Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro.

DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine.

HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation.

Treatment of relapse after related HLA-haploidentical T cell-replete bone marrow transplantation (haploBMT) with post-transplantation cyclophosphamide (PTCy) using haploidentical donor lymphocyte infusion (haploDLI) is not documented. All patients who received haploDLI after haploBMT with PTCy between June 2003 and October 2012 were identified and assessed for graft-versus-host disease (GVHD) and outcomes. Forty patients received 52 haploDLI doses.

Screening for undiagnosed atrial fibrillation in the community.

Purpose Of Review: Recent years have seen significant advances in knowledge about the prevalence of 'silent' atrial fibrillation and the morbidity associated with this condition. Data are emerging on improved strategies for screening, and new technologies for detecting atrial fibrillation are becoming available, making a review of this field timely.

Recent Findings: Studies suggest that, when screening is performed, undiagnosed atrial fibrillation is present in around 1% of the screened population, rising to 1.

Multicenter accuracy and interobserver agreement of spot sign identification in acute intracerebral hemorrhage.

Background And Purpose: Rapid, accurate, and reliable identification of the computed tomography angiography spot sign is required to identify patients with intracerebral hemorrhage for trials of acute hemostatic therapy. We sought to assess the accuracy and interobserver agreement for spot sign identification.

Methods: A total of 131 neurology, emergency medicine, and neuroradiology staff and fellows underwent imaging certification for spot sign identification before enrolling patients in 3 trials targeting spot-positive intracerebral hemorrhage for hemostatic intervention (STOP-IT, SPOTLIGHT, STOP-AUST).

Real-time in vivo Cherenkoscopy imaging during external beam radiation therapy.

Cherenkov radiation is induced when charged particles travel through dielectric media (such as biological tissue) faster than the speed of light through that medium. Detection of this radiation or excited luminescence during megavoltage external beam radiotherapy (EBRT) can allow emergence of a new approach to superficial dose estimation, functional imaging, and quality assurance for radiation therapy dosimetry. In this letter, the first in vivo Cherenkov images of a real-time Cherenkoscopy during EBRT are presented.

Superficial dosimetry imaging based on Čerenkov emission for external beam radiotherapy with megavoltage x-ray beam.

Purpose: Čerenkov radiation emission occurs in all tissue, when charged particles (either primary or secondary) travel at velocity above the threshold for the Čerenkov effect (about 220 KeV in tissue for electrons). This study presents the first examination of optical Čerenkov emission as a surrogate for the absorbed superficial dose for MV x-ray beams.

Methods: In this study, Monte Carlo simulations of flat and curved surfaces were studied to analyze the energy spectra of charged particles produced in different regions near the surfaces when irradiated by MV x-ray beams.

The CLOQS trial protocol: a cluster-randomized trial evaluating a simple, low-cost intervention to reduce treatment times in acute stroke.

Rationale: In acute stroke, time is brain: faster tissue plasminogen activator treatment improves patient outcomes. Published guidelines for door-to-scanner time are <25 minutes, and for door-to-needle time <60 minutes. These benchmarks are rarely met.

Superficial dosimetry imaging of Čerenkov emission in electron beam radiotherapy of phantoms.

Čerenkov emission is generated from ionizing radiation in tissue above 264 keV energy. This study presents the first examination of this optical emission as a surrogate for the absorbed superficial dose. Čerenkov emission was imaged from the surface of flat tissue phantoms irradiated with electrons, using a range of field sizes from 6 cm × 6 cm to 20 cm × 20 cm, incident angles from 0° to 50°, and energies from 6 to 18 MeV.

Absence of post-transplantation lymphoproliferative disorder after allogeneic blood or marrow transplantation using post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis.

Immunosuppressive regimens that effectively prevent graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (allo-BMT) have been associated with an increased incidence of post-transplantation lymphoproliferative disorder (PTLD) in the first year after transplantation. We evaluated the incidence of PTLD associated with the use of high-dose post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis. Between 2000 and 2011, a total of 785 adult allo-BMT recipients were given PTCy as GVHD prophylaxis at the Johns Hopkins Hospital, including 313 patients who received PTCy as sole GVHD prophylaxis.

Oxygen tomography by Čerenkov-excited phosphorescence during external beam irradiation.

The efficacy of radiation therapy depends strongly on tumor oxygenation during irradiation. However, current techniques to measure this parameter in vivo do not facilitate routine monitoring in patients. Herein, we demonstrate a noninvasive method for tomographic imaging of oxygen partial pressure (pO(2)) in deep tissue using the phosphorescence decay of an oxygen-sensitive probe excited by Čerenkov radiation induced by external beam radiotherapy.

Čerenkov excited fluorescence tomography using external beam radiation.

Radiation treatment of cancer induces an optical Čerenkov emission throughout the treated volume, which could be used to excite molecular reporters in vivo, allowing molecular sensing of tissue response during fractionated therapy. In this Letter, the idea that spatial mapping of this signal can be achieved with tomographic recovery of the fluorophore distribution is tested for the first time using 6 MV photons from a linear accelerator in a heterogeneous tissue phantom. Čerenkov light excited fluorophores throughout the tissue phantom, and diffuse tomography was used to recover images.

Three-dimensional Čerenkov tomography of energy deposition from ionizing radiation beams.

Since its discovery during the 1930s the Čerenkov effect (light emission from charged particles traveling faster than the local speed of light in a dielectric medium) has been paramount in the development of high-energy physics research. The ability of the emitted light to describe a charged particle's trajectory, energy, velocity, and mass has allowed scientists to study subatomic particles, detect neutrinos, and explore the properties of interstellar matter. However, to our knowledge, all applications of the process to date have focused on the identification of particles themselves, rather than their effect upon the surroundings through which they travel.

Spot sign number is the most important spot sign characteristic for predicting hematoma expansion using first-pass computed tomography angiography: analysis from the PREDICT study.

Background And Purpose: The spot sign score (SSS) provides risk stratification for hematoma expansion in acute intracerebral hemorrhage; however, external validation is needed. We sought to validate the SSS and assess prognostic performance of individual spot characteristics associated with hematoma expansion from a prospective multicenter intracerebral hemorrhage study.

Methods: Two hundred twenty-eight intracerebral hemorrhage patients within 6 hours after ictus were enrolled in the Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT (PREDICT) study, a multicenter prospective intracerebral hemorrhage cohort study.

Iron oxide nanoparticle enhancement of radiation cytotoxicity.

Iron oxide nanoparticles (IONPs) have been investigated as a promising means for inducing tumor cell-specific hyperthermia. Although the ability to generate and use nanoparticles that are biocompatible, tumor specific, and have the ability to produce adequate cytotoxic heat is very promising, significant preclinical and clinical development will be required for clinical efficacy. At this time it appears using IONP-induced hyperthermia as an adjunct to conventional cancer therapeutics, rather than as an independent treatment, will provide the initial IONP clinical treatment.

Outcomes of related donor HLA-identical or HLA-haploidentical allogeneic blood or marrow transplantation for peripheral T cell lymphoma.

The role of allogeneic blood or marrow transplantation (alloBMT) for peripheral T cell lymphoma (PTCL) remains to be defined. There is growing interest in reduced-intensity conditioning (RIC) regimens and/or utilization of human leukocyte antigen haploidentical (haplo) grafts given concerns about treatment-associated toxicities and donor availability. We reviewed the outcomes of 44 consecutive, related donor alloBMTs for PTCL performed at Johns Hopkins Hospital from 1994 to 2011, including 18 RIC/haplo alloBMTs.

Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies.

The presence of donor human leukocyte antigen (HLA)-specific antibodies (DSA) increases engraftment failure risk in partially HLA-mismatched, or HLA-haploidentical, allogeneic marrow (alloBMT) transplantation. As pre-existing sensitization to HLA antigens is not well characterized among candidates for HLA-haploidentical alloBMT, we retrospectively evaluated both the incidence and relative strength of DSA in this patient population. Based on correlations of solid-phase antibody assays on the Luminex (Luminex, Austin, TX) platform with actual crossmatch tests, DSA were characterized as weak for results that were consistent with negative flow cytometric crossmatch results or as moderate-to-strong for results consistent with positive flow cytometric or cytotoxicity crossmatches.

Projection imaging of photon beams using Čerenkov-excited fluorescence.

Full 3D beam profiling and quality assurance (QA) of therapeutic megavoltage linear accelerator (LINAC) x-ray photon beams is not routinely performed due to the slow point-by-point measurement nature of conventional scanning ionization chamber systems. In this study we explore a novel optical-based dose imaging approach using a standard commercial camera, water tank, and fluorescent dye, which when excited by the Čerenkov emission induced by the radiation beam, allows 2D projection imaging in a fast timeframe, potentially leading toward 3D tomographic beam profiling. Detailed analysis was carried out to optimize the imaging parameters in the experimental setup.

Projection imaging of photon beams by the Čerenkov effect.

Purpose: A novel technique for beam profiling of megavoltage photon beams was investigated for the first time by capturing images of the induced Čerenkov emission in water, as a potential surrogate for the imparted dose in irradiated media.

Methods: A high-sensitivity, intensified CCD camera (ICCD) was configured to acquire 2D projection images of Čerenkov emission from a 4 × 4 cm(2) 6 MV linear accelerator (LINAC) x-ray photon beam operating at a dose rate of 400 MU∕min incident on a water tank with transparent walls. The ICCD acquisition was gated to the LINAC sync pulse to reduce background light artifacts, and the measurement quality was investigated by evaluating the signal to noise ratio and measurement repeatability as a function of delivered dose.

Maintaining hemostasis in acquired von Willebrand syndrome: a review of intravenous immunoglobulin and the importance of rituximab dose scheduling.

Background: The acute management of acquired von Willebrand syndrome (AVWS) is aimed at achieving hemostasis with von Willebrand factor replacement, counteracting the pathologic antibodies with intravenous immunoglobulin (IVIG), and supportive care with blood transfusions. However, strategies for the long-term management of AVWS are not described, resulting in persistent use of these acute strategies to achieve hemostasis via high utilization of blood products. Herein, we provide an updated review of the use of IVIG and rituximab for AVWS and present rituximab maintenance as an effective and durable strategy for the management of these patients.

Is the cultural transmission of irrelevant tool actions in adult humans (Homo sapiens) best explained as the result of an evolved conformist bias?

Background: Recent studies of social learning have revealed that adult humans are "over-imitators" who frequently reproduce a model's causally irrelevant tool actions to the detriment of task efficiency. At present our knowledge of adult over-imitation is limited to the fact that adults do over-imitate, we know very little about the causes of this behavior. The current study aimed to provide novel insights into adult over-imitation by extending a paradigm recently used with human children to explore social aspects of over-imitation.

Atrial fibrillation in ischemic stroke: predicting response to thrombolysis and clinical outcomes.

Background And Purpose: Atrial fibrillation (AF) increases the risk of stroke and is associated with poor stroke outcomes. Limited tools are available to evaluate clinical outcomes and response to thrombolysis in stroke patients with AF.

Methods: We applied the iScore (http://www.

Emergency noninvasive angiography for acute intracerebral hemorrhage.

Spontaneous ICH is a devastating condition and is associated with significant mortality in the acute phase due to ongoing hemorrhage and hematoma expansion. A growing body of evidence suggests that there may be considerable utility in performing noninvasive vascular imaging during the acute-to-early phase of ICH. CTA has become widely available and is sensitive and specific for detecting vascular causes of secondary ICH such as aneurysms, arteriovenous malformations, dural arteriovenous fistulas, intracranial dissections, and neoplasm.

Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias.

Purpose: Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776.