Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis.

Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.

Use of beta-blocker types and risk of incident prostate cancer in a multiethnic population.

PURPOSE: Increased adrenergic innervation is observed in prostate cancer (CaP) and is associated with aggressive disease. Emerging evidence suggests that beta-adrenergic blockade inhibits CaP progression. However, the association between type of beta-blocker use and risk of incident CaP on initial prostate biopsy has not been investigated in multiethnic populations. MATERIALS AND METHODS: A retrospective study of racially/ethnically diverse men (64% African-American and Hispanic), who underwent initial prostate biopsy between 2006 and 2016 in a large healthcare system was performed. Oral use of beta-blocker type was assessed by reviewing active prescriptions within the 5-year period preceding initial biopsy. Patient demographics and clinical factors were collected. RESULTS: Of 4,607 men who underwent initial prostate biopsy, 4,516 met criteria and 2,128 had a biopsy positive for CaP; 20% high-risk, 41% intermediate-risk, and 39% low or very-low risk (National Comprehensive Cancer Network classification). Overall, 15% of patients were taking a beta-blocker prior to initial biopsy, with Metoprolol, Atenolol, and Carvedilol accounting for the majority. Of beta-blocker types, Atenolol alone was associated with a 38% reduction in odds of incident CaP (P= 0.01), with a 40% and 54% reduction in risks of National Comprehensive Cancer Network intermediate and high-risk CaP (P = 0.03 and P = 0.03, respectively) compared to men not taking a beta-blocker. Furthermore, longer duration of Atenolol use (3-5 years) was associated with a 54% and 72% reduction in intermediate and high-risk disease, (P = 0.03 and P = 0.03, respectively). CONCLUSIONS: Among beta blocker types, long-term Atenolol use is associated with a significant reduction in incident CaP risk on initial prostate biopsy for clinically-significant intermediate and high-risk disease compared to men not taking a beta-blocker.

Circadian control of the immune system.

Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice.

Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-α-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.

Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion.

Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model suggest that adherent white blood cells (WBCs) play a key role in vaso-occlusion by capturing circulating red blood cells (RBCs) in venules. Commercial intravenous immunoglobulin (IVIG) given before the inflammatory stimuli increased microcirculatory blood flow and survival. To mimic the clinical situation in which SCD patients seek medical attention after the onset of symptoms, we developed an in vivo model in which the therapeutic intervention (eg, IVIG) was administered after in the inflammatory challenge. In this setting, IVIG rapidly (<10 minutes) reduced adherent leukocyte numbers and dramatically inhibited interactions between RBCs and WBCs, resulting in improved microcirculatory blood flow and survival of sickle cell "Berkeley" mice. Longer survival correlated positively with blood flow (P=.001) and negatively with the number of adherent leukocytes (P=.001) and RBC-WBC interactions (P=.002). Using multichannel digital fluorescence videomicroscopy, we found that IVIG affected specifically the recruitment of neutrophils. Moreover, further analyses of leukocyte behavior revealed that IVIG significantly increased rolling velocities, indicating that it alters adhesion pathways involved in slow rolling. These data suggest that the potential therapeutic benefits of IVIG in SCD crises should be evaluated in a clinical trial.