Doxorubicin (DOX) is a potent chemotherapeutic agent known to cause acute and long-term cognitive impairments in cancer patients. Cognitive function is presumed to be primarily mediated by neuronal circuitry in the frontal cortex (FC) and hippocampus, where glutamate is the primary excitatory neurotransmitter. Mice treated with DOX (25mg/kg i.p.) were subjected to in vivo recordings under urethane anesthesia at 24h post-DOX injection or 5 consecutive days of cognitive testing (Morris Water Maze; MWM). Using novel glutamate-selective microelectrode arrays, amperometric recordings measured parameters of extracellular glutamate clearance and potassium-evoked release of glutamate within the medial FC and dentate gyrus (DG) of the hippocampus. By 24h post-DOX injection, glutamate uptake was 45% slower in the FC in comparison to saline-treated mice. In the DG, glutamate took 48% longer to clear than saline-treated mice. Glutamate overflow in the FC was similar between treatment groups, however, it was significantly increased in the DG of DOX treated mice. MWM data indicated that a single dose of DOX impaired swim speed without impacting total length traveled. These data indicate that systemic DOX treatment changes glutamate neurotransmission in key nuclei associated with cognitive function within 24h, without a lasting impact on spatial learning and memory. Understanding the functional effects of DOX on glutamate neurotransmission may help us understand and prevent some of the debilitating side effects of chemotherapeutic treatment in cancer survivors.

We examined the effect of shared decision-making (SDM) on women’s adherence to breast and cervical cancer screenings and estimated the prevalence and adherence rate of screenings. The study used a descriptive cross-sectional design using the 2017 Health Information National Trends Survey (HINTS) data collected by the National Cancer Institute. Adherence was defined based on the guidelines from the American Cancer Society and the composite measure of shared decision-making was constructed using three items in the data. Multivariable logistic regression was performed to examine the association between the SDM and adherence, controlling for cancer beliefs and socio-demographic variables. The analysis included 742 responses. Weighted to represent the U.S. population, 68.1% adhered to both breast and cervical cancer screening guidelines. The composite measure of SDM was reliable (α = 0.85), and a higher SDM score was associated with women’s screening adherence (b = 0.17; p = 0.009). There were still women who did not receive cancer screenings as recommended. The results suggest that the use of the SDM approach for healthcare professionals’ communication with patients can improve screening adherence.

Cardiotoxicity is a major dose-limiting adverse effect of doxorubicin (DOX), mediated in part by overproduction of reactive oxygen species and oxidative stress. Abcc1 (Mrp1) mediates the efflux of reduced and oxidized glutathione (GSH, GSSG) and is also a major transporter that effluxes the GSH conjugate of 4-hydroxy-2-nonenal (HNE; GS-HNE), a toxic product of lipid peroxidation formed during oxidative stress. To assess the role of Mrp1 in protecting the heart from DOX-induced cardiac injury, wild-type (WT) and Mrp1 null (Mrp1^−/−) C57BL/6 littermate mice were administered DOX (15 mg/kg) or saline (7.5 ml/kg) i.v., and heart ventricles were examined at 72 hours. Morphometric analysis by electron microscopy revealed extensive injuries in cytosol, mitochondria, and nuclei of DOX-treated mice in both genotypes. Significantly more severely injured nuclei were observed in Mrp1^−/− versus WT mice (P = 0.031). GSH and the GSH/GSSG ratio were significantly increased in treatment-naïve Mrp1^−/− versus WT mice; GSH remained significantly higher in Mrp1^−/− versus WT mice after saline and DOX treatment, with no changes in GSSG or GSH/GSSG. GS-HNE, measured by mass spectrometry, was lower in the hearts of treatment-naïve Mrp1^−/− versus WT mice (P < 0.05). DOX treatment decreased GS-HNE in WT but not Mrp1^−/− mice, so that GS-HNE was modestly but significantly higher in Mrp1^−/− versus WT hearts after DOX. Expression of enzymes mediating GSH synthesis and antioxidant proteins did not differ between genotypes. Thus, despite elevated GSH levels in Mrp1^−/− hearts, DOX induced significantly more injury in the nuclei of Mrp1^−/− versus WT hearts.

The Food and Drug Administration has recently approved two autologous chimeric antigen receptor T-cell immunotherapies tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™) for patients with advanced lymphocytic malignancies. Both immunotherapies target the CD19-positive B-cell neoplasms. Kymriah™ is indicated for the treatment of relapsed or refractory acute lymphoblastic leukemia and large B-cell lymphoma. Yescarta™ is indicated for lymphoma only. Although the new therapy offers a promise for patients with advanced disease, it is associated with adverse events including neurotoxicity and cytokine release syndrome, which can be fatal and may require a high level of multidisciplinary supportive care. Due to the risks, both Kymriah™ and Yescarta™ are subject to Risk Evaluation and Mitigation Strategy (REMS) protocols. As active members of multidisciplinary clinical teams, pharmacists are likely to be responsible for the execution of Kymriah™ and Yescarta™ REMS programs. This manuscript describes foundational science and clinical knowledge of chimeric antigen receptor T-cell immunotherapies, common therapy-specific toxicities and REMS requirements for Kymriah™ and Yescarta™ in relation to practice of pharmacy.