What we mean when we talk about MRD in myeloma. A review of current methods. Part 1 of a two-part series.

Assessment of minimal residual disease (MRD) is becoming standard of care for potentially curable cancers, like some leukemias. For diseases not currently curable, like multiple myeloma (MM), the optimal methodology to assess MRD is much less clear, let alone the clinical significance. In this two-part series, we review each of these aspects of MRD in MM.

Controversies in the assessment of minimal residual disease in multiple myeloma: clinical significance of minimal residual disease negativity using highly sensitive techniques.

Minimal residual disease (MRD) assessment has gained importance in the response evaluation of multiple myeloma. As discussed in part 1 of this two-part series, techniques such as multiparameter flow cytometry, polymerase chain reaction, and next-generation sequencing, of both bone marrow and peripheral blood, have the potential to achieve a high level of sensitivity, up to 1 in 10(-6) cells, enabling analysis of genetically diverse subclones. Here, we review the clinical utility of MRD assessment using these techniques.

First measurement of the charge asymmetry in beauty-quark pair production.

The difference in the angular distributions between beauty quarks and antiquarks, referred to as the charge asymmetry, is measured for the first time in bb pair production at a hadron collider. The data used correspond to an integrated luminosity of 1.0 fb(-1) collected at 7 TeV center-of-mass energy in proton-proton collisions with the LHCb detector.

Precision measurement of the mass and lifetime of the Ξ(b)(0) baryon.

Using a proton-proton collision data sample corresponding to an integrated luminosity of 3 fb(-1) collected by LHCb at center-of-mass energies of 7 and 8 TeV, about 3800 Ξ(b)(0) → Ξ(c)(+)π(-), Ξ(c)(+)) → pK(-)π(+) signal decays are reconstructed. From this sample, the first measurement of the Ξ(b)(0) baryon lifetime is made, relative to that of the Λ(b)(0) baryon. The mass differences M(Ξ(b)(0))-M(Λ(b)(0)) and M(Ξ(c)(+))-M(Λ(c)(+)) are also measured with precision more than 4 times better than the current world averages.

Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma.

Unlabelled: Despite the unprecedented clinical activity of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in mantle cell lymphoma (MCL), acquired resistance is common. By longitudinal integrative whole-exome and whole-transcriptome sequencing and targeted sequencing, we identified the first relapse-specific C481S mutation at the ibrutinib binding site of BTK in MCL cells at progression following a durable response. This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation.

Observation of the resonant character of the Z(4430)(-) state.

Resonant structures in B^{0}→ψ^{'}π^{-}K^{+} decays are analyzed by performing a four-dimensional fit of the decay amplitude, using pp collision data corresponding to 3  fb^{-1} collected with the LHCb detector. The data cannot be described with K^{+}π^{-} resonances alone, which is confirmed with a model-independent approach. A highly significant Z(4430)^{-}→ψ^{'}π^{-} component is required, thus confirming the existence of this state.

Adverse medical complications: an under-reported contributory cause of death in New York City.

Objectives: The current death certification system in the USA fails to accurately track deaths due to adverse medical events. The aim of this study was to demonstrate the under-reporting of deaths due to adverse medical events due to limitations in the current death certification/reporting system, and the benefits of using the term 'therapeutic complication' as the manner of death.

Study Design: Retrospective review and comparison of death certificates and vital statistical coding.

Spectral measurement of electron antineutrino oscillation amplitude and frequency at Daya Bay.

A measurement of the energy dependence of antineutrino disappearance at the Daya Bay reactor neutrino experiment is reported. Electron antineutrinos (ν¯(e)) from six 2.9  GW(th) reactors were detected with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls.

Thalidomide, clarithromycin, lenalidomide and dexamethasone therapy in newly diagnosed, symptomatic multiple myeloma.

We studied T-BiRD (thalidomide [Thalomid(®)], clarithromycin [Biaxin(®)], lenalidomide [Revlimid(®)] and dexamethasone) in symptomatic, newly diagnosed multiple myeloma. In 28-day cycles, patients received dexamethasone 40 mg/day on days 1, 8, 15, 22, clarithromycin 500 mg twice daily on days 1-28; lenalidomide 25 mg/day on days 1-21; and thalidomide 100 mg/day (50 mg/day on days 1-7 of cycle 1 only) on days 1-28. Twenty-six patients received a median of 6 cycles (range 0-41).

IgG4 plasma cell myeloma: new insights into the pathogenesis of IgG4-related disease.

IgG4-related disease is a newly described systemic fibroinflammatory process, characterized by increase in IgG4-positive plasma cells. Its pathogenesis, including the role of IgG4, remains poorly understood. Plasma cell myeloma is typically associated with a large monoclonal serum spike, which is frequently of IgG isotype.

Thrombolysis in myocardial infarction risk score in an observation unit setting.

Objective: The Thrombolysis in Myocardial Infarction (TIMI) score is a validated tool for risk stratification of acute coronary syndrome. We hypothesized that the TIMI risk score would be able to risk stratify patients in observation unit for acute coronary syndrome.

Study Design: Retrospective cohort study of consecutive adult patients placed in an urban academic hospital emergency department observation unit with an average annual census of 65,000 between 2004 and 2007.

Transient B-cell depletion combined with apoptotic donor splenocytes induces xeno-specific T- and B-cell tolerance to islet xenografts.

Peritransplant infusion of apoptotic donor splenocytes cross-linked with ethylene carbodiimide (ECDI-SPs) has been demonstrated to effectively induce allogeneic donor-specific tolerance. The objective of the current study is to determine the effectiveness and additional requirements for tolerance induction for xenogeneic islet transplantation using donor ECDI-SPs. In a rat-to-mouse xenogeneic islet transplant model, we show that rat ECDI-SPs alone significantly prolonged islet xenograft survival but failed to induce tolerance.

Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kδ inhibition through PIK3IP1.

Phosphatidylinositol-3-kinase (PI3K) signaling is constitutive in most human cancers. Selective inhibition of PI3Kδ (p110δ) by GS-1101 has emerged as a promising therapy in chronic lymphocytic leukemia and indolent lymphomas. In aggressive non-Hodgkin lymphomas such as mantle cell lymphoma (MCL), however, efficacy has been observed, but the extent and duration of tumor control is modest.

Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.

Purpose: This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction.

Experimental Design: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide.

Fatal diabetic ketoacidosis and antipsychotic medication.

Hyperglycemia and new onset diabetes have been described with certain antipsychotic medications and some of the initial presentations are fatal diabetic ketoacidosis (DKA). We report 17 deaths due to DKA in psychiatric patients treated with second generation antipsychotic medications. Death certificates and toxicology data were searched for DKA and hyperglycemia.

Myeloid neoplasms secondary to plasma cell myeloma: an intrinsic predisposition or therapy-related phenomenon? A clinicopathologic study of 41 cases and correlation of cytogenetic features with treatment regimens.

We describe 41 cases of myeloid neoplasms (MNs) secondary to plasma cell myeloma (PCM). The types of MN included myelodysplastic syndrome (MDS) in 34 (82.9%), acute myeloid leukemia (AML) in 4 (9.

Utility of observation units for young emergency department chest pain patients.

Background: Determining which patients presenting to the Emergency Department (ED) require further work-up for acute coronary syndrome (ACS) can be difficult. The utility of routine observation for cardiac testing in low-risk young adult patients has been questioned.

Study Objectives: We investigated the rate of positive findings yielded by routine cardiac observation unit work-up in patients aged 40 years or younger.

Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4.

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases.

Lymph node vascular-stromal growth and function as a potential target for controlling immunity.

Lymphadenopathy occurs in many autoimmune and inflammatory diseases, and vascular proliferation is a common feature in the enlarged lymph nodes. The lymph node vasculature plays critical roles in delivering immune cells as well as oxygen and micronutrients, and therefore represents a potential target for therapeutic manipulation of immunity. In this review, we discuss recent insights made in understanding the growth and function of the vascular and associated stromal compartment in immune-stimulated lymph nodes and the potential utility of altering this process in autoimmune diseases.

Observation of electron-antineutrino disappearance at Daya Bay.

The Daya Bay Reactor Neutrino Experiment has measured a nonzero value for the neutrino mixing angle θ(13) with a significance of 5.2 standard deviations. Antineutrinos from six 2.

Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) carries an unfavorable prognosis and requires new treatment strategies. The associated t(11:14) translocation results in enhanced cyclin D1 expression and cyclin D1-dependent kinase activity to promote cell-cycle progression. A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease, using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3-deoxy-3[(18)F]fluorothymidine (FLT) positron emission tomography (PET) to study tumor metabolism and proliferation, respectively, in concert with pre- and on-treatment lymph node biopsies to assess retinoblastoma protein (Rb) phosphorylation and markers of proliferation and apoptosis.

MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.

Purpose: The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67(+) malignant cells.

Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma.

Purpose: The proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

Patients And Methods: Seventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.

Learning from radiation incidents: the new OTHEA website.

OTHEA is the name of a new website (www.othea.net), created by the Health Protection Agency (UK) and the Centre d'étude sur l'évaluation de la protection dans le domaine nucléaire (CEPN, France), and supported by several other stakeholders including national societies and associations.