Calcein release assay as a method for monitoring serum complement activity during monoclonal antibody therapy in patients with B-cell malignancies.

Monoclonal antibodies ofatumumab (anti-CD20) and alemtuzumab (anti-CD52) which are approved for usage in patients with chronic lymphocytic leukemia (CLL), efficiently activate the classical complement pathway. However complement is an exhaustible component and high doses of its activators may deplete complement-dependent cytotoxicity (CDC) potential, thus reducing the effect of repeated mAb dosing. Widely used method to measure CDC activity of patients' serum is hemolytic assay (CH50) on sheep erythrocytes.

Beyond Chemotherapy: Checkpoint Inhibition and Cell-Based Therapy in Non-Hodgkin Lymphoma.

Immune-based treatment strategies, such as checkpoint inhibition and chimeric antigen receptor (CAR) T cells, have started a new frontier for treatment in non-Hodgkin lymphoma (NHL). Checkpoint inhibition has been most successful in Hodgkin lymphoma, where higher expression of PD-L1 is correlated with better overall response rate. Combinations of checkpoint inhibition with various chemotherapy or biologics are in clinical trials, with initially promising results and manageable safety profiles.

Development of a translational medicine protocol for an NCTN genitourinary clinical trial: Critical steps, common pitfalls and a basic guide to translational clinical research.

Translational medicine (TM) components of prospective clinical trials provide an invaluable opportunity to test hypotheses that contribute to our knowledge of human disease biology and/or the mechanism of action of a given therapeutic intervention. Our ability to sample tumors and their microenvironment, and the depth and breadth of biological information that can be extracted from them, has increased exponentially in recent years. This information is critical to guide the next steps clinical research if we are to accelerate the pace of progress in cancer treatment.

ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer.

Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (Kras). We show that partial or total ATM deficiency cooperates with Kras to promote highly metastatic pancreatic cancer.

Intensive Care Unit Outcomes Among Patients With Cancer After Palliative Radiation Therapy.

Purpose: To inform goals of care discussions at the time of palliative radiation therapy (RT) consultation, we sought to characterize intensive care unit (ICU) outcomes for patients treated with palliative RT compared to all other patients with metastatic cancer admitted to the ICU.

Methods And Materials: We conducted a retrospective cohort study of patients with metastatic cancer admitted to an ICU in a tertiary medical center from January 2010 to September 2015. We compared in-hospital mortality between patients who received palliative RT in the 12 months before admission and all other patients with metastatic cancer.

Recent advances and future directions in mantle cell lymphoma research: report of the 2016 mantle cell lymphoma consortium workshop.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma typically associated with the t(11;14) chromosomal translocation, resulting in overexpression of cyclin D1. Although MCL is associated with clinical heterogeneity, outcomes are generally poor and no standard treatment has been established. However, the recent approval of ibrutinib provides a new therapeutic option.

Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy.

Uniformly adopted response criteria are essential for assessment of therapies incorporating conventional chemotherapy and chemoimmunotherapy regimens. Recently, immunomodulatory agents, such as immune checkpoint inhibitors, have demonstrated impressive activity in a broad range of lymphoma histologies. However, these agents may be associated with clinical and imaging findings during treatment suggestive of progressive disease (PD) despite evidence of clinical benefit (eg, tumor flare or pseudo-progression).

Functional characterization of NAD dependent de-acetylases SIRT1 and SIRT2 in B-Cell Chronic Lymphocytic Leukemia (CLL).

Sirtuins (SIRT) are nicotinamide adenine dinucleotide (NAD+) dependent deacetylases or ADP- ribosyl transferases (ARTs) that deacetylate lysine residues on various proteins regulating a variety of cellular and metabolic processes. These enzymes regulate metabolism, cell survival, differentiation and DNA repair. SIRT proteins play an important role in the survival and drug resistance of cancer cells.

Lymphocytosis, lymphadenopathy: benign or malignant?

The increasing use of immunophenotypic and molecular analysis in the routine evaluation of patients with lymphocytosis, lymphadenopathy, or other hematologic disorders has led to the identification of unexpected small clonal lymphoid populations. These clones, sometimes with disease-specific markers, such as the t(14;18), are especially challenging for the clinician because of their unknown biologic potential and uncertain clinical behavior. Study of these early lymphoid lesions is providing important clues to the process of lymphomagenesis, and may provide the rationale for preemptive therapy in the future.

Advances and issues in mantle cell lymphoma research: report of the 2014 Mantle Cell Lymphoma Consortium Workshop.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14) chromosomal translocation and cyclin D1 over-expression. A biologically and clinically heterogeneous lymphoma, MCL, remains clinically challenging, with no proven curative therapy and no established standard of care. However, there have been considerable advances in the last several years in the treatment and understanding of MCL with the FDA approval of lenalidomide and ibrutinib, the development of other potentially active novel agents and the identification of recurrent mutations through new genomic sequencing approaches that may contribute to the biology of MCL and to therapeutic resistance.

Recent advances in mantle cell lymphoma: report of the 2013 Mantle Cell Lymphoma Consortium Workshop.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by overexpression of cyclin D1 resulting from the t(11;14) chromosomal translocation. MCL is biologically and clinically heterogeneous and frequently disseminates to extranodal areas. MCL remains a clinically challenging lymphoma subtype, as there is no proven curative therapy and no standard of care has been established for initial or subsequent lines of therapy.

The application of Oncotype DX in early-stage lymph-node-positive disease.

The recurrence score derived from the 21-gene Oncotype DX assay is both prognostic and predictive of adjuvant chemotherapy benefit in node-negative, estrogen-receptor-positive breast cancer patients treated with tamoxifen. This has led to a remarkable shift in the treatment paradigm, with a sizeable number of patients being able to avoid adjuvant chemotherapy. The recurrence score was then analyzed in a large retrospective study with node-positive, estrogen-receptor-positive patients, in which it demonstrated both prognostic and predictive abilities.

Paradoxical regulation of hypoxia inducible factor-1α (HIF-1α) by histone deacetylase inhibitor in diffuse large B-cell lymphoma.

Hypoxia inducible factor (HIF) is important in cancer, as it regulates various oncogenic genes as well as genes involved in cell survival, proliferation, and migration. Elevated HIF-1 protein promotes a more aggressive tumor phenotype, and greater HIF-1 expression has been demonstrated to correlate with poorer prognosis, increased risk of metastasis and increased mortality. Recent reports suggest that HIF-1 activates autophagy, a lysosomal degradation pathway which may promote tumor cell survival.

β-Catenin activates the HOXA10 and CDX4 genes in myeloid progenitor cells.

HoxA10 is a homeodomain transcription factor that is involved in maintenance of the myeloid progenitor population and implicated in myeloid leukemogenesis. Previously, we found that FGF2 and CDX4 are direct target genes of HoxA10 and that HOXA10 is a Cdx4 target gene. We also found that increased production of fibroblast growth factor 2 (Fgf2) by HoxA10-overexpressing myeloid progenitor cells results in activation of β-catenin in an autocrine manner.

Fas-associated phosphatase 1 mediates Fas resistance in myeloid progenitor cells expressing the Bcr-abl oncogene.

The interferon consensus sequence binding protein (Icsbp) is a transcription factor that influences multiple aspects of myelopoiesis. Expression of Icsbp is decreased in the bone marrow of human subjects with chronic myeloid leukemia (CML), and studies in murine models suggest that Icsbp functions as an anti-oncogene for CML. We previously identified a set of Icsbp target genes that may contribute to this anti-oncogene effect.

Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma: a Children's Oncology Group study.

Infantile fibrosarcoma (IFS; also known as cellular congenital mesoblastic nephroma, CMN, when in the kidney) is a rare, undifferentiated tumour often characterized by the ETV6-NTRK3 fusion transcript. Our goal was to identify downstream pathways, diagnostic markers and potential therapeutic targets for IFS/CMN. Global gene expression, reverse-phase protein array and ETV6-NTRK3 fusion analyses were performed on 14 IFS/CMN and compared with 41 other paediatric renal tumours.

The leukemia-associated fusion protein Tel-platelet-derived growth factor receptor β (Tel-PdgfRβ) inhibits transcriptional repression of PTPN13 gene by interferon consensus sequence binding protein (Icsbp).

Icsbp is an interferon regulatory transcription factor with leukemia suppressor activity. In previous studies, we identified the gene encoding Fas-associated phosphatase 1 (Fap1; the PTPN13 gene) as an Icsbp target. In the current study, we determine that repression of PTPN13 by Icsbp requires cooperation with Tel and histone deacetylase 3 (Hdac3).

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma.

The RAS/RAF/MEK/ERK signaling pathway has been largely unexplored as a potential therapeutic target in lymphoma. The novel 2nd generation anti-MEK small molecule, AZD6244, down-regulated its direct downstream target, phospho-ERK (pERK) in germinal center and nongerminal center diffuse large B-cell lymphoma (DLBCL) cell lines and primary cells. Similar decreased pERK levels were noted despite constitutive activation (CA) of MEK.

PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells.

Purpose: We investigated the cytotoxicity and mechanisms of cell death of the broad-spectrum histone deacetylase (HDAC) inhibitor PCI-24781, alone and combined with bortezomib in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines and primary lymphoproliferative (CLL/SLL) cells.

Experimental Design: Apoptosis, mitochondrial membrane potential, cell cycle analysis, and reactive oxygen species (ROS) were measured by flow cytometry, whereas caspase activation was determined by Western blot. Nuclear factor kappaB (NF-kappaB)-related mRNAs were quantified by reverse transcription-PCR, NF-kappaB-related proteins by Western blotting, and NF-kappaB DNA-binding activity by electromobility shift assay.

Constitutively active SHP2 cooperates with HoxA10 overexpression to induce acute myeloid leukemia.

The homeodomain transcription factor HoxA10 is maximally expressed in myeloid progenitor cells. Sustained HoxA10 expression during differentiation has been described in poor prognosis human acute myeloid leukemia (AML). Consistent with this, engineered overexpression of HoxA10 in murine bone marrow induces a myeloproliferative disorder that progresses to AML over time.

Treatment of Hodgkin lymphoma: the past, present, and future.

Significant advances in the biology and treatment of Hodgkin lymphoma (HL) have been accomplished over the past decades. In a landmark study, DeVita and colleagues showed that half of patients with advanced-stage HL experienced long-term disease-free survival following treatment with a four-drug chemotherapy regimen. Subsequent reports and randomized clinical trials conducted over the past 40 years have defined prognostic categories and refined the treatment options for patients with early-stage and advanced-stage HL.