As a critical component in the PI3K/AKT/mTOR pathway, AKT has become an attractive target for therapeutic intervention. ARQ 092 and a next generation AKT inhibitor, ARQ 751 are selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors that potently inhibit phosphorylation of AKT. Biochemical and cellular analysis showed that ARQ 092 and ARQ 751 inhibited AKT activation not only by dephosphorylating the membrane-associated active form, but also by preventing the inactive form from localizing into plasma membrane. In endometrial PDX models harboring mutant AKT1-E17K and other tumor models with an activated AKT pathway, both compounds exhibited strong anti-tumor activity. Combination studies conducted in in vivo breast tumor models demonstrated that ARQ 092 enhanced tumor inhibition of a common chemotherapeutic agent (paclitaxel). In a large panel of diverse cancer cell lines, ARQ 092 and ARQ 751 inhibited proliferation across multiple tumor types but were most potent in leukemia, breast, endometrial, and colorectal cancer cell lines. Moreover, inhibition by ARQ 092 and ARQ 751 was more prevalent in cancer cell lines containing PIK3CA/PIK3R1 mutations compared to those with wt-PIK3CA/PIK3R1 or PTEN mutations. For both ARQ 092 and ARQ 751, PIK3CA/PIK3R1 and AKT1-E17K mutations can potentially be used as predictive biomarkers for patient selection in clinical studies.
Objective
To determine the effect of therapeutic plasma exchange (TPE) on hemodynamics, organ failure, and survival in children with multiple organ dysfunction syndrome (MODS) due to sepsis requiring extracorporeal life support (ECLS).
Design
A retrospective analysis.
Setting
A pediatric intensive care unit (PICU) in an academic children’s hospital.
Patients
14 consecutive children with sepsis and MODS who received TPE while on ECLS from 2005 to 2013.
Interventions
Median of 3 cycles of TPE with median of 1.0 times the estimated plasma volume per exchange.
Measurements and Main Results
Organ Failure Index (OFI) and Vasoactive-Inotropic Score (VIS) were measured before and after TPE use. PICU survival in our cohort was 71.4%. OFI decreased in patients following TPE [pre: 4.1 ± 0.7 vs. post: 2.9 ± 0.9 (mean ±SD); p = 0.0004]. Patients showed improved VIS following TPE [pre: 24.5 (13.0–69.8) vs. post: 5.0 (1.5–7.0), median (25th–75th); p = 0.0002]. Among all patients, the change in OFI was greater for early TPE use than late use [pre: −1.7 ±1.2 vs. post: −0.9 ±0.6; p = 0.14], similar to the change in VIS [pre: −67.5 (28.0–171.2) vs. post: −12.0 (7.2–18.5); p = 0.02]. Among survivors, the change in OFI was greater among early TPE use than late use [early: −2.3 ±1.0 vs. late: −0.8 ± 0.8; p = 0.03], as was the change in VIS [early: −42.0 (16.0–76.3) vs. late: −12.0 (5.3–29.0); p=0.17]. The mean duration of ECLS after TPE according to timing of TPE was not statistically different among all patients or among survivors.
Conclusions
The use of TPE in children on ECLS with sepsis-induced MODS is associated with organ failure recovery and improved hemodynamic status. Initiating TPE early in the hospital course was associated with greater improvement in organ dysfunction and decreased requirement for vasoactive and/or inotropic agents.
We report the smallest infant (4.5 kg) to receive leukapheresis as an immediate treatment for Infantile Acute Lymphocytic Leukemia. Leukodepletion helps prevent the risks of hyperviscosity and cerebrovascular and pulmonary leukostasis. In addition, it is a desirable precursor to chemotherapy to potentially reduce metabolic and renal complications associated with rapid cell lysis. Because of this infant's small size, she presented us with multiple concerns, including hypocalcemia from citrate anticoagulation, extracorporeal volume and fluid balance, inlet flow rates. and establishment of adequate interface. Our positive experience in performing this procedure suggests that cytapheresis is a feasible treatment even for very young infants.
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