni, Augusto B. Federici, and Marco Cicardi. "Lymphoproliferative Disorder and Acquired C1-INH Deficiency. A Case Series of 48 Patients." Blood 118, no. 21 (November 18, 2011): 1596. http://dx.doi.org/10.1182/blood.v118.21.1596.1596.
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Abstract Abstract 1596 Angioedema with acquired deficiency of C1 inhibitor (C1-INH) is a rare syndrome associated with B lymphocyte disorders, usually identified as acquired angioedema (AAE). The clinical features of C1-INH deficiency, more often of genetic origin (hereditary angioedema HAE), include subcutaneous swelling, edema of the gastrointestinal wall causing temporary bowel obstruction with severe pain and edema of the upper respiratory tract that can lead to asphyxia. AAE associated B cell disorders result in autoantibodies to C1-INH, monoclonal gammopathies of uncertain significance (MGUS) and non Hodgkin Lymphomas (NHL). The 3 conditions may be concomitantly present suggesting that expansion of an anti C1-INH B lymphocyte clone is the primum movens of the disease. The burden of AAE derives from either the associated limphoproliferative disorder or the frequency and severity of angioedema symptoms: both conditions may lead to death. Here we report on the long term follow up of 48 patients (median age at onset of angioedema symptoms 57, range 39/79) with AAE with specific focus on the fate of lymphoproliferative disease and on the therapeutic problems. Patients were followed for a median of 6 years ( 1–25); diagnosis was based on C1-INH activity <50% of normal. Autoantibodies to C1-INH were positive in 35 of 48 patients (13 IgG, 13 IgM, 5 IgA, 2 IgG-IgM, 2 IgA-IgM). Nineteen (40%) fulfilled diagnostic criteria for MGUS. MGUS and auto antibodies to C1-INH coexisted in 13 patients all, but one, sharing the same heavy chain isotype. In 7, binding of the M component to purified C1-INH could be demonstrated. Twelve patients presented NHL. Based on WHO classification 10 had indolent lymphoma (2 lymphoplasmocytic/Waldestrom disease; 4 small lymphocytic lymphoma, 4 splenic marginal zone lymphoma, 1 follicular lymphoma). Median time between onset of angioedema symptom and diagnosis of NHL was 1 year (ranging from 15 years before to 12 years after). One lymphocytic and 1 marginal splenic lymphoma did not need treatment at 5 and 8 years follow up respectively. Two marginal splenic lymphoma are in remission after splenectomy at 2 and 7 years follow up. One marginal splenic lymphoma remitted upon splenectomy, chemotherapy and rituximab (3 years follow up). One lymphoplasmocytic lymphoma is in remission 2 years after rituximab. Two lymphocytic lymphoma remain on control with chemotherapy at 16 and 3 years respectively. One lymphoplasmocytic lymphoma progessed to death despite chemotherapy and rituximab. One follicular lymphoma is in remission 6 years after chemotherapy. Two high grade malignant lymphoma, a large B cell and a mantle cell, both progressed to death within 12 months despite chemotherapy and splenectomy the first and chemotherapy the second. Reversal of complement abnormalities was achieved upon therapy induced remission of NHL. Because of the frequency of angioedema recurrences 28 patients required prophylactic treatment successfully achieved with tranexamic acid in 23 patients and with danazol in 5. Breakthrough angioedema attacks were treated with plasma derived C1-INH, which was effective in 16 patients and non effective in 8. In these 8 patients, angioedema attacks were successfully treated with icatibant, a specific antagonist of the B2 receptors of bradykinin, the mediator of symptoms (median time to resolution 6.75 hours, range 0.5–39.75 hours). Ecallantide, a recombinant small protein that blocks plasma kallikrein, the bradykinin releasing enzyme, has also been successfully used to treat two angioedema attacks in two patients. During the follow up period 5 patients died for causes other than NHL or angioedema and one patient is in irreversible cerebral coma for severe hypoxia following a laryngeal edema, which did not respond to plasma derived C1-INH (icatibant was not available at that time). Our data suggest that in AAE different forms of B cells disorders coexist and/or evolve into each other probably starting from the pathologic prolypheration of clone(s) autoreactive against C1-INH. Hence, angioedema symptoms and B cell disorders are two aspect of a single disease. Blocking bradykinin or its release are valid alternatives to treat angioedema symptoms and may be lifesaving therapies for those patients who do not respond to plasma derived C1-INH. Disclosures: Off Label Use: Icatibant, a specific antagonist of the B2 receptors of bradykinin, registered in Europe for the treatment of acute attacks in patients with Hereditary Angioedema. Zanichelli:Shire: Membership on an entity's Board of Directors or advisory committees. Cicardi:Shire: Consultancy, Speakers Bureau; Dyax: Consultancy, Speakers Bureau.
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Istrate Ofiteru, Anca Maria, Sabina Berceanu, Stefan Paitici, Gabriela Camelia Rosu, Larisa Iovan, Nicoleta Loredana Voicu, Daniel Pirici, et al. "Endometriosis of the Abdominal Wall - Clinical, Histopathological and Immunohistochemical Aspects." Revista de Chimie 70, no. 8 (September 15, 2019): 2860–65. http://dx.doi.org/10.37358/rc.19.8.7444.
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Endometriosis is a benign gynecological pathology that mostly affects the organs of the pelvis,but also organs located at a distance maybe affected. Tissue immunohistochemically identified as ectopic endometrium may undergo certain structural and functional changes that may lead to preneoplastic alterations (hyperplasia, dysplasia) in normal cellswhich can evolve to neoplasia. Clinical, genetic, metabolic conditions and local factors may influence degenerationof a benign pathology into a malignant pathology. Endometriosis of the abdominal wall is more frequently encountered, as the number of casarean section has increased. Endometriomas surrounding tissue has a direct impact on the structure of the cells that form the mass. By remodeling cellular morphology, corroborated with the hormonal factors action and the inflammatory response ( via lymphocyte cell secretion), the cell cycle is altered and antiapoptotic activity may be promoted. Immune system via lymphocyte cell secretion, the pressure exerted on the tumor area by surrounding tissueswith its size change, conditioned by the fluctuation of hormonal factors, act directly on the cellular structure and can increase anti-apoptotic action and decrease cell cycle regulation. The presence of endometriomas is identified by the positivity of immunohistochemical reactions for estrogen receptors (ER), progesteron receptors (PR), Cytokeratin 7 (CK7) for endometrial tissue. Negative reaction at Cytokeratin 20 (CK20) shows that the studied area is not a metastasis of a digestive tumor. The presence of abundant inflammatory, peritumoral cells markedwith anti-CD68 / Tryptase for macrophages / mast cells demonstrates the involvement of the inflammatory system in the structural and functional modification of endometrial cells.The pronounced cell division was demonstrated by intense reaction with the anti-Ki67 antibody.The signigicant anti-apoptotic action of the endometrial tissue is shown by the positivity of anti-B cell Lymphoma 2 (BCL2) / anti-Phosphatase and tensin homolog (PTEN) / anti-p53 antibodies.
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Ponader, Sabine, and Jan A. Burger. "Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies." Journal of Clinical Oncology 32, no. 17 (June 10, 2014): 1830–39. http://dx.doi.org/10.1200/jco.2013.53.1046.
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Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy.
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Thieblemont, Catherine, Remi Houlgatte, Pascale Felman, Alexandra Traverse-glehen, Lucile Baseggio, Delphine Rolland, Evelyne Callet-Bauchu, Gilles Salles, Francoise Berger, and Bertrand Coiffier. "Indolent Mantle Cell Lymphoma (MCL): A Retrospective Detailed Clinical and Morphological Analysis of 21 Patients, with Histological, Cytological, Cytogenetic, Interphase Genetic, Immunoglobulin Gene, and Gene Expression Profiling Analysis." Blood 112, no. 11 (November 16, 2008): 1780. http://dx.doi.org/10.1182/blood.v112.11.1780.1780.
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Abstract MCL is a well-defined lymphoid neoplasm characterized by a proliferation of mature B lymphocytes expressing CD5 and with a genetic hallmark, the t(11;14) (q13;q32) translocation leading to the overexpression of cyclin D1, considered as the initial oncogenic event. However this entity may show a spectrum of morphological features broader than initially described. Clinically most of the patients have a poor prognosis with a rapid acquisition of chemoresistance. It has been recently described that some patients may follow an indolent clinical evolution, with the possibility of confusion in diagnosis because of overlapping morphological features with other small B cell lymphomas such as marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL). The aim of our study was to analyze patients treated for a B cell lymphoma bearing the t(11;14)(q13;q32) who had a good outcome with a long survival. We retrospectively selected 21 patients (pts) with a t(11;14) B cell lymphoma and who followed an indolent outcome defined by an overall survival of more than 5 years after no more than 1 therapeutic regimen. Feature review included morphologic aspect, immunophenotype, cytogenetics, immunoglobulin (Ig) variable heavy chain (VH) gene usage and mutation patterns. Expression of CD5, CD10, CD23, and CD43, were evaluated on CD19+ cells by FCM. Cytogenetic analysis consisted in conventional cytogenetics on fresh tissue samples completed by a FISH analysis against 11q, 12p, 17p, and 18p realized on fresh frozen material. We further analysed the gene expression profiling of available samples using quantitative real-time PCR using microfluidic cards designed with selected genes of 3 independent signatures (Rosenwald A, et al. Cancer Cell 2003 - Ruiz-Ballesteros E, et al. Blood 2005 - Thieblemont C, et al. Blood 2004). Clinical characteristics showed that median age was 61 (range 45–81). All pts had a good PS and presented with a disseminated disease: bone marrow and blood involvement in 19 (90%) and 11/17 (65%) pts, respectively; peripheral and profound nodes involvement in 15 (71%); and splenomegaly in 13 (62%). LDH and b2-microglobulin levels were elevated in 4 pts. None of the pts had a monoclonal component. IPI score was low in 18 (86%) pts. Splenectomy alone or with chemotherapy (chlorambucil or fludarabine in 4; CHOP in 1) was proposed in 7 pts; monochemotherapy (chlorambucil or fludarabine) in 4 pts, CHOP +/− rituximab (R) in 2 pts, CHOP +/− R followed by autotransplant in 8. One pt did not receive any treatment. With a median follow-up at 6.44 years, median overall survival was 9.18 years. Morphologic review distinguished 2 groups of cases: true MCL cases (MCL, n = 8) and BorderLine Cases (BLC, n=13). Among the 8 MCL and 13 BCL, 7 and 12 were CD5+, 1 and 4 CD5/CD23+, 4 and 5 CD43+, respectively. All cases exhibited a t(11;14), associated with a complex caryotype in 5/8 (62%) MCL and in 9/13 (69%) BLC. Chromosome 7q deletion (n=1) and trisomy chr3/3q (n=3) were present only in BLC cases. IgVH gene was unmutated in 10 cases (3 MCL, 7 BLC) and mutated in 4 (2 MCL, 2 BLC). The most common VH families were VH1 (n=4), VH 3 (n=8) and VH4 (n=3). From the gene expression profiling studies we selected 70 genes specific of the diagnosis of MCL, MZL and SLL. A set of 5 MCL, 5 SLL, and 5 MZL control samples allowed us to validate 25 out of these 70 genes. These 25 genes were further used to analyse MCL and BLC samples. All these samples exhibited a more heterogeneous profile than control samples. Three MCL were more similar to MCL samples, whereas two were closer to MZL samples. All the BLC exhibited a profile close to that of MZL. We further analysed these samples with the 18 gene-signature predicting MCL survival. This signature could not discriminate survival of these MCL and BCL pts. In conclusion, pts with B cell lymphoma bearing the translocation t(11;14)(q13;q32) and with an indolent outcome can be distinguished in at least 2 groups with different characteristics in terms of morphology, immunophenotype, caryotype, and molecular profiles. Using a 25 gene-signature, we found profiles similar to either MCL or MZL for MCL samples, and similar to MZL for BCL samples. The signature discriminating the survival of MCL could not discriminate these indolent MCL. These findings will be validated on a larger series.
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Julio Delgado, Ferran Nadeu, Dolors Colomer, and Elias Campo. "Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies." Haematologica 105, no. 9 (July 3, 2020): 2205–17. http://dx.doi.org/10.3324/haematol.2019.236000.
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Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. All this knowledge has offered new perspectives that are being exploited therapeutically with novel target agents and management strategies. In this review we provide an overview of these novel advances and highlight questions and perspectives that need further progress to translate into the clinics the biological knowledge and improve the outcome of the patients.
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Lombardo, Vania, Fania Puccia, Antonino Terranova, Andrea Affronti, Ada Maria Florena, Lydia Giannitrapani, and Maurizio Soresi. "Hemophagocytic syndrome in a patient with disseminated tuberculosis: a case report." Italian Journal of Medicine 12, no. 1 (March 20, 2018): 61. http://dx.doi.org/10.4081/itjm.2018.932.
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Hemophagocytic syndrome (HS) is a rare disorder of the immune system. It is characterized by fever, lymphadenopathy, hepatosplenomegaly, cytopenia and hyperferritinemia. The cause differs in each country suggesting a specific genetic background and epidemiology of infections, and it can be associated with malignant diseases. A rare cause of HS is tuberculosis (TB), we describe a case of HS associated with disseminated Mycobacterium tuberculosis (MT) infection in a patient from Sudan. He presented diarrhea, fever, pancytopenia, thickened and dilated bowel loops and lymph nodes enlargement at ultrasound and computed tomography scan. A bone marrow biopsy performed to rule out a lymphoma revealed a HS. The bronchoalveolar lavage (BAL) culture was then positive for MT and subsequently, radiologic aspects of lung and spleen TB involvement appeared. A disseminated tuberculosis was diagnosed. Despite antituberculous therapy, the patient died as in approximately 50% of the HS associated with TB.
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Fairlie, Walter Douglas, and Erinna F. Lee. "Co-Operativity between MYC and BCL-2 Pro-Survival Proteins in Cancer." International Journal of Molecular Sciences 22, no. 6 (March 11, 2021): 2841. http://dx.doi.org/10.3390/ijms22062841.
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B-Cell Lymphoma 2 (BCL-2), c-MYC and related proteins are arguably amongst the most widely studied in all of biology. Every year there are thousands of papers reporting on different aspects of their biochemistry, cellular and physiological mechanisms and functions. This plethora of literature can be attributed to both proteins playing essential roles in the normal functioning of a cell, and by extension a whole organism, but also due to their central role in disease, most notably, cancer. Many cancers arise due to genetic lesions resulting in deregulation of both proteins, and indeed the development and survival of tumours is often dependent on co-operativity between these protein families. In this review we will discuss the individual roles of both proteins in cancer, describe cancers where co-operativity between them has been well-characterised and finally, some strategies to target these proteins therapeutically.
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Johnston, Patrick B., Amanda F. Cashen, Petros G. Nikolinakos, Anne W. Beaven, Stefan Klaus Barta, Gajanan Bhat, Tao Song, et al. "Safe and Effective Treatment of Patients with Peripheral T-Cell Lymphoma (PTCL) with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial." Blood 126, no. 23 (December 3, 2015): 253. http://dx.doi.org/10.1182/blood.v126.23.253.253.
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Abstract Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis and repeated recurrence for most subtypes. Currently, anthracycline-based therapies such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like therapies are recommended as the first-line treatment for PTCL, but the prognosis remains poor with most patients relapsing within 5 years. Thus, improved treatment strategies are still needed. Belinostat is a potent, pan-histone deacetylase inhibitor that was recently approved in the United States for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 BELIEF study (O'Connor et al, JCO, 2015) of belinostat in R/R PTCL, which demonstrated durable clinical benefit (objective response rate [ORR] 25.8%) and tolerability. Since belinostat (Bel) and each of the components of the CHOP regimen target different aspects of the cell cycle with different mechanisms of action, there is potential for a synergistic effect of a Bel-CHOP combination treatment regimen for patients with PTCL. Methods: Patients with PTCL received CHOP in association with 1000 mg/m2 of belinostat on various schedules, repeated every 21-days for up to 6 cycles. The cohort schema followed a traditional "3+3" dose escalation design. The objective of Part A of the study was to determine the Maximum Tolerated Dose (MTD) of the Bel-CHOP combination. Once the MTD was determined, at least 10 more patients were to be treated in the Expansion Phase (Part B). Belinostat was to be administered as a 1000 mg/m2 IV infusion once daily for up to 5 days, depending on the assigned cohort (Fig 1). The starting cohort was Cohort 3 (CHOP + 1000 mg/m2 of daily belinostat on Days 1-3). Patients received primary prophylaxis with growth factor (G-CSF) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: non-hematological toxicity Grades 3-4, platelet count < 25 X 109/L at any time or ANC < 0.5 X 109/L lasting more than 7 days despite G-CSF administration. The primary endpoint of the study was the determination of the MTD of the Bel-CHOP combination. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Results: A total of 23 patients were enrolled in the study, 11 of which were treated in Part A. One patient in Part A was deemed inevaluable because the patient died due to disease progression before completing Cycle 1. The MTD was determined to be 1000 mg/m2 on Days 1-5 (Cohort 5); 12 more patients were then treated at this dose level (Part B). The only DLT experienced in the study was in Cohort 3 (Grade 3 Nausea and Vomiting). At the time of this abstract, 18/23 patients (78%) have completed all 6 cycles of Bel-CHOP, with 87% completing at least 4 cycles. Ten patients (43%) had at least one serious adverse event (SAE) and 18 (78%) had at least one Grade 3 or 4 adverse event (AE). The most frequent Grade 3/4 AEs were hematological in nature: neutrophil count decreased (26%), anemia (22%), neutropenia (17%) and white blood cell count decreased (17%). The ORR for the18 patients that have completed an End of Study Visit is 89% (16/18), with the vast majority achieving a CR [72% (n=13)], and 17% (n=3) a PR. Progressive disease was reported in 2 patients. Conclusions: These results demonstrate that the combination of belinostat with CHOP (Bel-CHOP) is well tolerated, with all components of CHOP and belinostat being given at their standard therapeutic doses. The rates of AEs were consistent with those typically reported with CHOP alone, and clinical activity was demonstrated with a response rate of 89% based on 18 evaluable patients. Thus, Bel-CHOP is a promising new regimen in PTCL that will be further tested in a Phase 3 randomized trial. Table. Table. Figure 1. Summary of Demographic and Baseline Characteristics AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Figure 1. Summary of Demographic and Baseline Characteristics. / AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Disclosures Barta: Seattle Genetics: Research Funding. Bhat:Spectrum Pharmaceuticals, Inc: Employment. Song:Spectrum Pharmaceutical, Inc: Employment. Choi:Apectrum Pharmaceuticals, Inc: Employment. Allen:Spectrum Pharmaceuticals, Inc: Employment. Foss:Spectrum Pharmaceuticals; Celgene: Seattle Genetics: Infinity; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau.
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Le, Anne, Charles R. Cooper, Arvin M. Gouw, Ramani Dinavahi, Anirban Maitra, Lorraine M. Deck, Robert E. Royer, David L. Vander Jagt, Gregg L. Semenza, and Chi V. Dang. "Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression." Proceedings of the National Academy of Sciences 107, no. 5 (January 19, 2010): 2037–42. http://dx.doi.org/10.1073/pnas.0914433107.
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As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1). Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood. Here, we report that reduction of LDHA by siRNA or its inhibition by a small-molecule inhibitor (FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid]) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD+ synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism.
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Navitski, Anastasia, Piyush Goyal, Salma Ahsanuddin, Serena Zheng, and Erel Joffe. "Automated identification of lymphoma involving the bone from PET/CT reports using natural language processing and adaptive learning." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e19201-e19201. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e19201.
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e19201 Background: Automated extraction of key clinical features from imaging reports, such as the site, size and FDG avidity of lesions would allow for automatic determination of disease stage, response to treatment and relapse. Since the language used in clinical notes is domain and often task-specific, generic Natural Language Processing (NLP) tools are of limited utility. We describe a strategy for a rapid construction of task-specific NLP algorithms. As a test case, we aimed to identify bone involvement with lymphoma from PET/CT reports. Methods: We use an adaptive-learning approach to facilitate the generation of task-specific lexicons by a domain expert. In the case of identifying bone lymphoma, these include words describing the primary aspect (PA: e.g., “ uptake”, “SUV”); the secondary aspect, in this case, osseous sites (SA: e.g., “skeleton”, “T5”); modifiers such as context-specific affirmation/ negation/ uncertainty (e.g., “increased”/ “likely reactive”/ “possibly disease”) and generic negation (e.g., “no evidence of”). Presented with sentences containing seed PA terms, an expert is tasked with an exhaustive identification of terms for the other lexicons. In an iterative process, unseen sentences that do not include terms previously identified are presented for lexicon expansion. The process is repeated until no further expansion is possible. An explicit rule-based algorithm is built based on the lexicons to classify sentences as supporting, negating or inconclusive (i.e., requiring manual review) for the feature of interest. We used 500 reports to develop the algorithm, evaluated performance against 516 unseen reports that were independently classified by a blinded annotator, and measured the amount of effort (number of iterations) required to complete the PA and SA lexicon expansion. Results: Of 44 reports with bone involvement identified by the algorithm, 43 had an actual involvement and 1 was a negative case (PPV: 98%). Of 380 reports flagged as negative, 379 were truly negative and 1 was positive (NPV: 99.7%). Sensitivity was 64% (43/67); specificity 84% (379/449); 18% (93) reports were flagged for manual review. It took 13 and 5 iterations to build the PA and SA lexicons, each involving the review of up to 10 sentences. Conclusions: With minimal effort, we were able to construct a high-accuracy NLP system specific for identifying bone lymphoma. This approach can be extended to other contexts (e.g., lung involvement), domains (e.g., pathology reports), or to be utilized in machine learning.
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Bezerra, Evandro Dantas, Leila Patricia Fontenele, Juliana Pereira, Luis Alberto de Padua Covas Lage, Felipe Maciel, Leticia Barquinero, Priscila R. Carvalho, Scheila Siqueira, and Elvira RP Velloso. "Splenic Diffuse Red Pulp Small B Cell Lymphoma: Transformation To Diffuse Large Cells B Lymphoma." Blood 122, no. 21 (November 15, 2013): 5070. http://dx.doi.org/10.1182/blood.v122.21.5070.5070.
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Abstract Objective Report immunophenotypic and genetic aspects and clinical course of a case of Splenic Diffuse Red Pulp Small B Cell Lymphoma with transformation to diffuse large cell. Introduction Until recently, only Hairy Cell Leukemia was recognized as B chronic lymphoproliferation with primary involvement of the splenic red pulp. The 2008 WHO classification included two new provisional entities: Splenic diffuse red pulp small-B cell lymphoma and Hairy Cell Leukemia variant. These entities are rare, encompassing less than 1% of B chronic lymphoproliferation, characteristically presenting as an indolent clinical course and good control with splenectomy. Case report Female, 29 years old, with non-replicative chronic hepatitis B, and splenomegaly detected 7 years before without evidence of portal hypertension or schistosomiasis. Two months before admission to our hospital, she developed increasing splenomegaly for 39cm, B symptoms and abdominal lymphadenopathy. CBC showed Hb: 8,1g/dl, platelet: 80.000/mm3, WBC: 12.000/mm3 with 85% of abnormal lymphoid cells with immunophenotyping CD45++/CD19+/CD20++/CD25+/CD23dim/CD200dim/FMC7+/CD11c-/CD103- and cykappa restriction. Complex karyotype in PB suggested lymphoproliferative disorder, with strutural abnormalities in 14q32, isocromosomes 8 and 17, deletions 6q and 7q and trisomy 18. FISH studies showed extra copy of MYC and p53 deletion. Bone marrow aspirate showed 7,6% of cells with same phenotype. CT and PET-CT showed splenomegaly of 39cm (SUV: 6.1), hepatomegaly (SUV: 3.2), abdominal lymph node conglomerate (SUV: 6.3), cervical and mediastinal lymphadenopathy with no increase in dimensions (SUV: 3,8). The patient was submitted to splenectomy and histological findings revelead mature lymphoid neoplasm, ranging from small to intermediate cells with few large cells, primary from spleen red pulp and diffusely infiltrating the sinusoidal spaces and secondly the white pulp (CD20+, DBA44+, CD5-, CD10-, CD23-, CD3-, cyclin D1- and Ki67: 40%). The cytogenetic analysis of the spleen showed similar complex karyotype as seen in PB. With the diagnosis of Splenic Diffuse Red Pulp Small B Cell Lymphoma with aggressive transformation to diffuse large cell, she was submitted to 8 cycles of R-CHOEP and is in complete remission, waiting for consolidation with high-dose chemotheraphy followed with peripheral stem cells rescue. Discussion Splenic Diffuse Red Pulp Small B-cell Lymphoma was included as a provisional entity in WHO 2008 classification. The few cases reported show an indolent course with good response to splenectomy. In this case the diagnosis was suspect with clinical course, cytogenetic and flow cytometry PB studies and confirmed after splenectomy when the clinical course of disease changed with B symptoms, spread to peripheral blood with atypical cells and increased proliferative markers, such as LDH. This fact highlights the difficulty in establishing the diagnosis of this entity during the course of prolonged and indolent disease, manifested by splenomegaly oligosymptomatic often neglected by physicians and by the patients themselves. Disclosures: No relevant conflicts of interest to declare.
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Tooze, Reuben M., Matthew A. Care, David R. Westhead, and Gina M. Doody. "An Expanded Set of Direct BLIMP-1 Targets Identifies Novel Links in Differentiation, Immune Response and Lymphoma." Blood 114, no. 22 (November 20, 2009): 1466. http://dx.doi.org/10.1182/blood.v114.22.1466.1466.
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Abstract Abstract 1466 Poster Board I-489 B-lymphocyte induced maturation protein 1 (BLIMP-1) has been defined as a key driver of the genetic reprogramming during differentiation of B-cells to plasma cells. Frequent inactivation of PRDM1, the BLIMP-1 gene, in diffuse large B-cell lymphoma (DLBCL) indicates that loss of function is an important event in lymphomagenesis. Only a limited set of direct BLIMP-1 target genes have been defined. In order to better understand the function of human BLIMP-1 in differentiation and malignancy we have established a more comprehensive set of occupied promoters. These data provide an extended view of the regulatory network controlled by BLIMP-1, and identify novel sets of targets involved in transcription and immune response. The composition of occupied promoters identifies complexity in BLIMP-1 binding motif selection, and substantial overlap between BLIMP-1 sites and Interferon regulatory factor (IRF) elements. Consistent with active competition between BLIMP-1 and IRFs, target genes associated with such overlapping motifs are found to be preferentially induced in response to BLIMP-1 knockdown. Finally BLIMP-1 targets are found to include key components of DLBCL gene expression signatures. This map of BLIMP-1 occupied promoters thus illuminates key aspects of function in normal and malignant cell biology. Disclosures: No relevant conflicts of interest to declare.
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Singh, Sitanshu S., Achyut Dahal, Leeza Shrestha, and Seetharama D. Jois. "Genotype Driven Therapy for Non-Small Cell Lung Cancer: Resistance, Pan Inhibitors and Immunotherapy." Current Medicinal Chemistry 27, no. 32 (September 25, 2020): 5274–316. http://dx.doi.org/10.2174/0929867326666190222183219.
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Eighty-five percent of patients with lung cancer present with Non-small Cell Lung Cancer (NSCLC). Targeted therapy approaches are promising treatments for lung cancer. However, despite the development of targeted therapies using Tyrosine Kinase Inhibitors (TKI) as well as monoclonal antibodies, the five-year relative survival rate for lung cancer patients is still only 18%, and patients inevitably become resistant to therapy. Mutations in Kirsten Ras Sarcoma viral homolog (KRAS) and epidermal growth factor receptor (EGFR) are the two most common genetic events in lung adenocarcinoma; they account for 25% and 20% of cases, respectively. Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor tyrosine kinase, and ALK rearrangements are responsible for 3-7% of NSCLC, predominantly of the adenocarcinoma subtype, and occur in a mutually exclusive manner with KRAS and EGFR mutations. Among drug-resistant NSCLC patients, nearly half exhibit the T790M mutation in exon 20 of EGFR. This review focuses on some basic aspects of molecules involved in NSCLC, the development of resistance to treatments in NSCLC, and advances in lung cancer therapy in the past ten years. Some recent developments such as PD-1-PD-L1 checkpoint-based immunotherapy for NSCLC are also covered.
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Habermann, Thomas M., Ruth A. Lentz, John J. Schmitz, Alexander G. von Bormann, Jason Young, Christopher H. Hunt, Grzegorz S. Nowakowski, et al. "An Analysis of a Multidisciplinary Lymphoma Virtual Tumor Board with Regional and International Participation." Blood 132, Supplement 1 (November 29, 2018): 2247. http://dx.doi.org/10.1182/blood-2018-99-112887.
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Abstract Introduction: Outcomes of multidisciplinary and molecular tumor boards have been reported. Lymphoma specific tumor board outcomes have not been reported in the molecular era. In addition, the utility of multi-site, interactive tumor boards using videoconference technology are not widely reported. We prospectively followed the outcomes of a multidisciplinary multi-site lymphoma tumor board in the molecular era and during a change in the revision of the World Health Organization Classification in first published in 2016. Methods: The Mayo Clinic Lymphoma Tumor Board is a component of the international Mayo Clinic Care Network (MCCN). The format includes the clinical case presentation, presentation of radiology and hematopathology findings by the appropriate specialist, proposed treatment options, review of the literature pertinent to the case, and discussion followed by recommendations. Requirement for presentation includes having a diagnosis of lymphoma with pathology reviewed at Mayo Clinic, Rochester, MN (MCR). Pathology and radiology material, when relevant to the case, are required to be reviewed at MCR and presented by MCR pathologists/radiologists. Patients must be presented prospectively, and have active clinical issues or questions to be addressed. Four cases are presented per 60-minute meeting. 309 consecutive highly selected cases with a diagnosis of lymphoma were presented at the Mayo Clinic Lymphoma Tumor Board from 2014 to 2018. The pathology material was independently reviewed by the presenting hematopathologists and radiology material by the presenting radiologist. Participants are office based and included multiple members of the health care team which also incudes pharmacists, clinical research associates affiliated with lymphoma research, and physicians in training. Recommendations were prospectively tracked for changes in radiology interpretation, pathologic diagnosis, and treatment approaches. Actual follow-up of all patients after the meeting was not allowed in the MCCN. Participation in the meeting can be either via in-room attendance at MCR, video conference at a participating MCCN site, or via non-participatory live-stream online. Results: 309 cases were presented were presented from 2014-2018. 258 cases were from MCR, and 51 were not physically seen at MCR. 16 cases were presented at a subsequent meeting for further recommendations in the course of their disease after the initial presentation. 54% of patients presented had changes in some aspect of their care as a result of the meeting. Changes in radiologic interpretation occurred in 5 (1.6%) patients. The pathologic diagnosis changed in 27 (8.7%). Additional testing was recommended in 44 (14%). Clinical management changes were recommended in 90 (29%) cases. These included alterations in treatment approach in 43 (14%), change from undecided to pursuit of treatment 10 (3%), change from undecided regarding treatment approach to further diagnostic testing 4 (1.3%), change from observation to treatment 9 (3%), change from treatment to observation 4 (1.3%), and treatment to further tests in 2 (0.6%) Site in room average attendance (internal/external) was 16.8/8.6. Non-participatory live-stream attendance was not possible to track. In an annual electronic evaluation of this activity, 93% of the responders reported an improvement in knowledge and competence, and 100% recommended no changes to the format of the conference. Enhancements over time have included Continuous Medical Education credit, an in room microscope, and real-time radiology images. Selected cases will now be on line on an international web site. Conclusion: In this highly selected group of lymphoma cases from multiple sites over a 4-year period, 54% of the (167/309) case presentations resulted in changes to some aspect of care as a direct result of this tumor board. A multidisciplinary lymphoma tumor board approach was of value, efficacious, and meaningfully impacted lymphoma patients while substantially enhancing interdisciplinary interactions. Disclosures Ansell: Celldex: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding.