Search

Background/Aim: There exists considerably large interpatient variability in pharmacokinetic exposure of high dose melphalan in multiple myeloma patients with hematopoietic stem-cell transplantation. In this study, we aimed to evaluate the potential impacts of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) variations on pharmacokinetic properties of melphalan and clinical outcomes in multiple myeloma (MM) patients. Patients and Methods: Genotypes of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) were determined by validated gene-specific real-time PCR (RT-PCR) assays using DNA samples from 108 MM patients; plasma concentrations of melphalan at different time points were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS). Results: CYP3A4*1B/*1B and CYP3A5*3/*3 carriers appeared to have a short median progression-free survival time and a higher maximum melphalan plasma concentration than non-carriers [792 vs. over 950 days, p=0.08; 9.91 (2.67, 34.03) vs. 8.66 (4.46, 17.61) mg/l, p=0.039]. Conclusion: CYP3A4*1B/*1B and CYP3A5*3/*3 variations might influence melphalan therapy in MM patients through yet-to-be-identified mechanisms.

Background There is currently limited guidance from the American Diabetes Association regarding transitions of care for patients with diabetes. Objective This study’s aim was to determine the impact of a diabetes-specific transitions of care clinic (TOCC) on hospital utilization and patient outcomes in recently discharged patients with diabetes. Methods This retrospective study evaluated patients seen by TOCC as compared with similar patients discharged from the study institution the year prior. The primary outcome was a composite of the number of unique patients with readmissions/emergency department (ED) visits within 30 days of discharge. Secondary outcomes included a subcomponent analysis of readmissions/ED visits, index hospital length of stay (LOS), and to describe clinical interventions made in clinic. This study was approved by the institutional review board of the Office of Responsible Research Practice at the Ohio State University Wexner Medical Center. Results There were 165 patients in the TOCC group and 157 in the control group based on the matching criteria. There was a statistically significant decrease in the primary outcome in the TOCC group versus the control group (18% vs 36%, P < 0.001). In evaluation of its subcomponents, there was a statically significant decrease in patients with readmissions (11% vs 26%, P < 0.001) but not ED visits (10% vs 17%, P = 0.096). The LOS for the TOCC group was shorter at 4 days versus 5 days in the control group ( P = 0.055). Conclusions and Relevance The implementation of a diabetes-specific TOCC can decrease both readmissions and ED visits and may impact hospital LOS. In addition, a TOCC can be used to identify gaps in preventive care. The results from this study may help support the creation of similar TOCC at other institutions.

Video 3. N+/E- cells 3D reconstruction animation shows localization of ENT1 (red) and DAPI (blue)

Epithelial–mesenchymal transition (EMT) in cancer cells drives cancer chemoresistance, yet the molecular events of EMT that underpin the acquisition of chemoresistance are poorly understood. Here, we demonstrate a loss of gemcitabine chemosensitivity facilitated by human equilibrative nucleoside transporter 1 (ENT1) during EMT in pancreatic cancer and identify that cadherin switching from the epithelial (E) to neuronal (N) type, a hallmark of EMT, contributes to this loss. Our findings demonstrate that N-cadherin decreases ENT1 expression, membrane localization, and gemcitabine transport, while E-cadherin augments each of these. Besides E- and N-cadherin, another epithelial cell adhesion molecule, EpCAM, played a more prominent role in determining ENT1 membrane localization. Forced expression of EpCAM opposed cadherin switching with restored ENT1 expression, membrane localization, and gemcitabine transport in EMT-committed pancreatic cancer cells. In gemcitabine-treated mice, EpCAM-positive tumors had high ENT1 expression and reduced metastasis, whereas tumors with N-cadherin expression resisted gemcitabine treatment and formed extensive secondary metastatic nodules. Tissue microarray profiling and multiplexed IHC analysis of pancreatic cancer patient-derived primary tumors revealed EpCAM and ENT1 cell surface coexpression is favored, and ENT1 plasma membrane expression positively predicted median overall survival times in patients treated with adjuvant gemcitabine. Together, our findings identify ENT1 as an inadvertent target of EMT signaling mediated by cadherin switching and provide a mechanism by which mesenchymal pancreatic cancer cells evade gemcitabine therapy during EMT.

Video 2. Animation displays 3D reconstruction of PANC-1 cells grown in monolayer immunostained for ENT1 (red) and DAPI (blue)

Video 4. E+/N- cells animation displays 3D reconstruction of ENT1 (red) and DAPI (blue)

Video 5. PANC-1 cells stably overexpressing EpCAM are shown in this animation of a 3D reconstruction of compiled z-stack images. ENT1 (red), EpCAM (green), DAPI (blue).

Video 1. PANC-1 cells stably overexpressing E-cadherin are shown in this animation of a 3D reconstruction of compiled z-stack images. ENT1 (red), E-cadherin (green), DAPI (blue).

Background Storage pool deficiency (SPD) is a rare bleeding disorder characterized by reduction in the number of delta granules within platelets, interfering with hemostasis. Current literature lacks well-designed studies from which to draw concrete conclusions regarding pre-procedural management of bleeding complications. Objective: The purpose of this study is to describe bleeding and safety outcomes of SPD patients receiving either pre-procedural platelet transfusions or platelet-sparing regimens. Methods: An exploratory retrospective cohort study was conducted among SPD patients, comparing major bleeding events between those who received platelet transfusion and those who received desmopressin, tranexamic acid, and/or aminocaproic acid within 24 hours prior to procedure. Results: Rates of major bleeding were not found to be higher among patients who received a platelet-sparing regimen [platelet-sparing: 2/25 (8%); platelet transfusion: 2/29 (6.9%); P = .99]. Incidence of non-major bleeding was higher in the platelet transfusion group, but this was not statistically significant [platelet-sparing: 0/25 (0%); platelet transfusion: 3/29 (10.3%); P = .24]. Treatment-related adverse effects were observed following 8 of 54 procedures (14.8%). Conclusion: Use of a platelet-sparing regimen was not associated with a significantly higher incidence of major or non-major bleeding events. Future prospective trials are recommended to compare outcomes between therapies.

Accurately describing pharmacy productivity in the ambulatory oncology infusion setting is important to ensure appropriate labor utilization. The purpose of this study was to develop a productivity model utilizing weighted medication complexity and prospective schedule data to determine if predicted productivity corresponds to actual productivity across 6 ambulatory oncology infusion sites.This study was a 2-part analysis. Part 1 was to modify the historic productivity model from dispense code weighting to individual medication complexity weighting. Medication-specific relative value units were determined by analyzing 12 months of historic timestamp data from the electronic health record and gravimetric technology software. The productivity model containing updated relative value units was compared to the historic model to determine if the difference in total calculated full-time equivalents (FTEs) was within 2.0 FTEs. Part 2 applied prospective infusion schedule data to the updated model to determine if predicted productivity corresponded to actual productivity (within 2.0 FTEs) for pharmacy infusion services.The mean difference in total calculated FTEs for infusion during the study period was 2.46 (standard deviation = 1.87) and was within the range of 2.0 FTEs (P = 0.54), indicating that the updated model was not statistically different from the historic model. The mean difference in total calculated FTEs between the predictive and actual productivity model for infusion was 18.28 (standard deviation = 1.00) and was out of the range of 2.0 FTEs (P0.001), indicating that predicted productivity was statistically different from the actual productivity.Medication complexity weighting can be used to provide a comprehensive assessment of workload and productivity across pharmacy infusion services. The methodology used to assess predictive productivity should be explored further.

An essential function of DNA topoisomerase IIα (TOP2α; 170 kDa, TOP2α/170) is to resolve DNA topologic entanglements during chromosome disjunction by introducing transient DNA double-stranded breaks. TOP2α/170 is an important target for DNA damage-stabilizing anticancer drugs, whose clinical efficacy is compromised by drug resistance often associated with decreased TOP2α/170 expression. We recently demonstrated that an etoposide-resistant K562 clonal subline, K/VP.5, with reduced levels of TOP2α/170, expresses high levels of a novel C-terminal truncated TOP2α isoform (90 kDa, TOP2α/90). TOP2α/90, the translation product of a TOP2α mRNA that retains a processed intron 19 (I19), heterodimerizes with TOP2α/170 and is a resistance determinant through a dominant-negative effect on drug activity. We hypothesized that genome editing to enhance I19 removal would provide a tractable strategy to circumvent acquired TOP2α-mediated drug resistance. To enhance I19 removal in K/VP.5 cells, CRISPR/Cas9 was used to make changes (GAG//GTAAAC→GAG//GTAAGT) in the TOP2α gene’s suboptimal exon 19/intron 19 5′ splice site (E19/I19 5′ SS). Gene-edited clones were identified by quantitative polymerase chain reaction and verified by sequencing. Characterization of a clone with all TOP2α alleles edited revealed improved I19 removal, decreased TOP2α/90 mRNA/protein, and increased TOP2α/170 mRNA/protein. Sensitivity to etoposide-induced DNA damage (γH2AX, Comet assays) and growth inhibition was restored to levels comparable to those in parental K562 cells. Together, the results indicate that our gene-editing strategy for optimizing the TOP2α E19/I19 5′ SS in K/VP.5 cells circumvents resistance to etoposide and other TOP2α-targeted drugs. Significance Statement Results presented here indicate that CRISPR/Cas9 gene editing of a suboptimal exon 19/intron 19 5′ splice site in the DNA topoisomerase IIα (TOP2α) gene results in circumvention of acquired drug resistance to etoposide and other TOP2α-targeted drugs in a clonal K562 cell line by enhancing removal of intron 19 and thereby decreasing formation of a truncated TOP2α 90 kDa isoform and increasing expression of full-length TOP2α 170 kDa in these resistant cells. Results demonstrate the importance of RNA processing in acquired drug resistance to TOP2α-targeted drugs.

The introduction of direct oral anticoagulants (DOACs) to the market has expanded anticoagulation options for outpatient use. Routine evaluation by health care professionals is recommended as it is with warfarin, therefore requiring adjustments in practices of anticoagulation management services (AMS). This study aims to describe trends that occurred following the incorporation of DOACs into AMS at a large academic medical center. A retrospective chart review of pharmacist-run AMS was used to compare patients on DOAC therapy versus other types of anticoagulation, including warfarin and parenteral agents. Primary outcomes included trends in the number of unique patients, management encounters, and telephone encounters throughout the study period. Secondary outcomes included trends in new encounters, and changes in patient characteristics, resources utilized, and patient satisfaction scores. A total of 2976 unique patients, 74,582 management encounters, and 13,282 telephone encounters were identified. From study beginning to end, results showed stable numbers of unique patients, an increase in management encounters for the DOAC group and decrease in the other anticoagulants group, and stable numbers of telephone encounters. Additionally, the number of new encounters for both groups increased. Throughout the study, pharmacy resources were reallocated within anticoagulation to adapt to the changing trends and patient satisfaction reached targets. Patients' characteristics remained stable, with the DOAC group having fewer comorbid conditions and concomitant medications that could increase bleed risk. This study showed that by reallocating resources within anticoagulation, AMS can maintain stable patient populations while continuing to expand access and satisfy patients following DOAC inclusion.

Background/aim Genetic variations of the non-coding RNA gene, ANRIL, have been associated with human diseases including cancer, type-2 diabetes, and atherosclerosis. In the present study, we investigated the potential associations of select ANRIL single nucleotide polymorphisms (SNPs) with overall survival and other clinical outcomes in adult patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients and methods Genomic DNA was extracted from whole blood samples from 103 adult patients with hematologic malignancies who had received allo-HSCT followed by oral tacrolimus therapy. The genotypes of four select ANRIL SNPs, rs564398, rs1063192, rs2151280, and rs2157719 were determined using qRT-PCR-based genotyping assays. Results rs2151280 (C->T) in ANRIL was associated with worse overall survival in these patients (CT/CC vs. TT). Contrarily, rs2151280 and the other select ANRIL SNPs were not associated with death at Day-100 after transplantation, the incidence of graft-versus-host disease (GVHD), acute kidney injury (AKI), and neurotoxicity in the study cohort. Conclusion rs2151280 represents a potential prognostic biomarker for overall survival in adult patients with hematologic malignancies after allo-HSCT.

Purpose As health systems continue to expand pharmacy and clinical services, the ability to evaluate potential medication safety risks and mitigate errors remains a high priority. Workload and productivity monitoring tools for the assessment of operational and clinical pharmacy services exist. However, such tools are not currently available to justify medication safety pharmacy services. The purpose of this study is to determine methods used to assess, allocate, and justify medication safety resources in pediatric hospitals. Methods A 32-question survey was designed and distributed utilizing the Research Electronic Data Capture (REDCap) tool. The survey was disseminated to 46 pediatric hospitals affiliated with the Children’s Hospital Association (CHA). The survey was distributed in October 2018, and the respondents were given 3 weeks to submit responses. Data analysis includes the use of descriptive statistics. Categorical variables were summarized by frequencies and percentages to distinguish the differences between pediatric health systems. Results Of 26 respondents, 15.4% utilized metrics to justify medication safety resources. Metrics utilized were based on medication dispenses, projects, and error coding. Twenty-three percent of respondents were dissatisfied with current pharmacy-based medication safety resources within the organization. There was variability of medication safety resources within pediatric hospitals, including the number of dedicated full-time equivalents, time spent on tasks, and task prioritization. Conclusion Assessing medication safety resources at various pediatric hospitals highlights several potential barriers and opportunities. This information will serve as the foundation for the creation of a standardized workload assessment tool to assist pharmacy leaders with additional resource justification.

BACKGROUND Benign anastomotic esophageal stricture after surgical resection frequently occurs and requires endoscopic balloon dilation (EBD) or incision to maintain patency because of the significant recurrence rate. Our study was designed to evaluate the effectiveness and safety of endoscopic incision and selective cutting (EISC) as primary treatment on 5 patients for benign anastomotic esophageal stricture. METHODS Five patients with benign stricture of the esophageal anastomosis after radical resection for esophageal cancer underwent EISC in our center between April, 2018 and January, 2019. The effectiveness and safety of the procedure were observed during at least 12 months follow-up. RESULTS The EISC was successfully performed in all 5 patients. The diameters of the anastomoses were increased from 1-3 preoperatively to 14-18 mm (mean: 15.6 mm) intraoperatively (P

Purpose: Guidelines have differing recommendations for aspirin use in patients with an indication for anticoagulation. The purpose of this study was to evaluate the incidence of major bleeding and thromboembolic events (TEs) in patients with atrial fibrillation (AF) receiving warfarin alone (monotherapy group) versus warfarin plus aspirin (combination therapy group). Methods: This was a retrospective, cohort study including patients from a pharmacist-run anticoagulation clinic. Inclusion criteria were patients with AF receiving anticoagulation between January 2013 and January 2014 observed over 5 years. Results: One hundred forty-two patients were included in the combination group versus 89 in monotherapy group. In the combination group, 60 (42.3%) patients were on aspirin for no apparent indication, 19 (13.4%) had stable coronary artery disease and diabetes, and 26 (18.3%) had diabetes alone. Major bleeding occurred in 21 (14.9%) patients in the combination group versus 7 (7.9%) patients in the monotherapy group (odds ratio [OR] = 2.02, 95% confidence interval [CI]: 0.78-5.91; P = .17). TE occurred in 10 (7%) patients in the combination group versus 4 (4.5%) in the monotherapy group (OR = 1.61, 95% CI: 0.44-7.24; P = .57). There was no significant difference in bleeding ( P = .85) or TE ( P = .37) rates between aspirin indications in the combination group. Conclusion: Combination therapy versus monotherapy may increase bleeding risk with little benefit in decreasing AF-related stroke or cardiovascular events.

Background Additional use of cyclin-dependent kinase 4/6 inhibitors with endocrine therapy improves progression-free survival (PFS) in advanced hormone receptor (HR)-positive HER2-negative breast cancer. However, neutropenia is a common reason for dose reductions, leading to concerns about palbociclib efficacy at lower doses. A safety analysis confirmed no PFS differences between palbociclib doses in the second-line setting, but to our knowledge, this has not been evaluated for first-line treatment. Patients and Methods In this retrospective, single-center cohort study we evaluated real-world use of first-line palbociclib with aromatase inhibitor (AI) treatment in HR-positive, HER2-negative metastatic breast cancer patients who received treatment between February 2015 and July 2017. The primary objective was to determine PFS of treatment with palbociclib and an AI in a real-world first-line setting. Secondary objectives included determining the PFS for patients treated with palbociclib on the basis of final doses, time to first dose reduction, time to treatment failure (TTF), and safety. Results Seventy patients were included in the final analysis. Median PFS was 26.4 months. No significant differences in PFS were observed on the basis of final doses of palbociclib (P = .77). Time to first dose reduction was 2.3 months. Median TTF was 26.1 months. Dose delays, reductions, and Grade 3/4 neutropenia were common (63%, n = 44; 57%, n = 40; and 62%, n = 43, respectively). Conclusion Real-world first-line palbociclib treatment produced outcomes similar to those in PALOMA-2 (Palbociclib and Letrozole in Advanced Breast Cancer) (median PFS 26.4 months vs. 24.8 months) despite more dose reductions (57%, n = 40 vs. 36%, n = 160) and shorter time to first dose reduction (2.3 vs. 3.0 months). No significant differences in PFS were observed for the varying palbociclib doses. Palbociclib dose reductions might not significantly affect PFS in the first-line setting.

Background: Type III open fractures are associated with an infection rate as high as 50%. The optimal antibiotic for open fracture prophylaxis remains unclear, and the literature comparing the safe...

Background/aim Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. Materials and methods Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. Results Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. Conclusion Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.

BACKGROUND/AIM Aberrant expression of the BMI1 oncogene has been prevalently found in a variety of human cancers, including cervical cancer. Recent studies have shown that PTC209, a specific BMI1 inhibitor, exhibits high potency in inhibiting the growth of colon, breast, oral cancer cells and cancer-initiating cells, indicative of its chemotherapeutic potential. In the current study, we evaluated the inhibitory abilities of PTC209 in cervical cancer cells. MATERIALS AND METHODS Three cervical cell lines, C33A, HeLa, and SiHa were treated with PTC209. The impacts of PTC209 on BMI1 were investigated using quantitative reverse-transcription PCR assay (qRT-PCR) and western blotting; changes in cell viability, cell cycle distribution, and apoptosis were assessed using cell viability testing, colony formation assay and flow cytometry analyses, respectively. RESULTS PTC209 exhibited considerably high short-term and long-term cytotoxicities in all tested cervical cancer cell lines regardless of their HPV infection status, TP53 and pRb statuses. PTC209 significantly downregulated the expression of BMI1 in cervical cancer cell lines, and such downregulation led to G0/G1 arrest (p

Background As collaborative team-based healthcare expands, there is a need for effective interprofessional education (IPE). Although the desired outcomes of IPE are defined by the Interprofessional Education Collaborative (IPEC), resources often limit IPE implementation. The purpose of this study is to assess the effectiveness of a novel interprofessional activity in improving health professions students' interprofessional competencies using team-based learning (TBL). Interprofessional education activity Teams of second year pharmacy and medical students participated in a novel IPE session targeting roles and responsibilities. This activity was designed and implemented by a small number of faculty and used TBL to educate a large number of students using limited resources. Class averages for individual and team readiness assurance test (iRAT/tRAT) scores were collected, and students were invited to complete the Interprofessional Collaborative Competencies Attainment Survey (ICCAS) to evaluate the effectiveness of the activity. Discussion On average, tRAT scores were 20% higher than iRAT scores. While there was significant improvement for all items on the ICCAS, questions within the roles and responsibilities domain of the ICCAS were most affected. Implications This novel IPE activity was successful in teaching a large group of professional students in the targeted domain of roles and responsibilities in a single session. This activity was a rich experience in which students learned together using limited resources which can be easily replicated at other institutions to help professional students gain proficiency in interprofessional competencies.

Background For a vaccine to be successful, communities must perceive it as important, safe, effective, and necessary. However, there are many barriers and hesitancies to vaccination. Underserved patient populations may face additional challenges related to access and cost. Because community pharmacists improve vaccine access and increase vaccination rates, it is beneficial for pharmacists to understand perceptions and barriers to vaccinations in their community to increase vaccine confidence. Objectives This study aims to assess and compare barriers and perceptions of the annual influenza to the coronavirus disease 2019 (COVID-19) vaccine for underserved patients of a charitable pharmacy. Methods Patients who qualified to receive medications from an outpatient charitable pharmacy took an electronic survey when receiving medications. The survey incorporated questions developed by the World Health Organization’s Strategic Advisory Group of Experts on Vaccine Hesitancy on a 5-point Likert scale. Questions about the influenza and COVID-19 vaccines mirrored one another. Demographic data such as age, race, sex, and education level were also collected. Results Of the 189 patients surveyed at the charitable pharmacy, 71.7% were 55 years old and older and 58.9% were female. Of note, 78% and 77% of participants agreed or strongly agreed that the influenza and COVID-19 vaccines, respectively, were important for the health of others in their community. Adverse effects and the cost of the COVID-19 vaccine were noted to be statistically significantly more of a concern with the COVID-19 vaccine than that of the influenza vaccine (P Conclusion Ensuring equitable vaccine access, promoting the COVID-19 vaccine as free, and eliciting and addressing individual persons’ concerns related to vaccine safety and adverse effects are all important ways pharmacists and other health care providers and community stakeholders can help promote vaccine confidence within the populations they serve.