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1
Owens, Scott R., and Lauren B. Smith. "Molecular Aspects of H. pylori-Related MALT Lymphoma." Pathology Research International 2011 (January 24, 2011): 1–8. http://dx.doi.org/10.4061/2011/193149.
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Helicobacter pylori-related extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a paradigm for malignancy arising in an inflammatory background. While the diagnosis of H. pylori gastritis is often straightforward, distinction between severe gastritis and early lymphoma can be difficult and requires careful assessment of clinical findings in addition to histological features and immunohistochemical results. A number of cytogenetic abnormalities have been discovered in H. pylori-related lymphomas and several have clinical importance, related to the responsiveness of lymphoma to H. pylori eradication therapy, but routine molecular studies are not widely utilized. While molecular methods may be used in equivocal cases, a trial of conservative therapy is warranted given the propensity for these lymphomas to regress with eradication of the organism. Once therapy is initiated, care must be taken to avoid a premature assignment of disease refractoriness because complete response can take several months to more than a year. Cases truly refractory to H. pylori eradication therapy may be treated with adjuvant chemoradiation with a high response rate.
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Barth, Thomas F. E., Martin Bentz, Hartmut Döhner, and Peter Möller. "Molecular Aspects of B-Cell Lymphomas of the Gastrointestinal Tract." Clinical Lymphoma 2, no. 1 (June 2001): 57–64. http://dx.doi.org/10.3816/clm.2001.n.012.
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Burg, Günter, Werner Kempf, Antonio Cozzio, Josef Feit, Rein Willemze, Elaine S. Jaffe, Reinhard Dummer, et al. "WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects." Journal of Cutaneous Pathology 32, no. 10 (November 2005): 647–74. http://dx.doi.org/10.1111/j.0303-6987.2005.00495.x.
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Richards, Kristy L., Alison Motsinger-Reif, Hsiao-Wei Chen, Yuri D. Fedoriw, Cheng Fan, Dahlia M. Nielsen, Rachael Thomas, et al. "Characterizing Canine Lymphoma As a Potential Large Animal Model of Human Diffuse Large B-Cell Lymphoma." Blood 118, no. 21 (November 18, 2011): 5193. http://dx.doi.org/10.1182/blood.v118.21.5193.5193.
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Abstract Abstract 5193 Diffuse large B-cell lymphoma (DLBCL) affects ∼25,000 people in the U.S. each year, and fewer than half of them are cured with standard therapy. DLBCL can be divided into two subtypes by gene expression profiling, germinal center B-cell (GCB) type and activated B-cell (ABC) type. ABC-type DLBCL patients have significantly poorer outcomes. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL is one of the most common cancers in veterinary oncology. Similar to human DLBCL patients, dogs with lymphoma are treated with both CHOP-like regimens and autologous stem cell transplants. Morphologically, canine lymphomas are similar to hDLBCL, with shared histologic markers, such as CD20 and PAX5. With recent technologies based on knowledge of the canine genome sequence, it is now possible to evaluate dogs as a potential large-animal model for hDLBCL. We evaluated 58 canine B-cell lymphomas by generating comprehensive gene expression profiles and comparing them to previously published hDLBCL expression profiles. Canine B-cell lymphoma expression profiles were similar in some ways to hDLBCLs. For instance, increased expression of NF-kB pathway genes was noted in a subset of lymphomas, mirroring NF-kB pathway activation in human ABC-type DLBCL. Furthermore, immunoglobulin heavy chain (IGH) mutation status, which is correlated with ABC/GCB cell of origin in hDLBCL, separated canine DLBCL into two groups with statistically different progression-free and overall survival times. However, canine DLBCL differed from hDLBCL in other aspects, including rare immunohistochemical positivity for BCL6 and MUM1/IRF4. Collectively, these results define aspects of canine B-cell lymphomas that resemble hDLBCL, identifying molecular similarities that could allow dogs to be used as a representative model of hDLBCL. Further comparative studies, including therapeutic trials, could potentially improve outcomes in both species. Disclosures: No relevant conflicts of interest to declare.
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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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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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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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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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Barroca, Helena, and Cristina Marques. "A Basic Approach to Lymph Node and Flow Cytometry Fine-Needle Cytology." Acta Cytologica 60, no. 4 (2016): 284–301. http://dx.doi.org/10.1159/000448679.
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According to the World Health Organization (WHO), the new classification of lymphomas is mainly based on morphological, immunophenotypical, and molecular criteria. Consequently, this new approach has led from the substantial role that architecture played in the past to a secondary panel highlighting the role of fine-needle biopsy (FNB). Applied together with other ancillary techniques, such as flow cytometry (FC), FNB is a potential tool for the diagnosis of lymphomas, and enlarged lymph nodes represent an excellent target for the implementation of this technique. Despite the difficulties inherent in this technology, which might pose problems in differential diagnosis, in the majority of cases this joint work allows an accurate diagnosis of malignancy and even correct subcharacterization in routine lymphomas. Additionally, in selected cases, other molecular techniques like FISH and PCR can also be performed on FNB specimens, helping in the characterization and diagnosis of lymphomas. In this review, we discuss the basic aspects of the combination of FNB cytology and FC in the diagnosis and subclassification of lymphomas. The preanalytical phase is extensively discussed. The advantages, disadvantages, and technical limitations of this joint work are addressed in general and in terms of the accurate subclassification of lymphomas.
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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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Rijlaarsdam, Udo, Victor Bakels, Johan W. van Oostveen, Roel J. L. Gordijn, Marie-Louise Geerts, Chris J. L. M. Meijer, and Rein Willemze. "Demonstration of Clonal Immunoglobulin Gene Rearrangements in Cutaneous B-Cell Lymphomas and Pseudo–B-Cell Lymphomas: Differential Diagnostic and Pathogenetic Aspects." Journal of Investigative Dermatology 99, no. 6 (December 1992): 749–54. http://dx.doi.org/10.1111/1523-1747.ep12614479.
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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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Huang, Yenlin, Anne Moreau, Jehan Dupuis, Berthold Streubel, Barbara Petit, S. Legouill, Nadine Martin-Garcia, et al. "Peripheral T-Cell Lymphomas with Follicular Growth Patterns Are Derived from Follicular Helper T Cells (TFH): A Link with Angioimmunoblastic T-Cell Lymphomas?." Blood 110, no. 11 (November 16, 2007): 3568. http://dx.doi.org/10.1182/blood.v110.11.3568.3568.
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Abstract Nodal peripheral T-cell lymphomas represent a heterogeneous category, composed of three entities: anaplastic large cell lymphomas, peripheral T-cell lymphomas unspecified (PTCLu) and angioimmunoblastic T-cell lymphomas (AITL). The later entity has been recently recognized to derive from follicular helper T cells (TFH). Among PTCLu - which represents an ill-defined entity - a peculiar form with follicular growth pattern (PTCL-F) has been recently reported, and one article stated their association with t(5 ;9)(q33 ;q22) involving ITK and SYK (Leukemia2006; 20: 313–318). However, the origin of tumor cells and clinical aspects of this group of PTCL-F are still unknown. The aim of this study was to analyse a series of PTCL-F to describe their clinical and histopathological aspects, to identify their cell of origin, and their relationship with AITL. Fourty-two patients from 32 to 85 years of age with 51 biopsies were selected from three Departments of Pathology (Creteil, n=24, Nantes n=13, Vienna n=14). All patients showed histopathologic features of PTCL-F in at least one biopsy. Biopsies were classified into three categories according to predominant morphological features at low power magnification: follicular lymphoma-like (n=7), progressive transformation of germinal center-like (n=22), and AITL-like features with follicular colonization (n=19). Several cases have combinations of patterns. The neoplastic population is characterized by medium-sized cells with clear cytoplasm surrounded by IgD+ B-cells. Tumor cells are of helper T-cell immunophenotype [CD2+ (33/33 = 100%), CD3+ (45/48 = 93%), CD4+ (35/42 = 83%), CD5+ (39/39 = 100%), CD7+ (7/37 = 19%)], with frequent expression of CD10 (29/43 = 67%) and of TFH markers [PDCD-1 (32/36 = 88%), CXCL13+ (33/38 = 87%), BCL6+ (15/25 = 60%), CD57+ (9/16 = 56%)]. Scattered CD20+ B-immunoblasts (27/28 = 96%) and EBV+ cells (18/30 = 60%) are also frequently observed. Seven out of 31 patients (22%) in the 3 morphological patterns have t(5 ;9)(q33 ;q22) detected by fluorescent in situ hybridization. At prentation and/or at relapse, most patients had multiple lymphadenopathies (19/23 = 83%) and disseminated disease (stages III–IV, 22/28 = 79%). Skin lesions and B symptoms were present in 7/19 (37%) and 6/22 (27%) patients, respectively. In addition, 2 patients with sequential biopsies disclosed typical clinical & histopathological features of AITL in one episode. Our results show that this rare form of PTCL has an immunophenotype indicative of TFH origin, is associated with t(5 ;9) in a proportion of cases, shows some similarities in morphology and immunophenotype with AITL, suggesting a relationship, and generates diagnostic pitfalls, especially with atypical reactive lymphoid lesions and some B-cell lymphomas. The use of immunohistochemistry with TFH markers and molecular studies can help to make a correct diagnosis.
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Wei, Eric X., Vasiliki Leventaki, John K. Choi, Susana C. Raimondi, Elizabeth M. Azzato, Sheila A. Shurtleff, Menchu G. Ong, Diana M. Veillon, James D. Cotelingam, and Rodney E. Shackelford. "γδ T-Cell Acute Lymphoblastic Leukemia/Lymphoma: Discussion of Two Pediatric Cases and Its Distinction from Other Mature γδ T-Cell Malignancies." Case Reports in Hematology 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/5873015.
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Gamma delta (γδ) T-cell antigen receptor (TCR) expression and its related T-cell differentiation are not commonly reported in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Here we report two pediatric T-ALL cases and present their clinical features, histology, immunophenotypes, cytogenetics, and molecular diagnostic findings. The first patient is a two-year-old girl with leukocytosis, circulating lymphoblasts, and a cryptic insertion of a short-arm segment at 10p12 into the long-arm segment of 11q23 resulting in an MLL and AF10 fusion transcript, which may be the first reported in γδ T-ALL. She responded to the chemotherapy protocol poorly and had persistent diseases. Following an allogeneic bone marrow transplant, she went into remission. The second patient is an eleven-year-old boy with a normal white cell count, circulating blasts, and a normal karyotype, but without any immature cellular markers by flow cytometric analysis. He responded to the chemotherapy well and achieved a complete remission. These cases demonstrate the diverse phenotypic, cytogenetic, and molecular aspects of γδ T-ALL. Early T-precursor- (ETP-) ALL and their differential diagnosis from other mature γδ T-cell leukemia/lymphomas are also discussed.
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Ganzel, Chezi, Galina Pogrebijsky, Svetlana Krichevsky, Tzahi Neuman, and Dina Ben-Yehuda. "The Separate Diagnosis of Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL) In a Single Patient May Not Signify a Common Clonal Origin." Blood 116, no. 21 (November 19, 2010): 4824. http://dx.doi.org/10.1182/blood.v116.21.4824.4824.
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Abstract Abstract 4824 Background: HL and NHL have traditionally been considered as two distinct entities. However, there have been reported rare cases of patients that over time develop both diseases. It is an unresolved issue whether the origin of the two diseases is from the same clone. The literature is replete with anecdotal reports but it has never been prospectively or retrospectively evaluated in consecutive patients from a large series. In this study we attempted to retrospectively investigate this phenomenon by reviewing the clinical and molecular aspects of a group of patients who developed both lymphomas. Although not absolutely definitive, a differing gene rearrangement (GR) pattern is currently thought to be highly suggestive of a different clonal origin. Methods: Study patients were all patients treated at the Hadassah University Medical Center, Jerusalem, Israel, who developed both kinds of lymphoma throughout their lives and were treated for at least one of the lymphomas during the period 1989–2010. The clinical and pathologic records of these patients were reviewed. Archival, formalin fixed, paraffin embedded tissue samples from all the patients that had available samples from both diseases were obtained. The rearranged immunoglobulin heavy-chain variable region genes from both diagnoses were amplified by polymerase chain reaction (PCR) and were compared to each other. Results: There were 26 patients who presented with two diagnoses. Twelve had HL as the primary disorder and the majority of these (75%) presented with aggressive lymphoma as the second lymphoma. The mean survival from the second lymphoma was 4.06 years. Five patients are still alive. In contrast, in the 11 patients where NHL was the primary disorder, this was usually (82%) of low grade histology. The mean survival in this case was 2.16 years. Four patients are still alive. Three patients were diagnosed concurrently with both diseases. For 11 patients there were available diagnostic samples for molecular analyses from both diagnoses of HL and NHL. In 6 of these 11 patients gene rearrangement studies were informative providing data for both diagnoses. The same GR was not found in any of the 6 patients. DLBCL=Diffuse Large B Cell Lymphoma, CLL/SLL=Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, marginal=marginal zone lymphoma, low grade=low grade B cell lymphoma unspecified Although the numbers are small, these data suggest that it is likely that in the case of two different lymphoproliferative disorders they are of separate clonal origin. Conclusions: The development of HL and NHL at different time points should be assumed to be a different biologic disease, until proven otherwise. Disclosures: No relevant conflicts of interest to declare.
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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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McHugh, Donal, Renier Myburgh, Nicole Caduff, Michael Spohn, Yik Lim Kok, Christian W. Keller, Anita Murer, et al. "EBV renders B cells susceptible to HIV-1 in humanized mice." Life Science Alliance 3, no. 8 (June 23, 2020): e202000640. http://dx.doi.org/10.26508/lsa.202000640.
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HIV and EBV are human pathogens that cause a considerable burden to worldwide health. In combination, these viruses are linked to AIDS-associated lymphomas. We found that EBV, which transforms B cells, renders them susceptible to HIV-1 infection in a CXCR4 and CD4-dependent manner in vitro and that CXCR4-tropic HIV-1 integrates into the genome of these B cells with the same molecular profile as in autologous CD4+ T cells. In addition, we established a humanized mouse model to investigate the in vivo interactions of EBV and HIV-1 upon coinfection. The respective mice that reconstitute human immune system components upon transplantation with CD34+ human hematopoietic progenitor cells could recapitulate aspects of EBV and HIV immunobiology observed in dual-infected patients. Upon coinfection of humanized mice, EBV/HIV dual-infected B cells could be detected, but were susceptible to CD8+ T-cell–mediated immune control.
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Shivdasani, R. A., J. L. Hess, A. T. Skarin, and G. S. Pinkus. "Intermediate lymphocytic lymphoma: clinical and pathologic features of a recently characterized subtype of non-Hodgkin's lymphoma." Journal of Clinical Oncology 11, no. 4 (April 1993): 802–111. http://dx.doi.org/10.1200/jco.1993.11.4.802.
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PURPOSE We present a comprehensive review of clinical, pathologic, molecular, and prognostic features and therapy of intermediate lymphocytic (mantle cell) lymphoma (ILL/MCL), a recently characterized subtype that represents 2% to 8% of non-Hodgkin's lymphomas (NHLs), but which has not been included in most classification schemes, including the International Working Formulation. DESIGN The English-language literature encompassing the above aspects, published between 1977 and 1992, is critically reviewed. RESULTS AND CONCLUSION ILL/MCL is a disease of proliferating B lymphocytes that is characterized by generalized lymphadenopathy and frequent, often extensive, involvement of the spleen, bone marrow, and gastrointestinal tract. The malignant cells usually express the markers CD5 and IgM with or without IgD, but not CD10, on the cell surface, and grow in one of two dominant histologic patterns: mantle zone and diffuse. The characteristic cytogenetic abnormality is a t(11;14)(q13;q32) translocation, which juxtaposes the bcl-1 locus on chromosome 11 with the immunoglobulin (Ig) heavy-chain locus on chromosome 14, and appears to result in dysregulated expression of the gene encoding cyclin D1. Median survival is in the range of 2 to 5 years. While responses to chemotherapy may be seen in up to half the patients, relapses are the rule, and longterm survival is uncommon. The optimal treatment remains undefined, although therapy may be deferred until there are symptoms or complications, at which time judicious administration of alkylating agents and glucocorticoids may result in effective palliation.
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Pham, Lan V., Archito Tamayo, Hai-Jun Zhou, Yen-Chiu Lin Lee, Lingchen Fu, Carlos E. Bueso-Ramos, Elias Drakos, L. Jeffrey Medeiros, and Richard J. Ford. "Networking Modules of Canonical and Alternative NFkB Signaling in Growth and Survival Regulations of Large B Cell Lymphomas." Blood 112, no. 11 (November 16, 2008): 3776. http://dx.doi.org/10.1182/blood.v112.11.3776.3776.
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Abstract Constitutive NF-kB activation is considered a “hallmark” in B-cell malignancies, especially in large B-cell lymphoma (LBCL), a common but heterogenous Non-Hodgkin’s lymphoma type. However, the mechanism(s) of activation and interactions of NF-kB components in the nuclear compartment of B-cell lymphomas are still poorly defined. Our findings demonstrate that both the canonical and the alternative NF-kB pathways are constitutively activated in both LBCL cell lines and primary lymphoma cells. NF-kB DNA binding ELISA analysis showed that the canonical NF-kB components p65 and c-rel as well as the non-canonical NF-kB components p52 and relB are constitutively activated in 14 LBCL cell lines and in 14 primary lymphoma patients’ cells (both ABC-and GCB-like subtypes). Based on the ELISA data, we found that the p65/c-rel ratio is relatively higher in ABC-like LBCL subtype when compared to GCB-like LBCL subtype, but the alternative NF-kB members’ p52 and rel-B are differentially activated in both GCB- and ABC-like LBCL subtypes. Micro-tissue array (MTA) studies confirmed that both NF-kB pathways are constitutively active in LBCL biopsy-cores. The components of both NF-kB pathways were also found to merge and form functional “hybrid” NF-kB complexes in the nuclear compartment. Besides the common hetero-dimeric complexes occur between p50, p65, and c-rel of the canonical NF-kB pathway and between p52 and relB of the alternative NF-kB pathway, components of both pathways also merged to form “hybrid” dimeric complexes, such as p52-relB, p52-c-rel, relB-p65, and relB-c-rel in LBCL cells. Interestingly, p65 and c-rel binds to relB and p52, respectively, with higher affinity in GCB- than in ABC-like LBCL subtype. Our data also showed that activation of both NF-kB pathways and their cross-interaction are not restricted to only neoplastic B cells but that they are also activated and utilized in highly proliferative activated normal B-lymphocyte. Specific siRNA that target individual NF-kB members p65, c-rel, and rel-B have inhibitory activity in lymphoma cell growth, but similar p52 siRNAs do not have inhibitory activity. These studies indicated that in both LBCL cell lines and patient samples (GCB-and ABC-like subtypes), both the canonical and the alternative NF-kB pathways are not only constitutively activated but also interact to form multimeric NF-kB complexes in the nuclear compartment, giving rise to an NF-kB signaling module that not only controls lymphoma cell growth and survival but likely contributes to the heterogeneity of the disease processes. These findings reveal additional aspects of molecular heterogeneity and complexity in NF-kB signaling mechanisms and interacting transcriptional modules, contributing to the pathophysiology of LBCL. These results also highlight the critical importance of multiple constitutively active NF-kB signaling pathways in LBCL and may also contribute to therapeutic refractoriness, particularly in relapsed/refractory LBCLs.
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Jacobs, Cassandra L., Patricia L. Lugar, Qingquan Liu, Jenny Zhang, Peter Lipsky, and Sandeep Dave. "Molecular Profiling Identifies Plasmablasts as the Cells of Origin of Activated Diffuse Large B Cell Lymphoma." Blood 114, no. 22 (November 20, 2009): 621. http://dx.doi.org/10.1182/blood.v114.22.621.621.
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Abstract Abstract 621 The classification of leukemias and lymphomas is based upon the state of differentiation of hematopoietic cells from which the malignancy is derived. These malignancies frequently preserve aspects of their lineage and lineage-specific markers are a standard in the pathology diagnosis of these tumors. Diffuse large B cell lymphoma (DLBCL) is the most common form of non Hodgkin lymphoma and comprises at least 2 different molecular subsets. The first subset is derived from germinal center B cells (GCB DLBCL) and is characterized by a relatively good prognosis when treated with standard chemotherapy. The second subset, activated B cell like (ABC) DLBCL, is characterized by higher expression of plasmacytic genes (IRF4, PRDM1 and XBP1), an activated phenotype and poorer prognosis. Unlike multiple myeloma, ABC DLBCLs lack the morphology and phenotype of plasma cells. The normal B cell counterpart of ABC DLBCLs is unknown. Thus, there are 2 major aspects of the molecular phenotype ABC DLBCLs—first, ABC DLBCLs demonstrate features of plasma cell differentiation, suggesting that they are derived from post-germinal center cells that are undergoing plasmacytic differentiation. Second, ABC DLBCLs are characterized by high activity of the NF-KB pathway, which is responsible for their activated phenotype. The etiology of NF-KB activation is not known, but is thought to result from acquired mutations in genes that encode the NF-KB pathway. Although plasmablasts have been studied extensively in vitro, using a variety of techniques to induce plasmacytic differentiation, comprehensive studies of in vivo, lymph node-derived human plasmablasts have been lacking. Methods and Results: Using flow cytometry for a standard set of B cell markers (CD19, CD20, IgD, CD38, CD27, CD10, CD138), we identified mature B cell subsets including naive, germinal center (GC), memory, plasmablast (PB) and plasma cells (PC) from healthy patients undergoing routine tonsillectomy. These subsets were profiled for gene expression at the whole genome-level and we constructed Bayesian predictors to distinguish these subsets. These gene expression-based predictors could distinguish the normal B cell subsets perfectly. We then applied these Bayesian predictors to identify the lineage of 350 tumors from patients with DLBCL and 125 patients with multiple myeloma. Tumors with ABC and GCB DLBCLs were distinguished based on their gene expression profiles. Using the Bayesian gene expression predictors, we found that GCB DLBCLs were classified as germinal center B cells, whereas ABC DLCBLs were classified as plasmablasts and multiple myeloma cases were classified as plasma cells. We found over 90% concordance between the lineage-based (PB vs GC) predictor and the previously defined gene expression-based predictor that distinguishes ABC from GCB DLBCL (P<1E-10, chi-squared test). Notably, PBs demonstrated lower expression of BCL6 and CD10, and higher expression of IRF4 and PRDM1 compared to GC cells. The expression pattern was reversed when compared to plasma cells. Thus, the gene expression profile of PBs was intermediate between germinal center (GC) and plasma cells (PC), with regard to expression of genes related to plasmacytic differentiation (p=0.008, Figure 1A). We further investigated the expression of the NF-KB pathway in these B cell subsets and DLBCL and multiple myeloma. We found that higher expression of NF-KB in ABC DLBCL compared to GCB DLBCL and multiple myeloma reflects the differences in NF-KB activity of their normal counterparts, results that were highly statistically significant (p=0.009, Figure 1B). Thus the higher expression of genes related to plasmacytic differentiation as well as NF-KB activation in ABC DLBCL appears to be directly related to their origin from plasmablasts. Conclusion: The key aspects of the molecular phenotype of ABC DLBCLs, i.e. plasmacytic differentiation and NF-KB expression, are a direct reflection of their normal counterpart B cells. Our data provide the basis for a better understanding of the pathogenesis of DLBCL. Disclosures: No relevant conflicts of interest to declare.
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Roue, Gael, Vianney Pichereau, Hubert Lincet, Xavier Troussard, and Brigitte Sola. "Cyclin D1 Mediates Resistance towards p53-Independent and -Dependent Apoptosis through Anti-Apoptotic Factors and Molecular Chaperones." Blood 106, no. 11 (November 16, 2005): 4294. http://dx.doi.org/10.1182/blood.v106.11.4294.4294.
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Abstract Cyclin D1 is a key regulator of the G1 to S transition of the cell cycle, physiologically absent in normal lymphocytes, but overexpressed in some lymphoproliferative disorders such as mantle cell lymphoma or multiple myeloma. While cyclin D1 has also been shown to control other aspects of the cellular fate, such as cellular senescence, apoptosis or tumorigenesis, its precise role in the pathogenesis of B-cell lymphomas and leukemias is still unclear. In this context, using various cell lines derived from the pre-B murine cell line BaF3 and conditionally expressing cyclin D1, we have previously reported that when expressed at a level comparable to the one detected in tumoral cells, cyclin D1 impairs cell proliferation mainly by inducing apoptosis. We now report that the BaF3-derived cell line BD1-A21, which constitutively expresses a low but notable level of cyclin D1, presents a recurrent resistance towards various apoptotic stimuli involving different signaling pathways, such as cytokine withdrawal, etoposide treatment and staurosporine-mediated kinases inhibition, when compared to the parental BaF3 cells. This lack of sensitivity towards apoptosis was correlated in cyclin D1-expressing cells with an increase in the basal levels of several antiapoptotic factors such as IAPs (c-IAP1, c-IAP2, XIAP and survivin) or the death receptors pathway inhibitor cFLIP, and the relative maintenance of these factors in IL-3-starved cells. 2D-PAGE analysis also pointed out in cyclin D1 expressing cells the accumulation of a series of molecular chaperones, which the most overexpressed is hsp70, concording with previous works describing the cyclin D1-dependent synthesis of hsp70 in lymphoid cells. Consistently with a protective role of hsp70 in cyclin D1-expressing cells, its pharmacological inhibition by the mean of the flavonoid quercetin allowed to re-sensitize BD1-A21 cells to the apoptotic stimulus evoked by IL-3 starvation. Hsp70 protective efect appeared to act upstream of mitochondrion, as determined by mesurement of mitochondrial membrane potential and western-blot or FACS analysis of the main Bcl-2 family members. The relationship between cyclin D1 constitutive expression, antiapoptotic factors and chaperones accumulation, and resistance to apoptosis is currently under investigation.
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Havranek, Ondrej, Jingda Xu, Stefan Koehrer, Zhiqiang Wang, Justin M. Comer, Lisa Becker, Allen F. Yi, et al. "Molecular Aspects of Tonic B-Cell Receptor Signaling in Diffuse Large B-Cell Lymphoma Provide Biomarkers and Targets for Specific Inhibition." Blood 128, no. 22 (December 2, 2016): 779. http://dx.doi.org/10.1182/blood.v128.22.779.779.
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Abstract Introduction. Targeting antigen-driven B-cell receptor (BCR) signaling with the BTK inhibitor ibrutinib is clinically effective against most B-cell lymphomas, including activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), but not germinal center B-cell (GCB) DLBCL. We have formally confirmed that GCB-DLBCL cell lines utilize tonic BCR signaling, by showing: 1) sensitivity (variable) to knockout (KO) of the BCR, SYK, and CD19; 2) dependence on CD79A ITAM phosphorylation; and 3) independence from BCR antigen specificity. However, uncertainty remains about molecular events in upstream parts of tonic BCR signaling, why dependence of GCB-DLBCL cells on tonic BCR signaling is variable, and their clinical relevance. Methods. We used CRISPR/Cas9 methods to modify selected genes by KO and/or knock-in (KI) of the cDNA of a fluorescent protein (FP; e.g., GFP), with the FP serving as a marker of cells with gene KO or modification, or as a gene-fused tag for localization or quantitation. Cells expressing a membrane-targeted Forster resonance energy transfer (FRET) based AKT activity reporter (Lyn-AktAR2) were used to measure AKT activity directly by flow cytometry (FCM). Results. The effect of KI of CD79A Y188F mutation alone was similar to complete BCR KO, implying that CD79A Y188 phosphorylation is essential for tonic BCR signal transduction. Western blot analysis of GCB-DLBCL cell lines after BCR KO showed variable decreases of AKT S473 phosphorylation (frequently used as surrogate measure of AKT activity), but these did not correlate well with the variable decreases in proliferation of GCB-DLBCL cell lines caused by BCR KO. Measuring AKT activity directly (Fig. 1), or by another indirect approach (surface expression of CXCR4, a target gene of FOXO1 inhibited by AKT activity), showed high correlation between decreases in AKT activity and proliferation after BCR KO. In contrast to the variable effect of BCR KO on growth, pan-AKT KO was uniformly growth-slowing in GCB-DLBCL lines (Fig. 2). Interestingly, baseline surface density of BCR units in GCB lines, quantified by FCM using CD79A-GFP KI cells or anti-CD79B staining, correlated highly with reduction in growth or AKT activity caused by BCR KO (Fig. 3). These findings lead us to conclude that the BCR contributes to AKT activation in GCB-DLBCL cell lines, to a variable degree determined by BCR surface density. We also conclude that BCR surface density is determined by cell line-specific factors, as well as immunoglobulin heavy (IgH) and light (IgL) hypervariable region (HVR) sequences, based on measurements of BCR surface levels after exchanging endogenous HVR sequences in OCI-Ly19 and OCI-Ly7 cell lines for HVRs derived from other GCB and ABC-DLBCL cell lines. Reduction of AKT activity after BCR KO (measured by FRET reporter) and baseline BCR surface density in GCB-DLBCL cell lines also correlated well with the sensitivity of GCB-DLBCL lines to the clinically-tested SYK inhibitor (P505-15, PRT062607) or FDA-approved PI3K p110d isoform specific inhibitor (idelalisib). Interestingly, isogenic GCB-DLBCL cell lines with KO of PTEN, a negative regulator of AKT activation, were substantially more resistant to both inhibitors. A crucial role of PTEN deletion in overcoming dependence on tonic BCR signaling in GCB-DLBCL is supported by evidence from two naturally PTEN-deficient cell lines: SUDHL10, which adjusts to BCR KO and resumes normal growth, and HT, which lacks BCR expression, due to a frameshifting deletion in its IgH HVR. Re-expression of the BCR in HT, by KI to correct the IgH sequence, does not affect HT cell line growth. Conclusion. Our findings suggest a biomarker-guided therapeutic strategy in GCB-DLBCL: targeting tonic BCR signaling in BCR-high patients, by inhibiting CD79A phosphorylation, SYK, or PI3K, and downstream targeting of AKT in BCR-low and/or PTEN-deficient patients. Figure 1. Correlation of relative proliferation after BCR KO with decrease of AKT activity (as measured by FRET efficiency of AKT activity reporter) in GCB-DLBCL cell lines. Figure 1. Correlation of relative proliferation after BCR KO with decrease of AKT activity (as measured by FRET efficiency of AKT activity reporter) in GCB-DLBCL cell lines. Figure 2. Effect of BCR KO or pan-AKT KO in GCB-DLBCL cell lines. Figure 2. Effect of BCR KO or pan-AKT KO in GCB-DLBCL cell lines. Figure 3. Correlation of relative proliferation after BCR KO with baseline BCR surface density (as measured by flow cytometry of cells with CD79A-GFP fusion) in GCB-DLBCL cell lines. Figure 3. Correlation of relative proliferation after BCR KO with baseline BCR surface density (as measured by flow cytometry of cells with CD79A-GFP fusion) in GCB-DLBCL cell lines. Disclosures Burger: Pharmacyclics: Research Funding. Westin:Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees.
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Locke, Darren, Steven Bernstein, Frank Lynch, Koushan Siami-Namini, Jackie M. Walling, Thomas Yonker, and Geoffrey Yarranton. "An IHC Screen For EphA3 Positive FFPE Tumors." Blood 122, no. 21 (November 15, 2013): 4965. http://dx.doi.org/10.1182/blood.v122.21.4965.4965.
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Abstract Eph receptors are the largest subgroup of the receptor tyrosine kinases (RTK). Unlike other RTK, these function principally during development. Quiescent in postembryonic tissues, Eph expression by adult tissues is abnormal and implicated in tumor initiation, invasion and metastasis. Aberrant EphA3 expression is seen in solid and hematologic tumors, particularly advanced stage lymphoproliferative and myeloproliferative diseases. In this regard, targeting EphA3 may constitute a novel treatment for hematological malignancy. With clinical utility in mind, i.e., patient selection for anti-EphA3 therapy, a panel of commercial and proprietary (KaloBios) antibodies was screened by Western Blot for reactivity to recombinant Eph receptors (EphA3, EphA4, EphA5, EphA7, EphB2, EphB3). Those with EphA3 binding selectivity were further screened (QualTek) by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) normal and diseased human bone marrow (NLBM, AML) as well the LK63 pre-B-ALL cell line from which EphA3 was originally isolated. Different tissue pretreatments were used for antigen/epitope retrieval of EphA3, including steam-heating in citrate-based or Tris & chelator-based buffers, subsequent/or protease digestion, or neither. Following each antigen/epitope retrieval procedure, antibody reactivity for EphA3 was assessed by light microscopy using enzymatic biotin, tyramide and polymer-based detection techniques. In each instance, the location of the EphA3/antibody complex was visualized with 3,3-diaminobenzidine that precipitates a discrete insoluble reaction product in presence of enzyme (HRP). Nuclei were counterstained with hematoxylin to assess cell/tissue morphology. From this screen, one antibody (with an epitope in the cytoplasmic CT-domain of EphA3) was chosen for further assay optimization based on its selective reactivity towards LK63 and AML and low selective reactivity towards NLBM. Assay optimization included, amongst other aspects, evaluation of EphA3 expression in a panel of NLBM and hematopoietic tumors (200+ specimens inclusive of acute & chronic leukemia, peripheral T-cell & B-cell neoplasm, Hodgkin & non-Hodgkin lymphoma, multiple myeloma, myelodysplasic syndrome, myeloproliferative neoplasm) by a board-certified hematopathologist. In NLBM, the frequency of EphA3+ immature-blast cells (CD34+ or CD117+) was insignificant. Less than 10% CD34+/CD117+ cells were EphA3+. Elevated EphA3 expression (percentage EphA3+ nucleated cells) was observed in most hematopoietic tumors. For example, in multiple myeloma, tumor cells were typically EphA3+/CD138+ plasma cells. For AML, leukemic CD34+ or CD117+ blasts/initiating cells were typically EphA3+. Some CD138- plasma cells or leukemic CD34-/CD117- cells were also EphA3+. Correlation was made between EphA3 expression and specific tumor maturation stages, differentiation status and/or tumor aggressiveness. Tumors in blast crisis presented elevated EphA3 expression, e.g., CML in accelerated or blastic crisis but not chronic phase. Elevated EphA3 expression was noted in pre-B-ALL & pro-B-ALL (early pre-B-ALL) rather than mature B-cell ALL. EphA3 expression for some peripheral B-cell neoplasms correlated well with tumor grade: high grade, poorly differentiated (typically aggressive) B-cell lymphomas or follicular lymphomas were EphA3+. A similar relationship was noted for non-Hodgkin lymphoma (Hodgkin lymphoma was EphA3-). Preclinical screening also provided evidence for EphA3 expression by stroma/fibroblast (mostly lymphoma) and vasculature/endothelium, further rationale for development of reliable tools for profiling EphA3 in hematologic tumors and other malignancies. Using well-characterized normal and diseased FFPE bone marrow biopsies, this IHC assay for EphA3 has subsequently been validated (QualTek) to provide data that is not directly available from routine histopathology review and that supports use of the assay for profiling EphA3 in specific hematologic tumors and for patient selection in early Phase clinical trial/s of an anti-EphA3 monoclonal antibody (KB004, KaloBios). Beyond this, EphA3 targeted therapy with KB004 is anticipated for treatment of solid tumors. Recent genome-wide surveys identify EphA3 amongst the most frequently overexpressed genes in pancreatic, colon and lung carcinoma, melanoma and glioblastoma. Disclosures: Locke: QualTek Molecular Labs: Employment. Bernstein:QualTek Molecular Laboratories: Employment, Equity Ownership. Lynch:QualTek Molecular Laboratories: Employment, Equity Ownership. Siami-Namini:QualTek Molecular Laboratories: Consultancy. Walling:KaloBios: Consultancy; Corcept Therapeutics: Consultancy; Prothena: Consultancy; New Gen Therapeutics: Consultancy; Valent Technologies: Consultancy; LBC Pharmaceuticals: Consultancy; Amgen: Equity Ownership; BioMarin: Equity Ownership; Crown BioScience: Membership on an entity’s Board of Directors or advisory committees. Yonker:KaloBios: Employment, Equity Ownership. Yarranton:KaloBios: Employment, Equity Ownership; Glaxo: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; StemLine Therapeutics: Equity Ownership.
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Niu, Guanglin, Isabel Hellmuth, Tatiana Flisikowska, Hubert Pausch, Beate Rieblinger, Alexander Carrapeiro, Benjamin Schade, et al. "Porcine model elucidates function of p53 isoform in carcinogenesis and reveals novel circTP53 RNA." Oncogene 40, no. 10 (February 18, 2021): 1896–908. http://dx.doi.org/10.1038/s41388-021-01686-9.
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AbstractRecent years have seen an increasing number of genetically engineered pig models of human diseases including cancer. We previously generated pigs with a modified TP53 allele that carries a Cre-removable transcriptional stop signal in intron 1, and an oncogenic mutation TP53R167H (orthologous to human TP53R175H) in exon 5. Pigs with the unrecombined mutant allele (flTP53R167H) develop mainly osteosarcoma but also nephroblastomas and lymphomas. This observation suggested that TP53 gene dysfunction is itself the key initiator of bone tumorigenesis, but raises the question which aspects of the TP53 regulation lead to the development of such a narrow tumour spectrum. Molecular analysis of p53 revealed the presence of two internal TP53 promoters (Pint and P2) equivalent to those found in human. Consequently, both pig and human express TP53 isoforms. Data presented here strongly suggest that P2-driven expression of the mutant R167H-Δ152p53 isoform (equivalent to the human R175H-Δ160p53 isoform) and its circular counterpart circTP53 determine the tumour spectrum and play a critical role in the malignant transformation in flTP53R167H pigs. The detection of Δ152p53 isoform mRNA in serum is indicative of tumorigenesis. Furthermore, we showed a tissue-specific p53-dependent deregulation of the p63 and p73 isoforms in these tumours. This study highlights important species-specific differences in the transcriptional regulation of TP53. Considering the similarities of TP53 regulation between pig and human, these observations provide useful pointers for further investigation into isoform function including the novel circTP53 in both the pig model and human patients.
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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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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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Ferreri, A. J. M., I. Ernberg, and C. Copie-Bergman. "Infectious agents and lymphoma development: molecular and clinical aspects." Journal of Internal Medicine 265, no. 4 (April 2009): 421–38. http://dx.doi.org/10.1111/j.1365-2796.2009.02083.x.
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Lage, Luis Alberto de Padua Covas, Claudio Vinicius Brito, Debora Levy, Hebert Fabricio Culler, Samuel Campanelli Freitas Couto, Lucas BO Alves, Maria C. Zerbini, Vanderson Rocha, and Juliana Pereira. "GATA3 Gene - a Potential New Biomarker Associated with Adverse Outcomes in ALK1-Negative Anaplastic Large Cell Lymphoma: Preliminary Results from a Retrospective Cohort of 80 South American Cases of Nodal Peripheral T Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 38. http://dx.doi.org/10.1182/blood-2020-140833.
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Introduction: Nodal peripheral T-cell lymphomas (nPTCLs) comprise a heterogeneous group of mature and aggressive T-cell lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphomas (ALCL) ALK1-positive and ALK1-negative. The differential diagnosis of nPTCL can be very challenging in clinical practice and it has a markedly heterogeneous prognosis. Accurate biomarkers to distinguish the different histological subtypes of nPTCL and to stratify its prognosis are essential to improve the therapeutic approach. The aim of this study was to assess the prognostic impact of GATA3 gene expression, as well as its ability to discriminate between different histopathological subtypes of nPTCLs. Methods: In this observational, retrospective and single-center study, we analyzed clinical-epidemiological data, outcomes and molecular characteristics of 80 nPTCL patients treated at the largest Brazilian cancer center from January 2000 to December 2017. Analysis of GATA3 gene expression was assessed by quantitative real-time polimerase chain reaction (qRT-PCR) of tumor tissue biopsies fixed in formalin and embedded in paraffin (FFPE) at the time of diagnosis. The association of relative expression of the GATA3 gene with pathological variants of nPTCL was determined by the Kruskal-Wallis test and the Dunn's post-hoc test. The cutoff value of GATA3 expression capable of differentiating nPTCLs variants was determined by constructing receiver-operator-characteristic (ROC) curves. Overall survival (OS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method. Results: The clinical and epidemiological characteristics of the 80 nPTCL patients are summarized in Table 1. Median age was 49 years (IqR 34-59), 43-80 (53.7%) of patients were male. Of these, 36.3% were classified as PTCL-NOS, 31.2% as ALK-negative ALCL, 21.2% as ALK-positive ALCL and 11.3% as AITL. Most of the cases had an advanced stage (III and IV Ann Arbor). With a median follow-up of 1.72 years, the estimated OS at 2 years and PFS were 52.2% and 39.5%, respectively. The median level of GATA3 gene expression was 0.49% (range 0 - 7.07%) in the global cohort, being 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL, NOS and 0.67% for AITL. The difference in expression of the GATA3 gene between different nPTCL variants was statistically significant (p <0.001) - Figure 1. The levels of expression of the GATA3 gene ≥ 0.71% discriminated PTCL, NOS from ALK-negative ALCL and AITL with a sensitivity of 62% and specificity of 80.3%, contributing to the differential diagnosis of these neoplasms, particularly in cases of ALK-negative ALCL versus PTCL, NOS CD30-positive. Overexpression of GATA3 ≥ median was associated with poor 2-year OS for PTCL, NOS (46.7% x 21.4%, p = 0.04) and for ALK-negative ALCL (85.7% x 54.5%, p = 0.04) - Figures 2 and 3. Conclusion: Despite the relatively small number of patients in our cohort, preliminary results suggest that overexpression of the GATA3 gene may be an important biomarker associated with poor prognosis in PTCL, NOS and ALK-negative ALCL. Our results corroborate the findings of Iqbal et al, 2014, reinforcing the adverse prognostic impact of GATA3 gene expression in PTCL/NOS, and we show that its overexpression may be a potential novel biomarker related to poor prognosis for ALK-negative ALCL. In addition, it has been demonstrated here that GATA3 can play an auxiliary role in discriminating different subtypes of nPTCLs, aiding the differential diagnosis of these neoplasms, which often have overlapping clinical and pathological aspects. Other studies with larger series of patients should confirm our findings. Disclosures No relevant conflicts of interest to declare.
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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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Hecht, Jonathan L., and Jon C. Aster. "Molecular Biology of Burkitt’s Lymphoma." Journal of Clinical Oncology 18, no. 21 (November 1, 2000): 3707–21. http://dx.doi.org/10.1200/jco.2000.18.21.3707.
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The diagnostic category of Burkitt’s lymphoma encompasses a closely related group of aggressive B-cell tumors that includes sporadic, endemic, and human immunodeficiency virus–associated subtypes. All subtypes are characterized by chromosomal rearrangements involving the c-myc proto-oncogene that lead to its inappropriate expression. This review focuses on the roles of c-myc dysregulation and Epstein-Barr virus infection in Burkitt’s lymphoma. Although the normal function of c-Myc remains enigmatic, recent data indicate that it has a central role in several fundamental aspects of cellular biology, including proliferation, differentiation, metabolism, apoptosis, and telomere maintenance. We discuss new insights into the molecular mechanisms of these c-Myc activities and their potential relevance to the pathogenesis of Burkitt’s lymphoma and speculate on the role of Epstein-Barr virus.
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Boustani, Hassan, Elahe Khodadi, and Minoo Shahidi. "Autophagy in Hematological Malignancies: Molecular Aspects in Leukemia and Lymphoma." Laboratory Medicine 52, no. 1 (July 7, 2020): 16–23. http://dx.doi.org/10.1093/labmed/lmaa027.
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Abstract The organization of the hematopoietic system is dependent on hematopoietic stem cells (HSCs) that are capable of self-renewal and multilineage differentiation to produce different blood cell lines. Autophagy has a central role in energy production and metabolism of the cells during starvation, cellular stress adaption, and removing mechanisms for aged or damaged organelles. The role and importance of autophagy pathways are becoming increasingly recognized in the literature because these pathways can be useful in organizing intracellular circulation, molecular complexes, and organelles to meet the needs of various hematopoietic cells. There is supporting evidence in the literature that autophagy plays an emerging role in the regulation of normal cells and that it also has important features in malignant hematopoiesis. Understanding the molecular details of the autophagy pathway can provide novel methods for more effective treatment of patients with leukemia. Overall, our review will emphasize the role of autophagy and its different aspects in hematological malignant neoplasms.
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Gouveia, Gisele Rodrigues, Sheila Aparecida Coelho Siqueira, and Juliana Pereira. "Pathophysiology and molecular aspects of diffuse large B-cell lymphoma." Revista Brasileira de Hematologia e Hemoterapia 34, no. 6 (2012): 447–51. http://dx.doi.org/10.5581/1516-8484.20120111.
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Scott, David W., George W. Wright, Mickey Williams, Jason Lih, Elaine S. Jaffe, Andreas Rosenwald, Elias Campo, et al. "Accurate Diagnosis of Aggressive B Cell Non-Hodgkin Lymphomas Using Gene Expression Profiling of Formalin-Fixed, Paraffin-Embedded Tissues." Blood 124, no. 21 (December 6, 2014): 3016. http://dx.doi.org/10.1182/blood.v124.21.3016.3016.
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Abstract Background: Currently, diagnosis of aggressive B cell non-Hodgkin lymphomas (agg-B-NHL) uses a varying combination of morphology, immunophenotyping, cytogenetics, and/or other molecular techniques resulting in a fragmented, confusing diagnostic system. We sought to develop a multi-analyte gene expression signature assay that could consolidate the diagnostic process into a single platform to improve standardization and accuracy. Methods: We used formalin-fixed, paraffin-embedded tissue biopsies, qualified by an expert Hematopathology review panel, tumor content of ≥60%, and confirmed B cell immunophenotype. Diagnostic categories included diffuse large B cell lymphoma (DLBCL) including the activated B cell-like (ABC), germinal center B cell-like (GCB) subtypes, unclassifiable (UNC) DLBCL, primary mediastinal B cell lymphoma (PMBCL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL). Using our previous GEP data, diagnostic signatures, nCounter system (Nanostring, Seattle, WA), and employing published procedures (Scott et al, Blood 2014); we designed probes to 800 genes with utility in distinguishing between these pathological entities. The training cohort comprised 107 unique cases, whose FFPET biopsies were independently assayed at the Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research (Frederick, MD) and the Centre for Lymphoid Cancer, BC Cancer Agency (Vancouver, BC). The resulting algorithm was locked down and applied to an independent cohort of 199 cases. The nucleic acids from FFPET biopsies from these cases were extracted and run across the two independent laboratories with 83 cases run at both laboratories to assess inter-laboratory performance. The gold standard by which the Nanostring classification was compared was based on Affymetrix gene expression profiling of matched frozen biopsies in the cases of ABC, GCB, and UNC DLBCL (Lenz et al. NEJM 2008) and on the pathological diagnosis by the Hematopathology review panel in the cases of BL, MCL, and PMBCL. The use of human tissues and clinical data for this study was approved by the University of Arizona Institutional Review Board in accordance with the Declaration of Helsinki. Results: The final locked algorithm consisted of 297 gene probes including 47 housekeeping genes. Thirty-six cases from the training cohort were run again on the new lot of Nanostring code set to allow for cross code set calibration of the assay. The laboratory procedure and algorithm, together termed the "Lymph5Cx" test, consists of a hierarchical series of pair-wise comparisons. In the independent validation set, 257/282 assays (91.1%) yielded gene expression data of sufficient quality (total of 185 of the 199 cases). A classification summary is given in the Table below. In this cohort, 136 cases (82%) were correctly assigned while 11 cases (6.6%) were assigned incorrect diagnoses as follows: 6 BL assigned to GCB, 1 GCB labeled a PMBCL, and 4 PMBCL assigned to DLBCL subtypes. The Lymph5Cx test included categories of indeterminate results between two diagnostic entities and were declared borderline, as indicated in the Table. The agreement between the 2 laboratory sites was 71/72 (99%) of cases that yielded adequate gene expression data at both sites. Conclusions: The Lymph5Cx test was robust and able to discriminate the often clinically difficult diagnostic categories of agg-B-NHL using a single methodology for cases with histologic and immunophenotypic features of an agg-B-NHL. Misclassification errors were low, suggesting that this test would be useful adjunct to current diagnostic methods. In addition, targetable pathways, as well as genes associated with known prognostic signatures in DLBCL (stromal) and MCL (proliferation) were quantified. Investigation into these latter aspects is on-going. Gene expression signature assays have become a useful clinical and research tool in the on-going area of precision therapeutics based on highly-defined molecular entities. Table # cases % accurate % borderline % error ABC 26 76.9% 23.1% 0.0% GCB 27 88.9% 7.4% 3.7% BL 48 68.8% 19.8% 11.5% PMBL 30 80.0% 6.7% 13.3% MCL 34 100.0% 0.0% 0.0% Disclosures Scott: Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Wright:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Williams:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Lih:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Jaffe:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Rosenwald:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Campo:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Chan:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Connors:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Smeland:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Braziel:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Ott:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Delabie:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Weisenburger:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Cook:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Greiner:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Fu:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Walsh:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Gascoyne:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Staudt:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Rimsza:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties.
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Landgren, Ola, and Neil E. Caporaso. "New Aspects in Descriptive, Etiologic, and Molecular Epidemiology of Hodgkin's Lymphoma." Hematology/Oncology Clinics of North America 21, no. 5 (October 2007): 825–40. http://dx.doi.org/10.1016/j.hoc.2007.07.001.
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Hershkovitz-Rokah, Oshrat, Dana Pulver, Georg Lenz, and Ofer Shpilberg. "Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects." British Journal of Haematology 181, no. 3 (January 23, 2018): 306–19. http://dx.doi.org/10.1111/bjh.15108.
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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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Taylor, G. P. "Molecular aspects of HTLV-I infection and adult T-cell leukaemia/lymphoma." Journal of Clinical Pathology 60, no. 12 (December 20, 2006): 1392–96. http://dx.doi.org/10.1136/jcp.2007.052662.
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Tebeică, T., R. Andrei, Sabina Zurac, and Florica Stăniceanu. "Practical Aspects Regarding the Histopathological Diagnosis of Early Mycosis Fungoides." Romanian Journal Of Internal Medicine 54, no. 1 (March 1, 2016): 3–10. http://dx.doi.org/10.1515/rjim-2016-0001.
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Mycosis fungoides is the most common primary T-cell lymphoma of skin. The disease has a protean clinical and histological presentation in its early patch and plaque stages, when distinction from mimicking inflammatory dermatoses is difficult. Since no single criterion is specific enough, a reliable diagnosis in early stages requires integration of clinical, histopathological and molecular findings. In skin biopsies, the most helpful histologic features are the detection of atypical lymphocytes in the epidermis with minimal epidermal changes, basal alignment of lymphocytes along dermal-epidermal junction and formation of Pautrier microabscesses. An aberrant immunophenotype of T cells and molecular detection of a clonal T-cell population are factors that could allow a more specific diagnosis. This work recapitulates and discusses these features from a practical perspective.
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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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Hassan, Rocio, Fabricio Felisbino, Claudio Gustavo Stefanoff, Virginia Pires, Claudete E. Klumb, Jane Dobbin, Héctor N. Seuánez, and Ilana Zalcberg Renault. "Burkitt lymphoma/leukaemia transformed from a precursor B cell: clinical and molecular aspects." European Journal of Haematology 80, no. 3 (March 2008): 265–70. http://dx.doi.org/10.1111/j.1600-0609.2007.00992.x.
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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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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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MacKinnon, Andrew, Deepthi Bhupathi, Jason Chen, Tony Huang, Weiqun Li, Yong Ma, Natalija Sotirovska, Susanne Steggerda, Winter Zhang, and Francesco Parlati. "705 Anti-tumor activity of CB-668, a potent, selective and orally bioavailable small-molecule inhibitor of the immuno-suppressive enzyme Interleukin 4 (IL-4)-Induced Gene 1 (IL4I1)." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A747. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0705.
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BackgroundTumors evade destruction by the immune system through multiple mechanisms including altering metabolism in the tumor microenvironment. Metabolic control of immune responses occurs through depletion of essential nutrients or accumulation of toxic metabolites that impair immune cell function and promote tumor growth. The secreted enzyme interleukin 4 (IL-4)-induced gene 1 (IL4I1) is an L-phenylalanine oxidase that catabolizes phenylalanine and produces phenyl-pyruvate and hydrogen peroxide. IL4I1 regulates several aspects of adaptive immunity in mice, including inhibition of cytotoxic T cells through its production of hydrogen peroxide (reviewed in1). In human tumors, IL4I1 expression is significantly elevated relative to normal tissues and is notably high in ovarian tumors and B cell lymphomas. Motivated by the hypothesis that IL4I1 is an immuno-metabolic enzyme that suppresses anti-tumor immunity, we discovered CB-668, the first known small-molecule inhibitor of IL4I1.MethodsIL4I1 enzymatic activity was measured using an HRP-coupled enzyme assay. RNA in-situ hybridization was carried out on the RNAScope platform. Syngeneic mouse tumor models were used to evaluate the anti-tumor activity of CB-668. The level of phenyl-pyruvate in tumor homogenates was measured by LC/MS.ResultsOur clinical candidate, CB-668 is a potent and selective non-competitive inhibitor of IL4I1 (IC50 = 15 nM). CB-668 has favorable in vitro ADME properties and showed low clearance and high oral bioavailability in rodents. Twice-daily oral administration of CB-668 was well-tolerated in mice and resulted in single-agent anti-tumor activity in the syngeneic mouse tumor models B16-F10, A20, and EG7. Oral CB-668 administration reduced the levels of phenyl-pyruvate in the tumor, consistent with inhibition of IL4I1 enzymatic activity. Anti-tumor activity of CB-668 was immune cell-mediated since efficacy was abrogated in CD8-depleted mice, and CB-668 treatment caused increased expression of pro-inflammatory immune genes in the tumor. Moreover, CB-668 had no direct anti-proliferative activity on tumor cells grown in vitro (IC50 > 50 µM). CB-668 also favorably combined with anti-PD-L1 therapy to reduce tumor growth in the B16-F10 tumor model.ConclusionsThese data support an immune-mediated anti-tumor effect of IL4I1 inhibition by CB-668, and suggest inhibition of IL4I1 represents a novel strategy for cancer immuno-therapy.ReferencesMolinier-Frenkel V, Prévost-Blondel A, and Castellano F. The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment. Cells 2019;8:1–9.
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Lin, Wen-Ying, Hsin-Hui Wang, Yi-Wei Chen, Chun-Fu Lin, Hueng-Chuen Fan, and Yi-Yen Lee. "Gene Modified CAR-T Cellular Therapy for Hematologic Malignancies." International Journal of Molecular Sciences 21, no. 22 (November 17, 2020): 8655. http://dx.doi.org/10.3390/ijms21228655.
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With advances in the understanding of characteristics of molecules, specific antigens on the surface of hematological malignant cells were identified and multiple therapies targeting these antigens as neoplasm treatments were developed. Among them, chimeric antigen receptor (CAR) T-cell therapy, which got United States Food and Drug Administration (FDA) approval for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) as well as for recurrent acute lymphoblastic leukemia (ALL) within the past five years, and for r/r mantle cell lymphoma (MCL) this year, represents one of the most rapidly evolving immunotherapies. Nevertheless, its applicability to other hematological malignancies, as well as its efficacy and persistence are fraught with clinical challenges. Currently, more than one thousand clinical trials in CAR T-cell therapy are ongoing and its development is changing rapidly. This review introduces the current status of CAR T-cell therapy in terms of the basic molecular aspects of CAR T-cell therapy, its application in hematological malignancies, adverse reactions during clinical use, remaining challenges, and future utilization.
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Ornstein, Deborah L., Carlo B. Bifulco, Demetrios T. Braddock, and John G. Howe. "Histopathologic and Molecular Aspects of CD56+ Natural Killer/ T-Cell Lymphoma of the Testis." International Journal of Surgical Pathology 16, no. 3 (April 2, 2008): 291–300. http://dx.doi.org/10.1177/1066896907309687.
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Kiesewetter, Barbara, Leonhard Müllauer, Berthold Streubel, Hermine Agis, Alexander Hirschl, Athanasios Makristathis, and Markus Raderer. "Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the liver: clinical, molecular, and microbiological aspects." Annals of Hematology 91, no. 11 (April 4, 2012): 1817–18. http://dx.doi.org/10.1007/s00277-012-1459-5.
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Winter, Jane N., Randy D. Gascoyne, and Koen Van Besien. "Low-Grade Lymphoma." Hematology 2004, no. 1 (January 1, 2004): 203–20. http://dx.doi.org/10.1182/asheducation-2004.1.203.
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Abstract Folicular lymphoma (FL), the second most common subtype of non-Hodgkin lymphoma, shows considerable heterogeneity in its clinical behavior, representative of a biology that appears increasingly complex and diverse. As our knowledge of the molecular basis of FL increases, we strive for an integration between the bench and clinic that yields treatments based on our scientific understanding and biomarkers that allow us to prescribe treatment rationally. In Section I, Dr. Randy Gascoyne describes the histologic, cytogenetic and biologic features of FL that underlie its clinical variability. Key aspects of the pathologic diagnosis of FL that have particular relevance to the clinician are highlighted. A proposed model for follicular lymphomagenesis and diffuse large B cell lymphoma transformation has emerged and continues to evolve as the molecular story unfolds. A biologic basis for clinical outcome in FL also appears to be forthcoming. In Section II, Dr. Jane Winter addresses the complex process of selecting among the many treatment options for patients with FL. Previously a simple matter of deciding between oral or intravenous alkylators, clinicians and patients must now struggle to choose among vastly different approaches ranging from “watch and wait” to stem cell transplantation. The introduction of rituximab and radioimmunoconjugates is changing the treatment paradigm, but the optimal approach to integrating these and other new agents remains to be determined. At every decision point, the best approach is always a clinical trial. In Section III, Dr. Koen Van Besien provides a well-documented update on outcomes associated with autologous and allogeneic stem cell transplantation for FL. The results of trials of autologous stem cell transplantation in first remission and recent data supporting a role for graft purging are discussed. Based on the premise that a graft-versus-lymphoma effect is operative in FL, reduced-intensity allogeneic transplantation is the preferred approach in many cases, and recently reported results are summarized. Criteria for patient selection and the optimal role of transplantation in the overall therapeutic plan for the patient with FL are presented.
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Gallamini, Andrea, and Anna Borra. "FDG-PET SCAN: A NEW PARADIGM FOR FOLLICULAR LYMPHOMA MANAGEMENT." Mediterranean Journal of Hematology and Infectious Diseases 9, no. 1 (April 15, 2017): e2017029. http://dx.doi.org/10.4084/mjhid.2017.029.
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In the present review the reader will be led across the most relevant observations that prompted oncologists and haematologist to consider FDG-PET/CT as a new paradigm for FL management in clinical practice. The contribute of functional imaging for lymphoma staging, restaging, prognostication, and tumour burden definition before radio-chemo-immunotherapy will be reviewed in detail. Moreover, a special focus will be addressed to technical and practical aspects of PET scan reporting, which have been set during the last decade in order to ensure the reproducibility of the therapeutic results. Finally, the predictive role of PET/CT on long-term treatment outcome will be compared with other well-known prognosticator as minimal residual disease (MRD) detection by gene rearrangement assessment by molecular biology.
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Kamran, Hamza, Ariz Akhter, Hassan Rizwan, Meer-Taher Shahbani-Rad, Ghaleb Elyamany, Douglas A. Stewart, and Adnan Mansoor. "Plasmablastic Lymphoma: Synergism betweenWnt/B-Cateninand theRAS Signalling Molecules May Identify Potential Targets for Therapy." Blood 136, Supplement 1 (November 5, 2020): 36. http://dx.doi.org/10.1182/blood-2020-140651.
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Background:Plasmablastic lymphoma (PBL), is a rare aggressive B-cell lymphoma that shares many overlapping characteristics with activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL) and multiple myeloma (MM). High expression ofWnt/β-cateninpathway molecules has been linked with several aspects of tumour biology in ABC-DLBCL and MM. In MMWnt/β-cateninplay critical role in chemoresistance, while high FOXP1 in ABC-DLBCL exert poor prognosis through up-regulation of theWnt/β-cateninsignalling pathway. There is strong evidence that enhanced crosstalk between the Wnt/β-catenin andRASpathways impact tumorigenesis and metastasis of cancerous stem cells in various cancers. In breast cancer; targeting theWnt/β-cateninand RAS pathways with small molecular inhibitors have shown effective results. The role of the Wnt/β-catenin signalling pathway and its corresponding linkage toRASsignalling molecules remained unknown in PBL. This pilot study provides preliminary data in relation to expressionof Wnt/β-cateninandRASpathways molecules in PBL in contrast to ABC-DLBCL. Method:FFPE RNA from diagnostic tissue samples in PBL patients (n=31) were compared with ABC-DLBCLs (n=18) patients for keyWnt/β-cateninandRASpathway molecules expression, utilizing nCounter (NanoString Technologies) platform. Qlucore Omics Explorer software was employed with defined criteria (fold change >2.0; p<0.01 and q <0.05) for statistical analysis. Gene Set Enrichment Analysis (GSEA) from 5 publicly available gene data sets was used to analyze the expression of other accompanying pathways. Result:We identified significant differential expression of mRNA related toWnt/β-cateninsignalling between ABC-DLBCL and PBL (Figure 1). Expression ofWnt/β-cateninsignalling inhibitors (CXXC4, SFRP2, and DKK1) were significantly higher among PBL compared to ABC-DLBCL (8.12-3.22 log fold difference). In divergence, molecules linked withWnt/β-cateninsignalling activation were elevated in PBL when compared to ABC-DLBCL (FZD3andWNT10B). The GESA analysis proved that the RAS pathway was significantly up-regulated in PBL patients compared to ABC-DLBCL. In particular, the expression of crucial RAS pathway genes such asNRAS, RAF1, SHC1, andSOS1was significantly up-regulated in PBL patients when compared to ABC-DLBCL patients (Figure 2). Conclusion:Our data suggest that the expression ofWnt/B-catenintarget genes and ligands are enhanced in PBL patients along with the up-regulation of theRASsignalling pathway molecules as compared to ABC-DLBCL. The heightened expression of crucialWnt/B-catenininhibitors does not down-regulate the Wnt/β-catenin signalling. We anticipate that the combined down-regulation of theWnt/ β-cateninandRASpathways by targeting its key members (RAF1, NRAS, FZD3) may serve to contain tumor progression in PBL, hence impacting prognosis. Disclosures Stewart: Gilead:Honoraria;Sandoz:Honoraria;Teva:Honoraria;Amgen:Honoraria;Celgene:Honoraria;Abbvie:Honoraria;Roche:Honoraria;Janssen:Honoraria;Novartis:Honoraria;AstraZeneca:Honoraria.