Heparanase promotes the spontaneous metastasis of myeloma cells to bone

Although widespread skeletal dissemination is a critical step in the progression of myeloma, little is known regarding mechanisms that control metastasis of this cancer. Heparanase-1 (heparanase), an enzyme that cleaves heparan sulfate chains, is expressed at high levels in some patients with myeloma and promotes metastasis of some tumor types (eg, breast, lymphoma). Using a severe combined immunodeficient (SCID) mouse model, we demonstrate that enhanced expression of heparanase by myeloma cells dramatically up-regulates their spontaneous metastasis to bone. This occurs from primary tumors growing subcutaneously and also from primary tumors established in bone. Interestingly, tumors formed by subcutaneous injection of cells metastasize not only to bone, but also to other sites including spleen, liver, and lung. In contrast, tumors formed by injection of cells directly into bone exhibit a restricted pattern of metastasis that includes dissemination of tumor to other bones but not to extramedullary sites. In addition, expression of heparanase by myeloma cells (1) accelerates the initial growth of the primary tumor, (2) increases whole-body tumor burden as compared with controls, and (3) enhances both the number and size of microvessels within the primary tumor. These studies describe a novel experimental animal model for examining the spontaneous metastasis of bone-homing tumors and indicate that heparanase is a critical determinant of myeloma dissemination and growth in vivo.     

What can three-dimensional speckle-tracking echocardiography contribute to evaluate global left ventricular systolic performance in patients with heart failure?

Purpose

Three-dimensional speckle-tracking echocardiography (3D-STE) is a newly developed technique to evaluate left ventricular (LV) deformation by measuring the area strain (AS) of endocardial surface that combines information from both longitudinal (LS) and circumferential strain (CS). We performed a study to examine myocardial deformation in patients with heart failure (HF) using 3D-STE.

Method

A total of 149 subjects including 58 patients with HF and preserved ejection fraction (HFPEF), 45 patients with HF and reduced ejection fraction (HFREF), and 46 normal subjects were prospectively studied by 3D-STE.

Result

After adjusting for age, gender and BSA, global CS, LS, radial strain (RS) and AS derived from 3D-STE in patients with HFPEF were significantly higher than their counterparts in patients with HFREF (all p < 0.001), but lower than that in normal subjects (all p < 0.05). In addition, among all the strain parameters, global AS exhibited the highest correlation with LV ejection fraction (y = 1.243x + 6.332, r = 0.982, p < 0.001) and the best intra- (ICCs: 0.986, p < 0.001) and inter-observer variability (ICCs: 0.978, p < 0.001) than other parameters of 3D strain (CS: 0.981 and 0.974; LS: 0.908 and 0.841; RS: 0.946 and 0.915; all p < 0.001).

Conclusions

Measurement of endocardial surface AS based on 3D-STE technique is reproducible and proves to be accurate and comprehensive in assessing the global LV performance and multidirectional deformation of the LV myocardium in HF patients.     

Left anterior descending coronary artery flow impaired by right ventricular apical pacing: The role of systolic dyssynchrony

Introduction

Right ventricular (RV) pacing may affect myocardial perfusion and coronary blood flow; however, it remains unknown whether this is related to systolic dyssynchrony induced by RV pacing. This prospective study was aimed to assess the relationship between dyssynchrony and the changes of coronary blood flow.

Methods

Seventy patients with sinus node dysfunction were prospectively enrolled. Coronary flow was evaluated by measuring diastolic velocity time integral (VTI) and duration at the distal-portion of left anterior descending coronary artery (LAD) with transthoracic echocardiography at baseline and follow-up. Systolic dyssynchrony was assessed with tissue Doppler imaging by time standard deviation to peak systolic velocity of 12 left ventricular segments (Ts-SD, cutoff value ≥ 33 ms).

Results

Adequate data for analysis was available from 65 patients. At follow-up (mean follow up time: 127 ± 45 days), LAD velocity-time integral (LAD-VTI: 12.1 ± 4.2 vs. 10.7 ± 4.6 cm, p < 0.001) was decreased and there was deterioration of left ventricular systolic function (left ventricular ejection fraction: 65 ± 7% vs. 62 ± 7%). However, these changes were only detected in those with RV pacing induced systolic dyssynchrony. Significant reduction of LAD-VTI (defined as ≥ 5%) occurred in 34 (52%) patients which was more prevalent in those with pacing-induced systolic dyssynchrony than those without (85.3% versus 16.1%, χ² = 31.1, p < 0.001). Though similar at baseline, LAD-VTI was significantly lower in the dyssynchrony group at follow up (p < 0.001). Cox-regression analysis showed that pacing-inducing systolic dyssynchrony [hazard ratio (HR): 3.62, p = 0.009] and higher accumulative pacing percentage (HR: 1.02, p = 0.002) were independently associated with reduction of LAD-VTI. ROC curve demonstrated that accumulative pacing percentage ≥ 35% was 97% sensitive and 84% specific in revealing significant reduction (area under the curve: 0.961, p < 0.001).

Conclusions

RV pacing induced dyssynchrony is associated with reduced coronary flow and this may account for, in part, the deleterious effect of RV pacing on ventricular function over time.     

The ABC’s of Teaching Social Skills to Adolescents with Autism Spectrum Disorder in the Classroom: The UCLA PEERS ® Program

Social skills training is a common treatment method for adolescents with autism spectrum disorder (ASD), yet very few evidence-based interventions exist to improve social skills for high-functioning adolescents on the spectrum, and even fewer studies have examined the effectiveness of teaching social skills in the classroom. This study examines change in social functioning for adolescents with high-functioning ASD following the implementation of a school-based, teacher-facilitated social skills intervention known as Program for the Education and Enrichment of Relational Skills (PEERS ^® ). Seventy-three middle school students with ASD along with their parents and teachers participated in the study. Participants were assigned to the PEERS ^® treatment condition or an alternative social skills curriculum. Instruction was provided daily by classroom teachers and teacher aides for 14-weeks. Results reveal that in comparison to an active treatment control group, participants in the PEERS ^® treatment group significantly improved in social functioning in the areas of teacher-reported social responsiveness, social communication, social motivation, social awareness, and decreased autistic mannerisms, with a trend toward improved social cognition on the Social Responsiveness Scale. Adolescent self-reports indicate significant improvement in social skills knowledge and frequency of hosted and invited get-togethers with friends, and parent-reports suggest a decrease in teen social anxiety on the Social Anxiety Scale at a trend level. This research represents one of the few teacher-facilitated treatment intervention studies demonstrating effectiveness in improving the social skills of adolescents with ASD in the classroom: arguably the most natural social setting of all.     

Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2

Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.     

Soluble syndecan-1 promotes growth of myeloma tumors in vivo

Syndecan-1 (CD138) is a transmembrane heparan sulfate-bearing proteoglycan expressed by most myeloma plasma cells that regulates adhesion, migration, and growth factor activity. In patients with myeloma, shed syndecan-1 accumulates in the bone marrow, and high levels of syndecan-1 in the serum are an indicator of poor prognosis. To test the effect of soluble syndecan-1 on tumor cell growth and dissemination, ARH-77 B-lymphoid cells were engineered to produce a soluble form of syndecan-1. Controls included vector only (neo)-transfected cells and cells transfected with full-length syndecan-1 complementary DNA that codes for the cell surface form of syndecan-1. Assays reveal that all 3 transfectants have similar growth rates in vitro, but cells expressing soluble syndecan-1 are hyperinvasive in collagen gels relative to controls. When injected into the marrow of human bones that were implanted in severe combined immunodeficient mice, tumors formed by cells expressing soluble syndecan-1 grow faster than tumors formed by neo-transfected cells or by cells expressing cell surface syndecan-1. In addition, cells bearing cell surface syndecan-1 exhibit a diminished capacity to establish tumors within the mice as compared with both neo- and soluble syndecan-1-transfected cells. Tumor cell dissemination to a contralateral human bone is detected significantly more often in the tumors producing soluble syndecan-1 than in controls. Thus, high levels of soluble syndecan-1 present in patients with myeloma may contribute directly to the growth and dissemination of the malignant cells and thus to poor prognosis.     

Suicide assessment: Clinical interview vs. self-report

This study examined whether patients disclosed the same information about suicidal behaviors on a self-report instrument that they conveyed to a clinician in a face-to-face interview. The results indicated a generally high level of agreement between these two forms of suicide assessment. The one exception was the question that concerns recent suicidal ideation, where patients tended to disclose more on the self-report form.     

Contamination of detergent cleaning solutions during hospital cleaning

Twenty-two detergent cleaning solutions from different ward areas were sampled for bacteria when freshly prepared, during use and at discard. Contamination, mainly by Gram-negative bacilli, was found in 10 freshly prepared solutions and in 21 of the 22 at discard. Preliminary studies showed that the detergent solution was bactericidal to Staphylococcus aureus but allowed the survival but not multiplication of Escherichia coli.     

Combined first-pass perfusion and viability study at MR imaging in patients with non-ST segment-elevation acute coronary syndromes: feasibility study

PURPOSE: To assess the feasibility of combined perfusion and viability testing by using magnetic resonance (MR) imaging in one setting in patients with non-ST segment-elevation acute coronary syndromes. MATERIALS AND METHODS: The data of 13 patients (mean age, 68 years; range, 40-85 years) at high risk for myocardial infarction who underwent MR imaging at 1.5 T were reviewed. Risk factors were increased troponin T levels in seven, reversible ST depression on an electrocardiogram in four, history of myocardial infarction in two, and presence of heart failure in four. Cine imaging of the left ventricle was performed with a true-fast imaging with steady-state precession (FISP) sequence to assess the regional myocardial contraction and ejection fraction. After injection of 0.1 mmol per kilogram of body weight of gadopentetate dimeglumine, first-pass MR images were obtained by using an inversion-recovery true-FISP sequence at rest and during infusion of adenosine (140 microg/kg/min). Resting and stress images were assessed qualitatively for abnormal regional perfusion (hypoenhancement). The myocardium was divided into three radial segments corresponding to the three coronary artery territories. Delayed (after 15 minutes) contrast material-enhanced images were acquired with use of a segmented inversion-recovery fast low-angle shot sequence. Conventional coronary angiograms were compared with the first-pass images. A more than 50% stenosis in diameter in any coronary artery was considered substantial. Mann-Whitney test was used to assess any significant difference between the left ventricular ejection fraction (LVEF) in patients with and those without myocardial infarct. RESULTS: Mean LVEF was 51.5% (range, 30%-77%). First-pass stress perfusion studies depicted 25 segments of hypoenhancement in 11 patients. Comparison of first-pass perfusion defects with findings on coronary angiograms indicated an overall sensitivity of 92% (24 of 26) and specificity of 92% (12 of 13) in detection of substantial coronary artery disease. Infarcts detected from hyperenhancement on delayed contrast-enhanced images were present in eight segments (four were transmural) in five patients. No significant difference was noted in the LVEF between patients with and those without infarct (P =.724). CONCLUSION: Combined stress perfusion and viability MR imaging was feasible in patients with acute coronary syndromes. First-pass MR perfusion defects compare well with the presence of substantial coronary artery stenosis on conventional angiograms.