Rasburicase dose optimization for tumor lysis syndrome management in a network of community oncology practices.

INTRODUCTION: Single, fixed-dose rasburicase administration has been evaluated as an effective strategy in the management of hyperuricemia in the hospital setting, but this has not yet been described within ambulatory community oncology practices. The objective of this study is to evaluate and optimize the dosing strategy for rasburicase in the management of tumor lysis syndrome (TLS)-associated hyperuricemia in The US Oncology Network (The Network). METHODS: A network-wide guideline was revised to standardize rasburicase dosing from a previous recommended fixed doses of 4.5 or 7.5 mg to either 3 or 6 mg for outpatient rasburicase use in management and prevention of TLS. The primary outcome evaluated mean dose of rasburicase among all patients before and after guideline revision. A retrospective chart review evaluated secondary endpoints. RESULTS: The primary analysis included 291 patients (128 pre-revised and 163 post-revised guideline implementation). The primary outcome, mean rasburicase dose, was reduced in the post-revision compared to the pre-revision population (mean 6.2 mg pre vs. 4.5 mg post, p < 0.00001) resulting in a reduced cost per rasburicase dose of $974. Fifty patients were included for the secondary analysis. Guideline concordance was identified in 12 (48%) and 16 patients (64%), and uric acid <8 mg/dL post-rasburicase administration occurred in 14 (56%) and 16 patients (64%) before and after guideline revision, respectively. CONCLUSIONS: Guideline revision and electronic health record modification resulted in a 27% reduction in the mean rasburicase dose and a 50% reduction in repeat rasburicase dosing without a negative impact on clinical efficacy.

Evaluation of denosumab in adult oncology patients for the prevention of skeletal related events across a large academic health system.

INTRODUCTION: Denosumab (Xgeva®) and zoledronic acid (Zometa®) are widely utilized for prevention of skeletal related events (SREs) in oncology patients. Drug costs, renal function, ease and logistics of administration, and adverse effect profile are factors frequently considered by patients and/or providers when selecting an optimal agent. Given the significantly higher drug cost of denosumab compared to zoledronic acid, an evaluation of our institution's denosumab use and investigation into opportunities to shift denosumab administrations to zoledronic acid and/or to lower cost sites-of-care was warranted. METHODS: A single-center, multi-site, retrospective, observational analysis of the electronic medical record (EMR) was conducted for adult oncology patients who received denosumab 120 mg for prevention of SREs from October 1st, 2018 to September 30th, 2019 at three institutions within our health system. Additional information was collected to characterize the patient population based on cancer diagnosis, renal function, and concomitant calcium and vitamin D supplementation. Our primary objective was to evaluate if the use of denosumab met current formulary restrictions of the health system. RESULTS: In total, 304 adult oncology patients received 1411 doses of denosumab for the prevention of SREs. The majority of reviewed patients had a primary oncology diagnosis of breast (35%) or lung (24%) cancer. Of the patients who received denosumab, 278 (93%) met the health system's current formulary restrictions. The majority of patients who did not meet formulary restrictions were those with multiple myeloma (MM) (20/22; 91%). Of the 304 patients reviewed, 70 had the appropriate parameters in the EMR to calculate creatinine clearance (CrCl) using Cockcroft-Gault Equation. Of those 70 patients, 59 (84%) would have been eligible to receive zoledronic acid instead of denosumab given that their CrCl >30 mL/min with no documented intolerance to bisphosphonates. Concurrent use of calcium and vitamin D is recommended when using denosumab. Based on the most recent prior to admission (PTA) medication list obtained from the 304 patients evaluated, 222 (73%) had both calcium and vitamin D listed as "taking". CONCLUSIONS: Within our health system, denosumab is restricted to those who meet formulary restrictions. Additional education is recommended to help limit the use of denosumab, specifically in MM, to reduce drug costs when zoledronic acid is also an appropriate first-line agent.

Classification of orthostatic intolerance through data analytics.

Imbalance in the autonomic nervous system can lead to orthostatic intolerance manifested by dizziness, lightheadedness, and a sudden loss of consciousness (syncope); these are common conditions, but they are challenging to diagnose correctly. Uncertainties about the triggering mechanisms and the underlying pathophysiology have led to variations in their classification. This study uses machine learning to categorize patients with orthostatic intolerance. We use random forest classification trees to identify a small number of markers in blood pressure, and heart rate time-series data measured during head-up tilt to (a) distinguish patients with a single pathology and (b) examine data from patients with a mixed pathophysiology. Next, we use Kmeans to cluster the markers representing the time-series data. We apply the proposed method analyzing clinical data from 186 subjects identified as control or suffering from one of four conditions: postural orthostatic tachycardia (POTS), cardioinhibition, vasodepression, and mixed cardioinhibition and vasodepression. Classification results confirm the use of supervised machine learning. We were able to categorize more than 95% of patients with a single condition and were able to subgroup all patients with mixed cardioinhibitory and vasodepressor syncope. Clustering results confirm the disease groups and identify two distinct subgroups within the control and mixed groups. The proposed study demonstrates how to use machine learning to discover structure in blood pressure and heart rate time-series data. The methodology is used in classification of patients with orthostatic intolerance. Diagnosing orthostatic intolerance is challenging, and full characterization of the pathophysiological mechanisms remains a topic of ongoing research. This study provides a step toward leveraging machine learning to assist clinicians and researchers in addressing these challenges. Graphical abstract Machine learning tools utilized to analyze heart rate (HR) and blood pressure (BP) time-series data from syncope and control patients. Results show that machine learning can provide accurate classification of disease groups for 98% of patients and we identified two subgroups within the control patients differentiated by their BP response.

Cardiovascular dynamics during head-up tilt assessed via pulsatile and non-pulsatile models.

This study develops non-pulsatile and pulsatile models for the prediction of blood flow and pressure during head-up tilt. This test is used to diagnose potential pathologies within the autonomic control system, which acts to keep the cardiovascular system at homeostasis. We show that mathematical modeling can be used to predict changes in cardiac contractility, vascular resistance, and arterial compliance, quantities that cannot be measured but are useful to assess the system's state. These quantities are predicted as time-varying parameters modeled using piecewise linear splines. Having models with various levels of complexity formulated with a common set of parameters, allows us to combine long-term non-pulsatile simulations with pulsatile simulations on a shorter time-scale. We illustrate results for a representative subject tilted head-up from a supine position to a [Formula: see text] angle. The tilt is maintained for 5 min before the subject is tilted back down. Results show that if volume data is available for all vascular compartments three parameters can be identified, cardiovascular resistance, vascular compliance, and ventricular contractility, whereas if model predictions are made against arterial pressure and cardiac output data alone, only two parameters can be estimated either resistance and contractility or resistance and compliance.

A single center retrospective analysis of a protocol for high-dose methotrexate and leucovorin rescue administration.

BACKGROUND: Methotrexate has a wide dosing range. High-dose methotrexate is a dose of 1000 mg/m2 or greater. In the 1970s, the incidence of mortality associated with High-dose methotrexate ranged from 4.6 to 6%. In 2012, the University of Maryland Medical Center implemented a standardized high-dose methotrexate protocol. The purpose of this study was to evaluate whether the institution followed recommendations based on the Bleyer nomogram for the administration of high-dose methotrexate more closely after the implementation of the protocol. METHODS: In this retrospective chart review, 37 patients received 119 cycles of high-dose methotrexate before the protocol implementation (1 January 2009 through 31 December 2010) and 45 patients received 106 cycles of high-dose methotrexate after protocol implementation (1 January 2013 through 31 December 2014). Patient characteristics, protocol data, and complications were analyzed. RESULTS: Protocol implementation significantly reduced the deviation of methotrexate level timing at 24, 48, and 72 h: median 7.47 vs. 1.46 h, 7.23 vs. 1.35 h, and 7.00 vs. 1.52 h before and after implementation, respectively (p < 0.0001 for each). The protocol significantly reduced deviation of the first dose of leucovorin administration: median 5.2 vs. 0.675 h before and after implementation, respectively (p<0.0001). After protocol implementation, there was an increase in the use of leucovorin prescriptions written appropriately for patients discharged before methotrexate levels reached a value of ≤0.05 µmol/L. CONCLUSIONS: Implementation of a protocol for the administration of high-dose methotrexate improved the adherence to consensus recommendations. Further analysis is needed to assess clinical pharmacist involvement and the cost savings implications within this protocol.

Dose Rounding of Biologic and Cytotoxic Anticancer Agents: A Position Statement of the Hematology/Oncology Pharmacy Association.

PURPOSE: To present a position statement from the Hematology/Oncology Pharmacy Association (HOPA) that pertains to dose rounding of biologic and cytotoxic anticancer agents. METHODS: The HOPA Standards Committee organized a work group of oncology pharmacist specialists to examine the safety and value of dose rounding of biologic and cytotoxic anticancer agents. Primary literature that describes methods for dose rounding, with clinical or economic data, were analyzed. Relevant pharmacokinetic characteristics and aspects of product formulation were considered. Issues for institutional application were addressed. RESULTS: Rounding of biologic and cytotoxic agents within 10% of the ordered dose is designated as acceptable for routine clinical care. Dose changes ≤ 10% are not expected to reduce the safety or effectiveness of therapy. The rounding amount-10%-is rational in the context of standard dose adjustments for patient tolerance and tumor response (≥ 20%), clinical trial deficiency criteria (> 10%), and the influence of interpatient pharmacokinetic variability. HOPA supports the use of the same threshold for dose rounding of anticancer drugs as that used for palliative and curative therapy. Potential exceptions to dose rounding are discussed. CONCLUSION: Dose rounding reduces waste and health care costs. HOPA recommends that each institution develop its own dose-rounding policy that addresses biologic and cytotoxic agents. Institutional guidelines for dose rounding of anticancer agents, including criteria for automatic dose rounding, the allowable percentage, and institutional processes for operationalizing and documenting dose rounding, should be determined by collaborative stakeholder consensus. Exceptions to dose rounding should be determined a priori. Additional studies that evaluate the impact of dose rounding on patient outcome are warranted.

Evaluation of pegfilgrastim use at an academic medical center.

PURPOSE: Pegfilgrastim is indicated to reduce the risk of febrile neutropenia. As a cost-savings initiative, Pegfilgrastim Process Guidelines were developed and implemented at a large, academic teaching institution to improve appropriate use of pegfilgrastim and to decrease costs of outpatient infusion center administration by deferring doses to home self-administration for eligible patients. METHODS: A retrospective medical record review was conducted post-implementation of the Pegfilgrastim Process Guideline to evaluate the use of pegfilgrastim and to assess the safety and efficacy of transferring pegfilgrastim orders from outpatient infusion center to home administration for eligible patients. RESULTS: Fifty-nine patients were included in the study, with 35 patients receiving pegfilgrastim in the outpatient infusion center, 13 patients self-injecting at home, and 11 patients receiving doses in both settings. The total wholesale cost avoidance for pegfilgrastim orders transferred to self-administration at home during this time period totaled $205,163. The revenue from outpatient prescriptions of pegfilgrastim totaled $291,111.93. The percentage of febrile neutropenia admissions was 11.4%, 0%, and 9.1% in the outpatient infusion, home, and outpatient/home group, respectively. CONCLUSION: Implementation of the Pegfilgrastim Process Guidelines demonstrated decreased total pegfilgrastim orders to be dispensed by the infusion center and a cost avoidance of $205,163 in four months without any perceivable changes in patient outcomes. This represents a significant cost-savings opportunity.

Australian dermatologists' perspective on skin of colour: Results of a national survey.

BACKGROUND/OBJECTIVES: This study documents the perspectives of Australian dermatologists on the adequacy of teaching and training in skin of colour (SOC), and their confidence in diagnosing and treating common medical, surgical and cosmetic issues in SOC and to gauge their desire for further training in this area. METHODS: Surveys were distributed to Australasian Dermatologists during their annual scientific meeting in Melbourne, Australia in 2014. Completed surveys from dermatologists nationwide were collected and evaluated. Altogether 270 surveys were distributed. RESULTS: In total, 140 surveys were completed and returned. Four surveys were excluded as they were completed by dermatologists who were not practicing in Australia. Thus, 136 surveys were deemed appropriate for analysis. While 75% of participants were confident in managing common medical issues in SOC 85% were not confident in managing common cosmetic issues in SOC and 75% were not confident performing procedures on SOC. Over 80% stated they would have liked more teaching in SOC during their training and over 50% of those surveyed believe they had enough time to undertake further training in this area. CONCLUSION: We propose here the first analysis of issues relating to SOC dermatology among Australian dermatologists in the context of the changing patient demographic in the country. The findings of this survey clearly demonstrate there is a need and desire for more training in medical, cosmetic and procedural aspects of SOC dermatology and that most of the Australian dermatologists surveyed have the desire and time to undertake such training.

Chemotherapy dose reduction due to chemotherapy induced peripheral neuropathy in breast cancer patients receiving chemotherapy in the neoadjuvant or adjuvant settings: a single-center experience.

PURPOSE: Taxanes are a cornerstone treatment in early and advanced stage breast cancer and in other common solid tumor malignancies; however, the development of chemotherapy induced peripheral neuropathy (CIPN) often necessitates dose-reduction, which may hamper the effectiveness of the drug and compromise survival outcomes especially when used in the adjuvant setting. Limited literature is available on the prevalence and severity of dose reduction due to CIPN. We sought to determine the frequency and severity of CIPN-induced dose reduction in early stage breast cancer patients who received taxane-based chemotherapy in the neoadjuvant or adjuvant settings. METHODS: We conducted a retrospective single-institution breast cancer clinic chart review of 123 newly diagnosed breast cancer patients and treated with taxane-based neoadjuvant/adjuvant chemotherapy at the University of Maryland Greenebaum Cancer Center between January 2008 and December 2011. RESULTS: Forty-nine of 123 (40%; 95% CI: 31-49%) patients required dose reduction. Twenty-one (17%; 95% CI: 11-25%) of these patients were dose-reduced specifically due to CIPN that developed during treatment. The median relative dose intensity (received dose/planned dose) for the 21 CIPN-induced dose reduction patients was 73.4% (range, 68.0-94.0%). Patients with diabetes appeared to have a higher risk of taxane-induced dose reduction (p-value=0.01). African-American patients and those treated with paclitaxel (rather than docetaxel) experienced a higher-risk of CIPN-induced dose reduction (p-values are <0.001 and 0.001, respectively). CONCLUSIONS: The incidence of CIPN-associated dose reduction in our patient population was 17%. African-American patients, diabetics and subjects treated with paclitaxel had a higher risk for CIPN-associated dose reduction in our study.

Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining.

The solution structure and dynamics of the BRCT domain from human DNA polymerase mu, implicated in repair of chromosome breaks by nonhomologous end joining (NHEJ), has been determined using NMR methods. BRCT domains are typically involved in protein-protein interactions between factors required for the cellular response to DNA damage. The pol mu BRCT domain is atypical in that, unlike other reported BRCT structures, the pol mu BRCT is neither part of a tandem grouping, nor does it appear to form stable homodimers. Although the sequence of the pol mu BRCT domain has some unique characteristics, particularly the presence of >10% proline residues, it forms the characteristic alphabetaalpha sandwich, in which three alpha helices are arrayed around a central four-stranded beta-sheet. The structure of helix alpha1 is characterized by two solvent-exposed hydrophobic residues, F46 and L50, suggesting that this element may play a role in mediating interactions of pol mu with other proteins. Consistent with this argument, mutation of these residues, as well as the proximal, conserved residue R43, specifically blocked the ability of pol mu to efficiently work together with NHEJ factors Ku and XRCC4-ligase IV to join noncomplementary ends together in vitro. The structural, dynamic, and biochemical evidence reported here identifies a functional surface in the pol mu BRCT domain critical for promoting assembly and activity of the NHEJ machinery. Further, the similarity between the interaction regions of the BRCT domains of pol mu and TdT support the conclusion that they participate in NHEJ as alternate polymerases.

Evaluation of energetic and dynamic coupling networks in a PDZ domain protein.

A number of computational and experimental studies have identified intramolecular communication "pathways" or "networks" important for transmitting allostery. Here, we have used mutagenesis and NMR relaxation methods to investigate the scope and nature of the communication networks found in the second post-synaptic density-95/discs large/zonula occludens-1 (PDZ) domain of the human protein tyrosine phosphatase 1E protein (hPTP1E) (PDZ2). It was found that most mutations do not have a significant energetic contribution to peptide ligand binding. Three mutants that showed significant changes in binding also displayed context-dependent dynamic effects. Both a mutation at a partially exposed site (H71Y) and a buried core position (I35V) had a limited response in side-chain (2)H-based dynamics when compared to wild-type PDZ2. In contrast, a change at a second core position (I20F) that had previously been shown to be part of an energetic and dynamic network, resulted in extensive changes in side-chain dynamics. This response is reminiscent to that seen previously upon peptide ligand binding. These results shed light on the nature of the PDZ2 dynamic network and suggest that position 20 in PDZ2 acts as a "hub" that is energetically and dynamically critical for transmitting changes in dynamics throughout the PDZ domain.

Dynamic coupling and allosteric behavior in a nonallosteric protein.

Long-range intraprotein interactions give rise to many important protein behaviors. Understanding how energy is transduced through protein structures to either transmit a signal or elicit conformational changes is therefore a current challenge in structural biology. In an effort to understand such linkages, multiple V --> A mutations were made in the small globular protein eglin c. The physical responses, as mapped by NMR spin relaxation, residual dipolar couplings (RDCs), and scalar couplings, illustrate that the interior of this nonallosteric protein forms a dynamic network and that local perturbations are transmitted as dynamic and structural changes to distal sites as far as 16 A away. Two basic types of propagation responses were observed: contiguous pathways of enhanced (attenuated) dynamics with no change in structure; and dispersed (noncontiguous) changes in methyl rotation rates that appear to result from subtle deformation of backbone structure. In addition, energy transmission is found to be unidirectional. In one mutant, an allosteric conformational change of a side chain is seen in the context of a pathway of propagated changes in picosecond to nanosecond dynamics. The observation of so many long-range interactions in a small, rigid system lends experimental weight to the idea that all well-folded proteins inherently possess allosteric features [Gunasekaran et al. (2004) Proteins 57, 433-443], and that dynamics are a rich source of information for mapping and gaining mechanistic insight into communication pathways in individual proteins.