ABSTRACT
In 2003, the Human Disease Ontology (DO, https://disease-ontology.org/) was established at Northwestern University. In the intervening 20 years, the DO has expanded to become a highly-utilized disease knowledge resource. Serving as the nomenclature and classification standard for human diseases, the DO provides a stable, etiology-based structure integrating mechanistic drivers of human disease. Over the past two decades the DO has grown from a collection of clinical vocabularies, into an expertly curated semantic resource of over 11300 common and rare diseases linking disease concepts through more than 37000 vocabulary cross mappings (v2023-08-08). Here, we introduce the recently launched DO Knowledgebase (DO-KB), which expands the DO's representation of the diseaseome and enhances the findability, accessibility, interoperability and reusability (FAIR) of disease data through a new SPARQL service and new Faceted Search Interface. The DO-KB is an integrated data system, built upon the DO's semantic disease knowledge backbone, with resources that expose and connect the DO's semantic knowledge with disease-related data across Open Linked Data resources. This update includes descriptions of efforts to assess the DO's global impact and improvements to data quality and content, with emphasis on changes in the last two years.
Subject(s)
Ecosystem , Knowledge Bases , Humans , Rare Diseases , Semantics , Time FactorsABSTRACT
BACKGROUND: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported. METHODS: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity. RESULTS: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4+ central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells. CONCLUSIONS: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.
Subject(s)
Central Nervous System Neoplasms , Lymphoma , Receptors, Chimeric Antigen , Humans , Chemokine CXCL10 , Central Nervous System Neoplasms/therapy , Antigens, CD19ABSTRACT
The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24-2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27-3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.
Subject(s)
Blast Crisis/physiopathology , Leukemia, Myeloid, Acute/blood , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Leukemia, Myeloid, Acute/complications , Male , Middle Aged , Prognosis , Young AdultABSTRACT
Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.
Subject(s)
Antibodies, Bispecific/therapeutic use , Antigens, CD19/metabolism , Antineoplastic Agents/therapeutic use , Imidazoles/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Pyridazines/therapeutic use , Adult , Cell- and Tissue-Based Therapy , Drug Therapy, Combination , Humans , Male , Philadelphia Chromosome , Receptors, Antigen, T-Cell/therapeutic use , RecurrenceSubject(s)
Antibodies, Bispecific/therapeutic use , Antigens, CD19/analysis , Antineoplastic Agents, Immunological/therapeutic use , Leukemia, Biphenotypic, Acute/drug therapy , Molecular Targeted Therapy , Adult , Antigens, CD19/immunology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Lineage , Combined Modality Therapy , Cytarabine/administration & dosage , Dasatinib/administration & dosage , Daunorubicin/administration & dosage , Drug Substitution , Female , Hematopoietic Stem Cell Transplantation , Humans , Immunophenotyping , Leukemia, Biphenotypic, Acute/pathology , Leukemia, Biphenotypic, Acute/therapy , Male , Middle Aged , Neoplasm, Residual , Neoplastic Stem Cells/chemistry , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/pathology , Remission InductionSubject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Myelodysplastic Syndromes/therapy , Red-Cell Aplasia, Pure/drug therapy , ABO Blood-Group System , Allografts , Erythrocyte Transfusion/adverse effects , Erythrocyte Transfusion/methods , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Middle Aged , Myelodysplastic Syndromes/blood , Red-Cell Aplasia, Pure/blood , Red-Cell Aplasia, Pure/etiology , Treatment OutcomeSubject(s)
Antigens, CD19/immunology , Immunotherapy, Adoptive , Lymphoma, B-Cell/therapy , Adenine/analogs & derivatives , Antibodies, Monoclonal, Humanized/administration & dosage , Antigens, CD19/administration & dosage , Antigens, CD19/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzamides/administration & dosage , Biological Products , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Fatal Outcome , Female , Humans , Isoindoles/administration & dosage , Lymphocyte Depletion , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/immunology , Lymphoma, Follicular/drug therapy , Male , Middle Aged , Neoplasms, Multiple Primary/drug therapy , Piperidines , Prednisone/administration & dosage , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Recurrence , Salvage Therapy , Vincristine/administration & dosageABSTRACT
Breast cancer is the most common women cancer and is the second leading cause of cancer-related mortality in women. While the last two decades revolutionized breast cancer treatment with the development and use of therapies targeting steroid receptors and HER2/neu, there are limits to the risk estimation provided by traditional clinicopathologic parameters and IHC. Therefore, there is continued potential for inaccurate risk stratification of breast cancer patients which may lead to over- or under-treatment. In this review, we discuss the latest developments in the area of breast cancer research which have lead to better understanding of the breast cancer mechanisms, provided more accurate risk stratification, and identified potential new treatment targets. Specifically, we review the new dualistic model of breast carcinogenesis, which can inform pathologic diagnosis and tumor grading; we also discuss the intrinsic molecular classification of breast cancer and its impact on diagnosis and treatment; lastly, we compare the most common commercial molecular prognostic and predictive assays, with their respective strengths and weaknesses, and their clinical utility.
Subject(s)
Breast Neoplasms/classification , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Transcriptome/genetics , Biomarkers, Tumor/analysis , Female , Gene Expression Profiling , HumansABSTRACT
Acute myeloid leukemia (AML) represents a heterogeneous disease entity that is continuously moving to a more genetically defined classification. The classification of AML with recurrent chromosomal translocations, including those involving core binding factor subunits, plays a critical role in diagnosis, prognosis, treatment stratification, and residual disease evaluation. Accurate classification of variant cytogenetic rearrangements in AML contributes to effective clinical management. We report here the identification of four variant t(8;V;21) translocations in newly diagnosed AML patients. Two patients showed a t(8;14) and a t(8;10) variation, respectively, with a morphologically normal-appearing chromosome 21 in each initial karyotype. Subsequent fluorescence in situ hybridization (FISH) on metaphase cells revealed cryptic three-way translocations t(8;14;21) and t(8;10;21). Each resulted in RUNX1::RUNX1T1 fusion. The other two patients showed karyotypically visible three-way translocations t(8;16;21) and t(8;20;21), respectively. Each resulted in RUNX1::RUNX1T1 fusion. Our findings demonstrate the importance of recognizing variant forms of t(8;21) translocations and emphasize the value of applying RUNX1::RUNX1T1 FISH for the detection of cryptic and complex rearrangements when abnormalities involving chromosome band 8q22 are observed in patients with AML.
Subject(s)
Core Binding Factor Alpha 2 Subunit , Leukemia, Myeloid, Acute , Humans , Core Binding Factor Alpha 2 Subunit/genetics , In Situ Hybridization, Fluorescence , Gene Rearrangement , Leukemia, Myeloid, Acute/genetics , Translocation, Genetic , KaryotypingABSTRACT
The classification of haematological neoplasms recently underwent revision, generating two separate schemes-the International Consensus Classification and the fifth edition of the WHO classification. The new division into separate classification systems presents challenges for haematopathologists, haematologists/oncologists and patients. While it is too early to assess the full clinical impact, we sought to identify diagnostic discordance which may arise from applying separate classification schemes in myeloid neoplasia, and particularly in the challenging category of myelodysplastic syndrome/myeloproliferative neoplasms. A review of 64 such cases found 1 case with a significant discrepancy between the WHO and International Consensus Classification systems, and 9 cases with nominal discrepancies. Confusion from the use of conflicting diagnostic terms represents a potential source of patient harm, increased pathologist workload and burnout and erosion of clinician and patient trust.
Subject(s)
Hematologic Neoplasms , Myelodysplastic Syndromes , Myeloproliferative Disorders , Humans , Myelodysplastic Syndromes/diagnosis , Myeloproliferative Disorders/diagnosis , Hematologic Neoplasms/diagnosis , World Health OrganizationABSTRACT
Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.
Subject(s)
Kidney Transplantation , Lymphoproliferative Disorders , Organ Transplantation , Receptors, Chimeric Antigen , Humans , Kidney Transplantation/adverse effects , Receptors, Chimeric Antigen/therapeutic use , Organ Transplantation/adverse effects , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/therapy , T-Lymphocytes/pathologyABSTRACT
CONTEXT.: Inappropriate laboratory testing and the threat it poses to patient care and rising health care costs has become an important focus in the medical literature. Pathology residents, as physicians with an intimate knowledge of laboratory testing, may be uniquely equipped with the tools to intervene in situations of inappropriate testing and also benefit from lab use experience as part of their clinical pathology training. OBJECTIVE.: To employ a resident-driven initiative aimed at incorporating pathology residents as consultants for appropriate ordering of high-volume, send-out myeloid mutation panel testing. DESIGN.: During a 6-month study period, all myeloid mutation panel send-out tests were screened by senior pathology residents on their clinical chemistry rotation prior to approval at an academic medical center. A retrospective review of myeloid mutation panels from the prior 6 months was conducted with the same criteria to determine effectiveness of the intervention. RESULTS.: Of the 234 tests ordered during the study period, screening resulted in cancellation of 17% (n = 39), with proportional cost savings. The number of inappropriate orders successfully cancelled was significant compared with the preintervention period (control, 0%; intervention, 76.5%; P < .001, Fisher exact test). There was no significant difference in the proportion of inappropriate tests before and after intervention. CONCLUSIONS.: Although test ordering patterns did not substantially change during the intervention period, pathology residents effectively reduced inappropriate myeloid mutation panel testing through prospective send-out auditing, leading to significant cost savings. Moreover, assessment of test use and appropriateness provided critical clinical pathology training within the areas of hematology, molecular genetics, and laboratory management.
Subject(s)
Pathology, Clinical , Consultants , Humans , Laboratories , Mutation , Prospective StudiesABSTRACT
New therapies for multiple myeloma have improved outcomes, but are associated with therapy-related hematologic malignancies. We report eight patients with therapy-related B-lymphoblastic leukemias (t-B-ALL) in the setting of therapy for multiple myeloma, which included lenalidomide maintenance. A subset of patients had pancytopenia and low-level marrow involvement by acute leukemia, an unusual finding in de novo B-ALL. One patient died of chemotherapy complications; the other seven responded. No patient died of B-ALL (median follow up of 1.0 years). Our series suggests that t-B-ALL is clonally unrelated to myeloma, presents with diverse cytogenetic abnormalities, and responds well to B-ALL therapy.
ABSTRACT
Humans and mice deficient in Fas, a tumor necrosis factor (TNF)-receptor family member, cannot induce apoptosis of autoreactive cells, and consequently develop progressive lymphoproliferative disorders and lupus-like autoimmune diseases. Previous studies have shown that short-term administrations of agonistic monoclonal antibodies against CD137, another TNF-receptor family member, activate T cells and induce rejection of allografts and established tumors. Here we report that treatment with an agonistic monoclonal antibody to CD137 (2A) blocks lymphadenopathy and spontaneous autoimmune diseases in Fas-deficient MRL/lpr mice, ultimately leading to their prolonged survival. Notably, 2A treatment rapidly augments IFN-gamma production, and induces the depletion of autoreactive B cells and abnormal double-negative T cells, possibly by increasing their apoptosis through Fas- and TNF receptor-independent mechanisms. This study demonstrates that agonistic monoclonal antibodies specific for costimulatory molecules can be used as novel therapeutic agents to delete autoreactive lymphocytes and block autoimmune disease progression.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Lupus Erythematosus, Systemic/therapy , Receptors, Nerve Growth Factor/antagonists & inhibitors , Receptors, Tumor Necrosis Factor/antagonists & inhibitors , Animals , Antigens, CD , Autoantibodies/biosynthesis , B-Lymphocytes/immunology , Female , Immunotherapy , Interferon-gamma/physiology , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/mortality , Mice , Mice, Inbred C57BL , Mice, Inbred MRL lpr , Receptors, Tumor Necrosis Factor/physiology , T-Lymphocytes/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 9 , fas Receptor/physiologyABSTRACT
BACKGROUND: Aspartate ß-hydroxylase (ASPH) is an embryonic transmembrane protein aberrantly upregulated in cancer cells, associated with malignant transformation and, in some reports, with poor clinical prognosis. OBJECTIVE: To report the expression patterns of ASPH in acute myeloid leukemia (AML). METHODS: Cell surface expression of ASPH was measured via 8-color multiparameter flow cytometry in 41 AML patient samples (31 bone marrow, 10 blood) using fluorescein isothiocyanate (FITC)-conjugated anti-ASPH antibody, SNS-622. A mean fluorescent intensity (MFI) of 10 was used as a cutoff for ASPH surface expression positivity. Data regarding patient and disease characteristics were collected. RESULTS: ASPH surface expression was found on AML blasts in 16 samples (39%). Higher ASPH expression was seen in myeloblasts of African American patients (p=0.02), but no correlation was found between ASPH expression and other patient or disease characteristics. No association was found between ASPH status and CR rate (p=0.53), EFS (p=0.87), or OS (p=0.17). CONCLUSIONS: ASPH is expressed on blasts in approximately 40% of AML cases, and may serve as a new therapeutically targetable leukemia-associated antigen.
ABSTRACT
The high affinity interleukin (IL)-15 receptor, IL-15Ralpha, is essential for supporting lymphoid homeostasis. To assess whether IL-15Ralpha's role in vivo is to trans present IL-15, we generated mixed bone marrow chimera from IL-15Ralpha- and IL-2/15Rbeta-deficient mice. We find that IL-15Ralpha-competent, IL-2/15Rbeta-deficient cells are able to support IL-15Ralpha-deficient natural killer (NK) and memory CD8+ T cells, thus ruling out secondary signals on these cells and demonstrating that IL-15Ralpha-mediated presentation of IL-15 in trans is the primary mechanism by which IL-15Ralpha functions in vivo. Surprisingly, using IL-15- and IL-15Ralpha-deficient mixed chimera, we also find that IL-15 and IL-15Ralpha must be expressed by the same cells to present IL-15 in trans, indicating that IL-15Ralpha is required on a cellular level for the elaboration of IL-15. These studies indicate that IL-15Ralpha defines homeostatic niches for NK and memory CD8+ T cells by controlling both the production and the presentation of IL-15 in trans to NK and CD8+ memory T cells.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Homeostasis/immunology , Interleukin-15/metabolism , Killer Cells, Natural/immunology , Receptors, Interleukin-2/metabolism , Animals , Bone Marrow Cells , Flow Cytometry , Immunologic Memory/immunology , Interleukin-15/immunology , Mice , Mice, Inbred C57BL , Models, Immunological , Radiation Chimera , Receptors, Interleukin-15 , Receptors, Interleukin-2/immunologyABSTRACT
Natural killer (NK) cells protect hosts against viral pathogens and transformed cells. IL-15 is thought to play a critical role in NK cell development, but its role in the regulation of peripheral NK cells is less well defined. We now find that adoptive transfer of normal NK cells into mice lacking the high affinity interleukin (IL)-15 receptor, IL-15Ralpha, surprisingly results in the abrupt loss of these cells. Moreover, IL-15Ralpha-deficient NK cells can differentiate successfully in radiation bone marrow chimera bearing normal cells. Finally, adoptively transferred IL-15Ralpha-deficient NK cells survive in normal but not IL-15Ralpha-deficient mice. These findings demonstrate that NK cell-independent IL-15Ralpha expression is critical for maintaining peripheral NK cells, while IL-15Ralpha expression on NK cells is not required for this function.