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For blood and money : billionaires, biotech, and the quest for a blockbuster drug
This book tells the little-known story of how an upstart biotechnology company created a one-in-a-million cancer drug, and how the core team - denied their share of the profits - went and did it again. In this epic saga of money and science, a veteran financial journalist explains how the invention of two of the biggest cancer drugs in history became (for their backers) two of the greatest Wall Street bets of all time. In the multibillion-dollar business of biotech, where pharmaceutical companies, the government, hedge funds, and venture capitalists have spent billions on funding, experimentation, and treatments, a single molecule can stop cancer in its tracks - and make the people who find that rare molecule astonishingly rich. This book follows a small team at a biotech start-up in California, who have found one of these rare molecules. Their compound, known as a BTK inhibitor, seems to work on a vicious type of leukemia. When patients start rising from their hospice beds, the team knows they're onto something big. What follows is a story of genius, pathos, and drama, in which vivid characters navigate a world of corporate intrigue and ambiguous morality. The author's narrative immerses readers in the explosion of biotech start-ups. He describes the scientists, doctors, and investors who are risking everything to develop new, life-saving treatments, and introduces suffering patients for whom the stakes are life-or-death. A gripping nonfiction read, this book illustrates why it's so hard to bring new drugs to market, explains why they are so expensive, and examines how profit-driven venture capitalists are shaping the future of medicine. -- Adapted from publisher's description.
Book
Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas
Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3′-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.
Journal Article
Improving survival of 3760 patients with lymphoma: Experience of an academic center over two decades
Background The treatment outcomes and prognosis of lymphoma are affected by various factors such as hospital types. This study was to describe the temporal trend in the survival of lymphoma in an academic center in China. Methods A total of 3840 consecutive patients with lymphoma diagnosed between 1996 and 2015 were reviewed. Eighty patients were excluded, and finally, 3760 patients were analyzed in this study. The cohort was divided into four groups according to calendar periods at diagnosis: 1996‐2000, 2001‐2005, 2006‐2010, and 2010‐2015. The overall survival (OS) rates among the four groups were compared. Results The 5‐ and 10‐year OS for the whole cohort were 62% and 52%, respectively. The 5‐year OS of patient with classic Hodgkin lymphoma (cHL), mature B‐cell lymphoma (BCL), and peripheral T‐cell lymphoma (PTCL) were 79%, 63%, and 50%, respectively. Among mature BCL, the 5‐year OS was highest in follicular lymphoma (77.8%), followed by Burkitt lymphoma (76.5%), marginal zone lymphoma (74.1%), diffuse large B‐cell lymphoma (61.5%), small lymphocytic lymphoma/chronic lymphocytic leukemia (55.1%), and mantle cell lymphoma (44.3%). Among PTCL, the 5‐year OS was highest in ALK+anaplastic large cell lymphoma (79.0%), followed by ALK−anaplastic large cell lymphoma (63.1%), natural killer/T‐cell lymphoma (57.7%), angioimmunoblastic T‐cell lymphoma (34.9%, and peripheral T‐cell lymphoma not otherwise specified (27.6%). Significant improvement in the survival of lymphoma was observed, with the 5‐year OS increasing from 48% in 1996‐2000 to 65% in 2011‐2015 (P < .001). The 5‐year OS of patients with cHL, mature BCL, and PTCL changed from 55%, 49%, and 41% in 1996‐2000 to 79%, 65%, and 51% in 2011‐2015, respectively (P values were .014, .002, and .592, respectively). Conclusion The survival of most types of lymphoma such as cHL and mature BCL, rather than PTCL, was improved significantly during the past two decades. Increase in overall survival of lymphoma from 1996 to 2015.
Journal Article
A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma
SummaryPurpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.
Journal Article
Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Glofitamab, a bifunctional antibody, was given to 154 patients with relapsed or refractory DLBCL. Complete response occurred in 39%; most of these responses were ongoing at 12 months. Cytokine release syndrome was common.
Journal Article
Estimating the global burden of Epstein–Barr virus-related cancers
BackgroundMore than 90% of the adult population globally is chronically infected by the Epstein–Barr virus (EBV). It is well established that EBV is associated with a number of malignancies, and advances in knowledge of EBV-related malignancies are being made every year. Several studies have analysed the global epidemiology and geographic distribution of EBV-related cancers. However, most have only described a single cancer type or subtype in isolation or limited their study to the three or four most common EBV-related cancers. This review will present an overview on the spectrum of cancers linked to EBV based on observations of associations and proportions in the published literature while also using these observations to estimate the incidence and mortality burden of some of these cancers.MethodWe have reviewed the literature on defining features, distribution and outcomes across six cancers with a relatively large EBV-related case burden: Nasopharyngeal carcinoma (NPC), Gastric carcinoma (GC), Hodgkin lymphoma (HL), Burkitt lymphoma (BL), Diffuse large B-cell lymphoma (DLBCL) and Extranodal NK/T-cell lymphoma, Nasal type (ENKTL-NT). We retrieved published region-specific EBV-related case proportions for NPC, GC, HL and BL and performed meta-analyses on pooled region-specific studies of EBV-related case proportions for DLBCL and ENKTL-NT. We match these pooled proportions with their respective regional incidence and mortality numbers retrieved from a publicly available cancer database. Additionally, we also reviewed the literature on several other less common EBV-related cancers to summarize their key characteristics herein.ConclusionWe estimated that EBV-related cases from these six cancers accounted for 239,700–357,900 new cases and 137,900–208,700 deaths in 2020. This review highlights the significant global impact of EBV-related cancers and extends the spectrum of disease that could benefit from an EBV-specific therapeutic.
Journal Article
Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy
Second tumors after CAR T-cell therapy are rare, and in one case of a secondary T-cell lymphoma, detailed analysis showed that the genetic construct that was used to make the CAR T cells was unrelated to the second tumor.
Journal Article
A small-molecule inhibitor of BCL10-MALT1 interaction abrogates progression of diffuse large B cell lymphoma
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the activated B cell-like subtype (ABC-DLBCL) is associated with particularly poor outcome. Many ABC-DLBCLs harbor gain-of-function mutations that cause inappropriate assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, a cytoplasmic complex that drives downstream NF-κB signaling. MALT1 is the effector protein of the CBM signalosome such that its recruitment to the signalosome via interaction with BCL10 allows it to exert both protease and scaffolding activities that together synergize in driving NF-κB. Here, we demonstrate that a molecular groove located between two adjacent immunoglobulin-like domains within MALT1 represents a binding pocket for BCL10. Leveraging this discovery, we performed an in silico screen to identify small molecules that dock within this MALT1 groove and act as BCL10-MALT1 protein-protein interaction (PPI) inhibitors. We report the identification of M1i-124 as a first-in-class compound that blocks BCL10-MALT1 interaction, abrogates MALT1 scaffolding and protease activities, promotes degradation of BCL10 and MALT1 proteins, and specifically targets ABC-DLBCLs characterized by dysregulated MALT1. Our findings demonstrate that small-molecule inhibitors of BCL10-MALT1 interaction can function as potent agents to block MALT1 signaling in selected lymphomas, and provide a road map for clinical development of a new class of precision-medicine therapeutics.
Journal Article
Long Non-Coding RNAs Guide the Fine-Tuning of Gene Regulation in B-Cell Development and Malignancy
With the introduction of next generation sequencing methods, such as RNA sequencing, it has become apparent that alterations in the non-coding regions of our genome are important in the development of cancer. Particularly interesting is the class of long non-coding RNAs (lncRNAs), including the recently described subclass of circular RNAs (circRNAs), which display tissue- and cell-type specific expression patterns and exert diverse regulatory functions in the cells. B-cells undergo complex and tightly regulated processes in order to develop from antigen naïve cells residing in the bone marrow to the highly diverse and competent effector cells circulating in peripheral blood. These processes include V(D)J recombination, rapid proliferation, somatic hypermutation and clonal selection, posing a risk of malignant transformation at each step. The aim of this review is to provide insight into how lncRNAs including circRNAs, participate in normal B-cell differentiation, and how deregulation of these molecules is involved in the development of B-cell malignancies. We describe the prognostic value and functional significance of specific deregulated lncRNAs in diseases such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Burkitt lymphoma and multiple myeloma, and we provide an overview of the current knowledge on the role of circRNAs in these diseases.
Journal Article
Characteristics of Central Nervous System (CNS) Involvement in Children With Non-Hodgkin’s Lymphoma (NHL) and the Diagnostic Value of CSF Flow Cytometry in CNS Positive Disease
Objective:
To investigate the characteristics of central nervous system (CNS) involvement in children with non-Hodgkin’s lymphoma (NHL) and the value of flow cytometry (FC) in the diagnosis of CNS disease in pediatric NHL.
Methods:
The data of 56 newly diagnosed pediatric NHL patients with CNS involvement (CNS+/mass, CNS+/palsy, CNS+/CSF) were analyzed. The proportions and formats of CNS disease in different pathological types were compared. In addition, FC and conventional cytology (CC) of cerebrospinal fluid (CSF) were carried out in 383 newly diagnosed NHL cases.
Results:
A total of 383 children with NHL were enrolled. Among these patients, 56 (14.6%) were diagnosed with positive CNS involvement (CNS+), 33 had bulky disease (tumor diameter >10 cm), 32 had bone marrow invasion, 32 had lactate dehydrogenase levels >1000 U/L, and 25 had invasion of more than 4 organs at the time of diagnosis. There were 14 patients with T lymphoblastic lymphoma (T-LBL), 9 with B lymphoblastic lymphoma (B-LBL), 26 with Burkitt’s lymphoma (BL), and 2 with Epstein-Barr virus-positive diffuse large B cell lymphoma (EBV + DLBCL). Among the 56 CNS+ patients, 35 were CSF-positive (CSF+); there were 2 patients who were CSF+ via CC detection and 35 who were CSF+ via FC detection. The difference between CC and FC was statistically significant (P < 0.01). In the T-LBL group, 14 patients were CNS+/CSF, and in the B-LBL group, 8 were CNS+/mass. In the BL group, 22 patients were CNS+/mass and 15 were CNS+/CSF. In the anaplastic large-cell lymphoma group, 5 patients were CNS+/mass. Nine of the 56 CNS+ patients had events. The 2-year overall survival rate was 87% ± 0.046%, and the 2-year event-free survival rate was 76.2% ± 0.07%.
Conclusion:
CNS+ diagnoses were more common in pediatric NHL patients with bulky disease and/or bone marrow involvement and/or involvement of more than 4 organs at the time of diagnosis, and they were also common in the EBV + DLBCL and BL groups. FC of CSF showed important clinical significance in the diagnosis of CNS disease in pediatric NHL patients, and it can be used to significantly improve the CNS+ detection rate.
Journal Article