Assessing the efficacy of endovascular therapy in stroke treatments: updates from the new generation of trials

Introduction: For the past 20 years, intravenous recombinant tissue plasminogen activator (rt-PA) has been the only proven treatment for acute ischemic stroke. Large arteries such as the internal carotid artery, the middle cerebral artery and the basilar artery supply blood to large volumes of brain tissue. When occluded, these vessels may have low response rates to rt-PA resulting in devastating injury and death.

Areas covered: In 2013, three trials evaluating the efficacy of mechanical thrombectomy in acute stroke were neutral, however, lessons learned from these trials resulted in a second generation of five trials in 2015 and a sixth in 2016 which all demonstrated significant benefit for select patients. Here we will review the evidence behind these new trials and. introduce new questions such as models of care, techniques of thrombectomy, the role of rt-PA, modes of anesthesia, the management of late presenting and wake up strokes among other real world challenges facing stroke medicine now that the thrombectomy is an evidence based treamtnent

Expert commentary: The mechanical thrombectomy is now the new standard of care and with that comes the need to find ways to provide it to all who will benefit.     

Endovascular management of acute ischemic stroke: advances in patient and treatment selection

Selection of patients for acute-stroke therapy has traditionally been based on rigid time criteria in clinical trials. Recent advances in radiographic imaging have allowed clinicians to estimate brain physiology and thus utilize radiographic parameters to select patients for acute-stroke therapies. Both a better understanding and the quantification methods of salvageable tissue versus irreversibly injured tissue can help guide clinicians to which treatment modality to utilize. The evolution of endovascular techniques to treat acute stroke has resulted in treatment modalities that include mechanical and chemical methods to revascularize occluded cerebral arteries. Prior technical limitations to accessing distal-cerebral arteries have been partially overcome by modifications in technology. Patient and treatment-modality selection can help reduce hemorrhagic complication rates and also potentially increase revascularization rates, which may translate into improved clinical outcomes. We review the recent advances in radiographic imaging that have advanced patient selection in treating acute ischemic stroke and also consider current endovascular treatment options that are available to interventionalists performing these procedures.     

Occult malignant breast lesions in 114 patients: relationship to age and the presence of microcalcifications

This study evaluates the mammographic findings in 352 patients, aged 30-85 years, who underwent spot localization and biopsy for evaluation of nonpalpable breast abnormalities. Malignancy was found at biopsy in 114 cases. The mammographic appearance (specifically, whether grouped microcalcifications, mass, or both were present) was correlated with patient age and histologic findings (specifically, whether the pathologic changes were infiltrating or noninfiltrating in nature). The prevalence of malignant conditions increased directly with age. The presence of grouped microcalcifications as the sole indicator of malignancy was seen in 100% (seven of seven) of the patients in the 30-39-year age group, 64% (18 of 28) in the 40-49-year age group, 37% (11 of 30) in the 50-59-year age group, 30% (seven of 23) in the 60-69-year age group, and 23% (six of 26) in the 70-85-year age group. Of the 49 tumors that were manifested solely as microcalcifications, 34 (69%) were noninfiltrating. The finding of grouped microcalcifications should be aggressively investigated, since it may indicate noninfiltrating carcinoma in an early stage, when the potential for cure is greatest.     

The obesity paradox: body mass index and outcomes in patients with heart failure

BACKGROUND: In the general population, obesity is associated with increased risk of adverse outcomes. However, studies of patients with chronic disease suggest that overweight and obese patients may paradoxically have better outcomes than lean patients. We sought to examine the association of body mass index (BMI) and outcomes in stable outpatients with heart failure (HF). METHODS: We analyzed data from 7767 patients with stable HF enrolled in the Digitalis Investigation Group trial. Patients were categorized using baseline BMI (calculated as weight in kilograms divided by the square of height in meters) as underweight (BMI <18.5), healthy weight (BMI, 18.5-24.9, overweight (BMI, 25.0-29.9), and obese (BMI > or =30.0). Risks associated with BMI groups were evaluated using multivariable Cox proportional hazards models over a mean follow-up of 37 months. RESULTS: Crude all-cause mortality rates decreased in a near linear fashion across successively higher BMI groups, from 45.0% in the underweight group to 28.4% in the obese group (P for trend <.001). After multivariable adjustment, overweight and obese patients were at lower risk for death (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.80-0.96, and HR, 0.81; 95% CI, 0.72-0.92, respectively), compared with patients at a healthy weight (referent). In contrast, underweight patients with stable HF were at increased risk for death (HR 1.21; 95% CI, 0.95-1.53). CONCLUSIONS: In a cohort of outpatients with established HF, higher BMIs were associated with lower mortality risks; overweight and obese patients had lower risk of death compared with those at a healthy weight. Understanding the mechanisms and impact of the "obesity paradox" in patients with HF is necessary before recommendations are made concerning weight and weight control in this population.     

Distribution of resting and ligand-bound ErbB1 and ErbB2 receptor tyrosine kinases in living cells using number and brightness analysis

Ligand-driven dimerizations of ErbB receptor subunits fulfill a fundamental role in their activation. We have used the number and brightness analysis technique to investigate the existence of preformed ligand-independent dimers and clusters and to characterize the initial steps in the activation of ErbB1 and ErbB2. In cells expressing 50,000–200,000 receptors, ErbB1 was monomeric in the absence of ligand stimulation, whereas in CHO cells with receptor levels > 500,000 as much as 30% of ErbB1 was present as preformed dimers. EGF induced the formation of ErbB1 dimers as well as larger clusters (up to pentamers) that colocalized with clathrin-coated pits. The distribution of unstimulated ErbB2 in cells expressing 3·10⁵ - 10⁶ receptors was fundamentally different, in that this receptor was present in preformed homoassociated aggregates containing 5–10 molecules. These constitutive ErbB2 homoclusters colocalized with caveolae, increased in size at subphysiological temperatures, but decreased in size upon EGF stimulation. We conclude that these ErbB2 clusters are promoted primarily by membrane-mediated interactions and are dispersed upon ligand stimulation.     

Regulation of neutrophil migration and superoxide production by recombinant tumor necrosis factors-alpha and -beta: comparison to recombinant interferon-gamma and interleukin-1 alpha

We compared the ability of recombinant human tumor necrosis factor- alpha (rHuTNF-alpha) and tumor necrosis factor-beta (rHuTNF-beta) to stimulate polymorphonuclear neutrophil (PMN) migration and superoxide production. Significant PMN migration occurred across polycarbonate filters after stimulation with rHuTNF-alpha at concentrations ranging from 10(-7) to 10(-10) mol/L and at 10(-7) to 10(-8) mol/L for rHuTNF- beta and N-formylmethionyl-leucyl phenylalanine (FMLP), whereas recombinant human interferon-gamma was only minimally active at 10(-7) mol/L and recombinant human interleukin-1 alpha was inactive at the doses tested. In addition, antibodies to rHuTNF-alpha completely inhibited rHuTNF-alpha but not rHuTNF-beta or FMLP-induced PMN migration. Combinations of rHuTNF-alpha and rHuTNF-beta (at similar molar concentrations) stimulated PMN migration levels comparable to that obtained with rHuTNF-alpha alone. Checkerboard analyses performed by placing different concentrations of rHuTNF-alpha and rHuTNF-beta above and below polycarbonate filters of microchemotaxis chambers demonstrated that rHuTNF-alpha and rHuTNF-beta stimulated both chemotactic and chemokinetic responses by PMN. Additional studies demonstrated that 1 X 10(-8) mol/L rHuTNF-alpha and 3 X 10(-9) mol/L rHuTNF-beta (which represents 10(4) U/mL of each cytokine) were similar in their ability to induce superoxide production by PMNs; however, at ten- to 100-fold lower molar concentrations (10(3) and 10(2) units), rHuTNF-alpha was significantly more active than rHuTNF-beta. At the doses tested, both cytokines were less active than phorbol myristate acetate at stimulating O2- release. The results demonstrate that rHuTNF- alpha and rHuTNF-beta differ quantitatively but not qualitatively in their effects on PMN functions in vitro and suggest that rHuTNF-beta may be less toxic than rHuTNF-alpha in vivo.     

The value of flow cytometric analysis of platelet glycoprotein expression of CD34+ cells measured under conditions that prevent P- selectin-mediated binding of platelets

In the present study, we show by adhesion assays and ultrastructural studies that platelets can bind to CD34+ cells from human blood and bone marrow and that this interaction interferes with the accurate detection of endogenously expressed platelet glycoproteins (GPs). The interaction between these cells was found to be reversible, dependent on divalent cations, and mediated by P-selectin. Enzymatic characterization showed the involvement of sialic acid residues, protein(s). The demonstration of mRNA for the P-selectin glycoprotein ligand 1 (PSGL-1) in the CD34+ cells by polymerase chain reaction (PCR) analysis suggests that this molecule is present in these cells. Under conditions that prevent platelet adhesion, a small but distinct subpopulation of CD34+ cells diffusely expressed the platelet GPIIb/IIIa complex. These cells were visualized by immunochemical studies. Furthermore, synthesis of mRNA for GPIIb and GPIIIa by CD34+ cells was shown using PCR analysis. The semiquantitative PCR results show relatively higher amounts of GPIIb mRNA than of PF4 mRNA in CD34+CD41+ cells in comparison with this ratio in platelets. This finding is a strong indication that the PCR results are not caused by contaminating adhering platelets. MoAbs against GPIa GPIb alpha, GPV, P- selectin, and the alpha-chain of the vitronectin receptor did not react with CD34+ cells. The number of CD34+ cells expressing GPIIb/IIIa present in peripheral blood stem cell (PBSC) transplants was determined and was correlated with platelet recovery after intensive chemotherapy in 27 patients. The number of CD34+CD41+ cells correlated significantly better with the time of platelet recovery after PBSC transplantation (r = .83, P = .04) than did the total number of CD34+ cells (r = .55). Statistical analysis produced a threshold value for rapid platelet recovery of 0.34 x 10(6) CD34+CD41+ cells/kg. This study suggests that if performed in the presence of EDTA the flow cytometric measurement of GPIIb/IIIa on CD34+ cells provides the most accurate indication of the platelet reconstitutive capacity of the PBSC transplant.