FOXN3-AS1: A Candidate Prognostic Marker and Epigenetic Target with Immunotherapeutic Implications in Acute Myeloid Leukemia.

AIM: We focused on the FOXN3 gene and selected its antisense transcripts (FOXN3-AS1) to investigate its potential involvement in acute myeloid leukemia (AML). BACKGROUND: Several integrated multi-omics datasets have expanded the horizons of the cancer landscape. With the emergence of new high-throughput technologies, a large number of non-coding RNAs have been confirmed to be involved in the pathogenesis of different types of hematological malignancies. METHODS: We conducted experimental validation using quantitative polymerase chain reaction (qPCR) with bone marrow specimens from AML patients. Then, Kaplan-Meier (KM) and Receiver Operating Characteristic (ROC) curves were used to substantiate the prognostic association between FOXN3-AS1 and AML patients within the TCGA database. Correlation between FOXN3-AS1 expression and gene mutation, immune, and immune function using Spearman correlation analysis. To explore the physical and functional interaction between FOXN3-AS1 and the DNMT1 protein, we utilized the RPISeq web tool from Iowa State University. Subsequently, we performed qPCR experiments to test the effect of 5AzaC (DNMT1 inhibitor) on FOXN3-AS1 expression AML cell lines (THP1 and OCI-AML3). We leveraged the "OncoPredict" R package in conjunction with the Genomics of Drug Sensitivity (GDSC) database to predict drug response in AML patients expressing FOXN3-AS1. RESULTS: We observed a significant upregulation of FOXN3-AS1 expression in AML patients compared to healthy controls using clinical samples. The TCGA database revealed an association between high FOXN3-AS1 expression and adverse prognosis. In our subsequent analysis, genes with poor prognostic implications in AML patients were exclusively identified in the FOXN3-AS1 high-expression group, further corroborating this relationship. AML patients with higher FOXN3-AS1 expression levels may respond less optimally to immunotherapy than patients with lower levels. Besides, we computationally predicted the interaction of FOXN3- AS1 and DNMT1 protein and experimentally confirmed that DNMT1i (GSK-3484862) affects the expression level of FOXN3-AS1. We also found that the chemotherapy drugs (5-Fluorouralic, Cisplatin, Dactolisib, Sapitinib, Temozolomide, Ulixertinib, Vinorelbine, Ruxolitinib, Osimertinib and Cisplatin) showed favorable responses in AML patients with high FOXN3-AS1 expression levels. CONCLUSION: Our candidate approach identifies FOXN3-AS1 as a prognostic indicator of survival in AML with a potential immune-related role. The preliminary observations we made on FOXN3-AS1/DNMT1 crosstalk warrant more in-depth invested immunotherapeutic approaches in AML.

Machine Learning Methods for Precision Dosing in Anticancer Drug Therapy: A Scoping Review.

INTRODUCTION: In the last decade, various Machine Learning techniques have been proposed aiming to individualise the dose of anticancer drugs mostly based on a presumed drug effect or measured effect biomarkers. The aim of this scoping review was to comprehensively summarise the research status on the use of Machine Learning for precision dosing in anticancer drug therapy. METHODS: This scoping review was conducted in accordance with the interim guidance by Cochrane and the Joanna Briggs Institute. We systematically searched the databases Medline (via PubMed), Embase and the Cochrane Library for research articles and reviews including results published after 2016. Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. RESULTS: A total of 17 relevant studies was identified. In 12 of the included studies, Reinforcement Learning methods were used, including Classical, Deep, Double Deep and Conservative Q-Learning and Fuzzy Reinforcement Learning. Furthermore, classical Machine Learning methods were compared in terms of their performance and an artificial intelligence platform based on parabolic equations was used to guide dosing prospectively and retrospectively, albeit only in a limited number of patients. Due to the significantly different algorithm structures, a meaningful comparison between the various Machine Learning approaches was not possible. CONCLUSION: Overall, this review emphasises the clinical relevance of Machine Learning methods for anticancer drug dose optimisation, as many algorithms have shown promising results enabling model-free predictions with the potential to maximise efficacy and minimise toxicity when compared to standard protocols.

Medication Risks and Their Association with Patient-Reported Outcomes in Inpatients with Cancer.

BACKGROUND: We aimed to assess medication risks and determine factors influencing the health-related quality of life (HRQOL) in cancer inpatients. METHODS: A retrospective analysis was conducted to identify drug-related problems (DRPs) based on medication reviews, including patient-reported outcomes (PROs). Multiple linear regression analyses were performed to identify sociodemographic, disease-related, and drug therapy-related factors influencing changes from hospital admission to discharge in the scales of the EORTC QLQ-C30 questionnaire. RESULTS: A total of 162 inpatients with various hematological and solid cancer diseases was analyzed. Patients received a mean of 11.6 drugs and 92.6% of patients exhibited polymedication resulting in a mean of 4.0 DRPs per patient. Based on PRO data, 21.5% of DRPs were identified. Multiple linear regression models described the variance of the changes in global HRQOL and physical function in a weak-to-moderate way. While drug therapy-related factors had no influence, relapse status and duration of hospital stay were identified as significant covariates for global HRQOL and physical function, respectively. CONCLUSION: This analysis describes underlying DRPs in a German cancer inpatient population. PROs provided valuable information for performing medication reviews. The multiple linear regression models for global HRQOL and physical function provided explanations for changes during hospital stay.

Assessment of body mass-related covariates for rifampicin pharmacokinetics in healthy Caucasian volunteers.

PURPOSE: Currently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin's pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM). METHODS: Twenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600 mg of rifampicin separated by a wash-out period of at least 9 days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin. RESULTS: A one-compartment model with nonlinear (Michaelis-Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height. CONCLUSION: Our results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin.

Paclitaxel therapeutic drug monitoring - International association of therapeutic drug monitoring and clinical toxicology recommendations.

Paclitaxel, one of the most frequently used anticancer drugs, is dosed by body surface area, which leads to substantial inter-individual variability in systemic drug exposure. We evaluated clinical evidence regarding the scientific rationale and clinical benefit of individualized paclitaxel dosing based on measured systemic concentrations, known as therapeutic drug monitoring (TDM). In retrospective studies, higher systemic exposure is associated with greater toxicity and efficacy of paclitaxel treatment across several disease types and dosing regimens. In prospective trials, TDM reduces variability in systemic exposure, and has been demonstrated to reduce toxicity while retaining treatment efficacy for 3-weekly dosing in patients with advanced non-small cell lung cancer. Despite the demonstrated benefits of paclitaxel TDM, clinical adoption has been limited due to the challenges with sample collection and analysis. Based on our review, we strongly recommend TDM for patients receiving every 3-week paclitaxel in combination with a platinum agent for advanced NSCLC, due to the prospectively demonstrated clinical benefits, and find moderate evidence to recommend TDM for paclitaxel 3-hour infusions for other tumor types and preliminary evidence suggesting potential usefulness for paclitaxel administered by 1-hour infusions.

Cytokine-Induced Killer Cells in Combination with Heat Shock Protein 90 Inhibitors Functioning via the Fas/FasL Axis Provides Rationale for a Potential Clinical Benefit in Burkitt's lymphoma.

Constant efforts are being made to develop methods for improving cancer immunotherapy, including cytokine-induced killer (CIK) cell therapy. Numerous heat shock protein (HSP) 90 inhibitors have been assessed for antitumor efficacy in preclinical and clinical trials, highlighting their individual prospects for targeted cancer therapy. Therefore, we tested the compatibility of CIK cells with HSP90 inhibitors using Burkitt's lymphoma (BL) cells. Our analysis revealed that CIK cytotoxicity in BL cells was augmented in combination with independent HSP90 inhibitors 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) and ganetespib. Interestingly, CIK cell cytotoxicity did not diminish after blocking with NKG2D (natural killer group 2, member D), which is a prerequisite for their activation. Subsequent analyses revealed that the increased expression of Fas on the surface of BL cells, which induces caspase 3/7-dependent apoptosis, may account for this effect. Thus, we provide evidence that CIK cells, either alone or in combination with HSP90 inhibitors, target BL cells via the Fas-FasL axis rather than the NKG2D pathway. In the context of clinical relevance, we also found that high expression of HSP90 family genes (HSP90AA1, HSP90AB1, and HSP90B1) was significantly associated with the reduced overall survival of BL patients. In addition to HSP90, genes belonging to the Hsp40, Hsp70, and Hsp110 families have also been found to be clinically significant for BL survival. Taken together, the combinatorial therapy of CIK cells with HSP90 inhibitors has the potential to provide clinical benefits to patients with BL.

Computational analysis of heat shock proteins and ferroptosis-associated lncRNAs to predict prognosis in acute myeloid leukemia patients.

Owing to their functional diversity in many cancers, long noncoding RNAs (lncRNAs) are receiving special attention. LncRNAs not only function as oncogenes or tumor suppressors by participating in various signaling pathways but also serve as predictive markers for various types of cancer, including acute myeloid leukemia (AML). Considering this, we investigated lncRNAs that may act as a mediator between two processes, i.e., heat shock proteins and ferroptosis, which appear to be closely related in tumorigenesis. Using a comprehensive bioinformatics approach, we identified four lncRNAs (AL138716.1, AC000120.1, AC004947.1, and LINC01547) with prognostic value in AML patients. Of interest, two of them (AC000120.1 and LINC01547) have already been reported to be AML-related, and AC004947.1 is considered to have oncogenic potential. In particular, the signature obtained showed a lower survival probability with high-risk patients, and vice versa. To our knowledge, this is the first predictive model of lncRNA that may correlate with the processes of heat shock proteins and ferroptosis in AML. Nevertheless, validation using patient samples is warranted.

Dose Recommendations for Common Drugs in Patients with Liver Cirrhosis: A Systematic Literature Review.

BACKGROUND AND OBJECTIVES: The presence of liver cirrhosis affects the selection and dosing of drugs metabolised by the liver as doses have to be adjusted to the remaining liver function. This is a major challenge in clinical practice as specific guidelines are lacking. The aim of this study was to identify drugs for which recommendations on selection and dose adjustments for patients with cirrhosis exist by assessing the literature according to certain quality standards, paying particular attention to the suitability of these recommendations for clinical practice. METHODS: A systematic literature review included peer-reviewed publications that were published by October 2020 in PubMed in the English language and aimed to generate recommendations on dose adjustment in patients with liver cirrhosis. Subsequently, the identified publications were checked for reporting quality against the relevant reporting guidelines and the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Finally, all specific dose recommendations were extracted, compared with the specifications of the Summaries of Product Characteristics and mapped according to the Anatomical Therapeutic Chemical/Defined Daily Dose Index. RESULTS: Eighteen publications covering a total of 1145 dose recommendations for 481 active substances were identified. There were 706 recommendations for 316 substances sufficiently specific for application in clinical practice. For 22 active substances, the specific recommendations were consistent across multiple publications, of which only six were also consistent with the respective Summaries of Product Characteristics. CONCLUSIONS: As the majority of dose recommendations were not sufficiently specific or even contradictory, there is an urgent need for the definition of standard parameters for a uniform assessment of drugs in liver cirrhosis. In addition, dose recommendations should be aligned by suitable methods.

Developing tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers.

BACKGROUND: To include the patient perspective in the assessment of adverse events in oncology, a patient-reported outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (CTCAE) was developed by the US National Cancer Institute, the so called PRO-CTCAE. The objective of this study was the development of disease-specific PRO-CTCAE item sets for patients with breast cancer (BC), multiple myeloma (MM), and prostate cancer (PC). METHODS: The cross-sectional survey was conducted at three German outpatient cancer centers. Prevalence and importance of the 78 PRO-CTCAE symptoms were assessed using a patient questionnaire. To select the most relevant PRO-CTCAE items for each tumor entity, symptoms were ranked based on patient answers. RESULTS: 101 patients with BC, 107 with MM, and 66 with PC participated. The final item sets contained 21 symptoms (BC) or 19 symptoms (MM and PC), respectively. Eight symptoms (fatigue, muscle pain, insomnia, joint pain, general pain, dizziness, shortness of breath, and swelling) were represented in all three item sets. Fatigue was the symptom with the highest ranking across item sets followed by insomnia. Symptoms with the highest rankings represented in only one item set were symptoms affecting the urogenital system in the PC item set, blurred vision in the BC item set, and decreased appetite in the MM item set. CONCLUSIONS: Individual PRO-CTCAE item sets for a German patient population were developed for the three tumor entities on the basis of patients' differences in symptom profiles and perceptions. The quality and psychometric criteria of the newly compiled item sets should be evaluated in validation studies.

Cefepime Population Pharmacokinetics, Antibacterial Target Attainment, and Estimated Probability of Neurotoxicity in Critically Ill Patients.

Cefepime has been reported to cause concentration-related neurotoxicity, especially in critically ill patients with renal failure. This evaluation aimed to identify a dosing regimen providing a sufficient probability of target attainment (PTA) and the lowest justifiable risk of neurotoxicity in critically ill patients. A population pharmacokinetic model was developed based on plasma concentrations over four consecutive days obtained from 14 intensive care unit (ICU) patients. The patients received a median dose of 2,000 mg cefepime by 30-min intravenous infusions with dosing intervals of every 8 h (q8h) to q24h. A time that the free drug concentration exceeds the MIC over the dosing interval (fT>MIC) of 65% and an fT>2×MIC of 100% were defined as treatment targets. Monte Carlo simulations were carried out to identify a dosing regimen for a PTA of 90% and a probability of neurotoxicity not exceeding 20%. A two-compartment model with linear elimination best described the data. Estimated creatinine clearance was significantly related to the clearance of cefepime in nondialysis patients. Interoccasion variability on clearance improved the model, reflecting dynamic clearance changes. The evaluations suggested combining thrice-daily administration as an appropriate choice. In patients with normal renal function (creatinine clearance, 120 mL/min), for the pharmacodynamics target of 100% fT>2×MIC and a PTA of 90%, a dose of 1,333 mg q8h was found to be related to a probability of neurotoxicity of ≤20% and to cover MICs up to 2 mg/L. Continuous infusion appears to be superior to other dosing regimens by providing higher efficacy and a low risk of neurotoxicity. The model makes it possible to improve the predicted balance between cefepime efficacy and neurotoxicity in critically ill patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01793012).

[Polypharmacy in nursing homes: options to improve drug therapy safety]. / Multimedikation in Einrichtungen der stationären Langzeitpflege: Möglichkeiten einer Verbesserung der Arzneimitteltherapiesicherheit (AMTS).

Patients in need of care usually suffer from multiple chronic conditions and therefore receive a high number of drugs. Polypharmacy involves multiple risks, for example, drug-drug and drug-disease interactions, adverse effects and potentially inappropriate medication (PIM), more hospital admissions, and increased mortality.Residents in long-term care facilities are particularly sensitive to adverse drug reactions because of age-related changes, frailty, and the high prevalence of dementia. Numerous drugs have side effects that lead to sedation, particularly in old age, and increase the risk of falls. In addition, anticholinergic effects negatively modify cognition. These PIMs are frequently prescribed to nursing home residents.The medication process in long-term care facilities is complex and requires numerous coordinated processes. In addition to the correct administration, the nursing staff have other important tasks such as monitoring the effects and potential adverse drug reactions and communicating their observations to the prescribing physicians and home-supplying pharmacists. The nursing staff therefore play a crucial role in the prescription of psychotropic drugs and contribute to the medication quality for nursing home residents. National and international studies indicate that improvements of polypharmacy and drug therapy safety in nursing homes can only be achieved by interprofessional collaboration.

Randomized Phase II Cabazitaxel Dose Individualization and Neutropenia Prevention Trial in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%). RESULTS: A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001). CONCLUSIONS: Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

Influence of the skeletal muscle index on pharmacokinetics and toxicity of fluorouracil.

BACKGROUND: The body composition of patients has been associated with tolerability and effectiveness of anticancer therapy. This study aimed to assess the influence of the skeletal muscle index (SMI) on the pharmacokinetics and toxicity of fluorouracil. METHODS: Patients treated in an oncological practice with fluorouracil-based chemotherapy and undergoing therapeutic drug monitoring were retrospectively investigated. Computed tomography images were analyzed to measure abdominal skeletal muscle areas in Hounsfield units for the psoas major muscle, back and total skeletal muscle to determine the SMI. For the latter, an automated segmentation method was used additionally. SMI measures were tested as covariates on fluorouracil clearance in a population pharmacokinetic model. Furthermore, regression analyses were performed to analyze the influence of SMI measures on the probability of clinically relevant adverse events (CTCAE grades ≥ 2). RESULTS: Fluorouracil plasma concentrations of 111 patients were available. Covariate analyses showed significant improvements of the model fit by all SMI measures. However, interindividual variability of fluorouracil clearance was only slightly reduced, whereas the SMI of the back muscle showed the largest reduction (-1.1 percentage points). Lower SMI values of the back muscle increased the probability for polyneuropathy and lower SMI of the psoas increased the probability for fatigue. CONCLUSIONS: Our results suggest that pharmacokinetics and toxicity of fluorouracil may be associated with specific SMI measures which deserve further investigation.

Medication errors in cancer therapy: Reports from German hospital pharmacists between 2008 and 2019.

OBJECTIVE: Since medication errors can have severe consequences, the development of methods to improve patient safety is becoming increasingly important. The aim of this evaluation was to identify frequent medication errors in oncology as well as characteristic correlations in the various error patterns. In addition, the implementation rate of the proposed pharmaceutical intervention was determined in order to assess the benefit of a clinical pharmacist in the field of oncology. METHODS: The evaluation was based on a data-set from a national documentation system for medication errors and interventions (DokuPIK) used by hospital pharmacists in the field of oncology from 2008 to 2019, namely 6684 reported cases in oncology, representing about 5% of all reports in DokuPIK. RESULTS: The most frequently reported errors were incorrect doses (22% of reported errors), followed by interactions (14%); in 10% of errors the prescription/documentation was incomplete/incorrect. The intervention suggested by the pharmacist was implemented in 97% of the cases. Based on the respective Anatomical Therapeutical Chemical Classification (ATC codes), drugs (or groups of drugs) were identified that were reported frequently in connection with medication errors, namely carboplatin and cyclophosphamide as anticancer drugs pantoprazole as non-anticancer drug. CONCLUSION: Frequently occurring medication errors in the field of oncology were identified, facilitating the development of specific recommendations for action and prevention strategies. The implementation of an electronic prescription software is particularly recommended for the avoidance of dosage errors in chemotherapy.

[Acceptance of an oncologic addendum for the application of the German Standardized Medication Plan in oral anticancer drug therapy]. / Akzeptanz eines onkologischen Addendums zur Anwendung des Bundeseinheitlichen Medikationsplans in der oralen Tumortherapie.

BACKGROUND: The Federal Standardized Medication Plan (BMP) offers the possibility of providing patients with specific information on drug therapy. Cancer patients who are treated with oral anticancer drugs have a great need for information as they take the drugs independently in their home environment. Providing specific instructions for oral anticancer drugs may enhance the patient role and improve medication safety. METHODS: In a four-step process (needs assessment, compilation of the text modules, pilot and main phase), an oncologic addendum for the BMP was developed and subjected to an acceptance test. Also, a needs assessment was conducted with oncologists, pharmacists and patients to identify important information to be included in the oncologic addendum. Subsequently, the acceptability of the BMP including the addendum ('Onko-BMP') was tested among health care providers and patients in two study phases (pilot and main phase). Updates made to the Onko-BMP were documented at each follow-up visit. At the end of the observation period, discrepancies between a brown bag review and the latest Onko-BMP were identified to evaluate its completeness. In addition, acceptance of the Onko-BMP was analyzed using qualitative methods. At the end of the pilot phase the patients were interviewed and completed a questionnaire at the end of the main phase. Focus interviews and a focus group were conducted with the health care providers. RESULTS: A total of 347 health care providers and cancer patients participated in the needs assessment, including 167 oncologists, 130 pharmacists, and 50 patients. Suggestions for additional information to be included in the oncologic addendum mainly included instructions for how to take the medication, therapy-limiting side effects as well as potentially relevant interactions with over-the-counter drugs. Ten patients participated in the pilot phase and 60 patients in the main phase of the project. The use of the Onko-BMP was positively evaluated by all participants. The majority of the 178 updates in the main phase were made by the patients themselves. Most frequently, missing items were added (62). After comparison with the brown bag at the end of the observation period, 175 discrepancies for a total of 270 products, including food supplements (mean 6.3 ±â€¯3.9), and 245 drugs (mean 5.7 ±â€¯3.1) taken by the patients were detected, 49 of which were due to missing drugs on the Onko-BMP, mainly on-demand medication (30). 82 documented discrepancies were for prescription drugs. In the qualitative surveys, health care providers indicated that there is a high need for the Onko-BMP. In particular, its use could strengthen the patient's role in therapy. The frequently missing or poor technical requirements for working with the BMP were perceived as limiting its widespread use. Assignment of clear responsibilities and remuneration of all professionals involved were identified as important influential factors for an efficient use of the Onko-BMP. Patients considered the added value of the Onko-BMP primarily to be in their being able to inform their treating physicians and pharmacists about their medication. CONCLUSIONS: The developed Onko-BMP gained a high level of acceptance among patients and health care providers. It can improve education about oral anticancer drugs and thereby strengthen the patient role. However, in order to ensure widespread use of the tool, the necessary conditions should be created on the part of the health care providers. In particular, the IT infrastructure for its use in daily routine needs to be improved in order to exploit its full potential and ensure its successful large-scale implemention.

Medication risks in older patients (70 +) with cancer and their association with therapy-related toxicity.

BACKGROUND: To evaluate medication-related risks in older patients with cancer and their association with severe toxicity during antineoplastic therapy. METHODS: This is a secondary analysis of two prospective, single-center observational studies which included patients ≥ 70 years with cancer. The patients' medication lists were investigated regarding possible risks: polymedication (defined as the use of ≥ 5 drugs), potentially inappropriate medication (PIM), and relevant potential drug-drug interactions (rPDDI). The risks were analyzed before and after start of cancer therapy. Severe toxicity during antineoplastic therapy was captured from medical records according to the Common Terminology Criteria for Adverse Events (CTCAE). The association between grade ≥ 3 toxicity and medication risks was evaluated by univariate as well as multivariate regression adjusted by ECOG and age. RESULTS: The study cohort comprised 136 patients (50% female, mean age 77 years, 42% hematological malignancies). Before the start of cancer therapy, patients took on average 5 drugs as long-term medication and 52% of patients were exposed to polymedication. More than half of patients used at least one PIM. Approximately one third of patients exhibited rPDDI. The prevalence of medication risks increased after start of cancer therapy. rPDDI were significantly associated with severe overall toxicity (OR, 5.07; p = 0.036; 95% Confidence Interval (CI) 1.11-23.14; toxicity in patients with rPDDI 94.1% (32/34) vs 75.9% (60/79) in patients without rPDDI) and hematological toxicity (OR, 3.95; p = 0.010; 95% CI 1.38-11.29; hematological toxicity in patients with rPDDI 85.3% (29/34) vs 59.5% (47/79) in patients without rPDDI). In the multivariate analysis adjusted by ECOG and age, only the association for rPDDI with hematological toxicity remained statistically significant (OR, 4.51; p = 0.007; 95% CI 1.52-13.38). These findings should be further investigated in larger studies. CONCLUSION: Medication risks are common in older patients with cancer and might be associated with toxicity. This raises the need for tailored interventions to ensure medication safety in this patient cohort.

Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP).

AIMS: Locally advanced rectal cancer (LARC) is an area of unmet medical need with one third of patients dying from their disease. With response to neoadjuvant chemo-radiotherapy being a major prognostic factor, trial SAKK 41/16 assessed potential benefits of adding regorafenib to capecitabine-amplified neoadjuvant radiotherapy in LARC patients. METHODS: Patients received regorafenib at three dose levels (40/80/120 mg once daily) combined with capecitabine 825 mg/m2 bidaily and local radiotherapy. We developed population pharmacokinetic models from plasma concentrations of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine as well as regorafenib and its metabolites M-2 and M-5 as implemented into SAKK 41/16 to assess potential drug-drug interactions (DDI). After establishing parent-metabolite base models, drug exposure parameters were tested as covariates within the respective models to investigate for potential DDI. Simulation analyses were conducted to quantify their impact. RESULTS: Plasma concentrations of capecitabine, regorafenib and metabolites were characterized by one and two compartment models and absorption was described by parallel first- and zero-order processes and transit compartments, respectively. Apparent capecitabine clearance was 286 L/h (relative standard error [RSE] 14.9%, interindividual variability [IIV] 40.1%) and was reduced by regorafenib cumulative area under the plasma concentration curve (median reduction of 45.6%) as exponential covariate (estimate -4.10 × 10-4 , RSE 17.8%). Apparent regorafenib clearance was 1.94 L/h (RSE 12.1%, IIV 38.1%). Simulation analyses revealed significantly negative associations between capecitabine clearance and regorafenib exposure. CONCLUSIONS: This work informs the clinical development of regorafenib and capecitabine combination treatment and underlines the importance of studying potential DDI with new anticancer drug combinations.

Prioritisation of Adverse Drug Events Leading to Hospital Admission and Occurring during Hospitalisation: A RAND Survey.

(1) Adverse drug events (ADEs) are a common cause of emergency department visits and occur frequently during hospitalisation. Instruments that facilitate the detection of the most relevant ADEs could lead to a more targeted and efficient use of limited resources in research and practice. (2) We conducted two consensus processes based on the RAND/UCLA appropriateness method, in order to prioritise ADEs leading to hospital admission (panel 1) and occurring during hospital stay (panel 2) for inclusion in future ADE measurement instruments. In each panel, the experts were asked to assess the "overall importance" of each ADE on a four-point Likert scale (1 = not important to 4 = very important). ADEs with a median rating of ≥3 without disagreement were defined as "prioritised". (3) The 13 experts in panel 1 prioritised 38 out of 65 ADEs, while the 12 experts in panel 2 prioritised 34 out of 63 ADEs. The highest rated events were acute kidney injury and hypoglycaemia (both panels), as well as Stevens-Johnson syndrome in panel 1 and rhabdomyolysis in panel 2. (4) The survey led to a set of ADEs for which there was consensus that they were of particular importance as presentations of acute medication-related harm, thereby providing a focus for further medication safety research and clinical practice.

Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib.

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

The WHO High 5s project: medication reconciliation in a German university hospital. A prospective observational cohort study.

BACKGROUND: Ensuring medication accuracy during transitions in care is one of the five highly prevalent patient safety problems focused on within the World Health Organization High 5s Project. Medication reconciliation is a standardized patient care process that can be used to address this problem. The aim of the current study is to implement medication reconciliation in a German university hospital. METHODS: The study was conducted at the Emergency Department of the University Hospital Aachen, Germany. All discrepancies between the Best Possible Medication History and the Admission Medication Order were documented and classified as documentation errors or medication errors. The type of error was also recorded. A negative binomial regression model was used to test several factors influencing the number of discrepancies. RESULTS: The medications of 105 patients were reconciled. The mean number of discrepancies per patient was 4.6± 3.6, with a total of 298 medication errors and 189 documentation errors. The most common type of medication error was the omission of a drug (n=208; 69.8 %). In the negative binomial regression analysis, the care status (p=0.0015) as well as the number of preadmission drugs (p=0.0007) were significantly associated with medication errors. DISCUSSION: A high number of discrepancies was detected and analysed. Patients admitted from nursing homes were less likely to have discrepancies in their medication reconciliation, perhaps because a structured documentation system for medications is already in place at nursing homes including error prone products (special dosage forms or food supplements). CONCLUSIONS: In this study, medication reconciliation was implemented at a German full-care university hospital. The actual number of discrepancies observed strongly indicates the need for medication reconciliation at hospital admission.