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Computational reactive-diffusive modeling for stratification and prognosis determination of patients with breast cancer receiving Olaparib.
Schettini, F, De Bonis, MV, Strina, C, Milani, M, Ziglioli, N, Aguggini, S, Ciliberto, I, Azzini, C, Barbieri, G, Cervoni, V, et al
Scientific reports. 2023;(1):11951
Abstract
Mathematical models based on partial differential equations (PDEs) can be exploited to handle clinical data with space/time dimensions, e.g. tumor growth challenged by neoadjuvant therapy. A model based on simplified assessment of tumor malignancy and pharmacodynamics efficiency was exercised to discover new metrics of patient prognosis in the OLTRE trial. We tested in a 17-patients cohort affected by early-stage triple negative breast cancer (TNBC) treated with 3 weeks of olaparib, the capability of a PDEs-based reactive-diffusive model of tumor growth to efficiently predict the response to olaparib in terms of SUVmax detected at 18FDG-PET/CT scan, by using specific terms to characterize tumor diffusion and proliferation. Computations were performed with COMSOL Multiphysics. Driving parameters governing the mathematical model were selected with Pearson's correlations. Discrepancies between actual and computed SUVmax values were assessed with Student's t test and Wilcoxon rank sum test. The correlation between post-olaparib true and computed SUVmax was assessed with Pearson's r and Spearman's rho. After defining the proper mathematical assumptions, the nominal drug efficiency (εPD) and tumor malignancy (rc) were computationally evaluated. The former parameter reflected the activity of olaparib on the tumor, while the latter represented the growth rate of metabolic activity as detected by SUVmax. εPD was found to be directly dependent on basal tumor-infiltrating lymphocytes (TILs) and Ki67% and was detectable through proper linear regression functions according to TILs values, while rc was represented by the baseline Ki67-to-TILs ratio. Predicted post-olaparib SUV*max did not significantly differ from original post-olaparib SUVmax in the overall, gBRCA-mutant and gBRCA-wild-type subpopulations (p > 0.05 in all cases), showing strong positive correlation (r = 0.9 and rho = 0.9, p < 0.0001 both). A model of simplified tumor dynamics was exercised to effectively produce an upfront prediction of efficacy of 3-week neoadjuvant olaparib in terms of SUVmax. Prospective evaluation in independent cohorts and correlation of these outcomes with more recognized efficacy endpoints is now warranted for model confirmation and tailoring of escalated/de-escalated therapeutic strategies for early-TNBC patients.
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Gastrointestinal pirfenidone adverse events in idiopathic pulmonary fibrosis depending on diet: the MADIET clinical trial.
Molina-Molina, M, Shull, JG, Vicens-Zygmunt, V, Rivera-Ortega, P, Antoniou, K, Bonella, F, Renzoni, E, Russell, AM, Maher, TM, Vancheri, A, et al
The European respiratory journal. 2023;(4)
Abstract
Individuals with IPF who follow a MUFA diet report a lower incidence of pirfenidone gastrointestinal adverse events than those that follow a SFA diet, which could explain the different prevalence in GI pirfenidone AEs reported by countries in IPF cohorts https://bit.ly/3LuzAUJ
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Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial.
Voorrips, SN, Boorsma, EM, Beusekamp, JC, DE-Boer, RA, Connelly, MA, Dullaart, RPF, VAN-DER-Meer, P, VAN-Veldhuisen, DJ, Voors, AA, Damman, K, et al
Journal of cardiac failure. 2023;(1):33-41
Abstract
BACKGROUND Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF. METHODS AND RESULTS This was a post hoc analysis of 79 patients with acute HF included in the EMPA-RESPONSE-AHF trial, which compared sodium-dependent glucose-cotransporter protein 2 inhibitor treatment with empagliflozin for 30 days with placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, β-hydroxybutyrate, and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures analysis of variance. In the total cohort, median total ketone body concentration was 251 µmol/L (interquartile range, 178-377 µmol/L) at baseline, which gradually decreased to 202 µmol/L (interquartile range, 156-240 µmol/L) at day 30 (P = .041). Acetone decreased from 60 µmol/L (interquartile range, 34-94 µmol/L) at baseline to 30 µmol/L (interquartile range, 21-42 µmol/L) ( P < .001), whereas β-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher N-terminal pro brain natriuretic peptide levels (r = 0.234; P = .039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. A higher acetone concentration at baseline was univariately associated with a greater risk of the composite end point, including in-hospital worsening HF, HF rehospitalizations, and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined end point. CONCLUSIONS Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.
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A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.
Okonogi, N, Murata, K, Yamada, S, Habu, Y, Hori, M, Kurokawa, T, Inaba, Y, Fujiwara, T, Fujii, Y, Hanawa, M, et al
International journal of molecular sciences. 2023;(13)
Abstract
We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.
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Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis.
Burmester, GR, Cohen, SB, Winthrop, KL, Nash, P, Irvine, AD, Deodhar, A, Mysler, E, Tanaka, Y, Liu, J, Lacerda, AP, et al
RMD open. 2023;(1)
Abstract
OBJECTIVE To evaluate the long-term safety profile for upadacitinib across rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and atopic dermatitis (AD). METHODS Safety data from clinical trials of upadacitinib 15 mg and upadacitinib 30 mg (AD only) for treating RA, PsA, AS and AD as of 30 June 2021 were analysed; some RA and PsA studies included adalimumab and methotrexate as active comparators. Treatment-emergent adverse events (TEAEs) were presented by disease as exposure-adjusted event rates per 100 patient years (E/100 PY). RESULTS The analysis included 6991 patients (RA, n=3209; PsA, n=907; AS, n=182; AD, n=2693) who received at least one dose of upadacitinib, representing 15 425 PY of exposure (maximum duration 2.75-5.45 years) across diseases. Rates (E/100 PY) of any TEAE (205.5-278.1) and TEAE leading to discontinuation (4.5-5.4) were similar across diseases; serious TEAEs were numerically higher in patients with RA and PsA. Rates of herpes zoster (1.6-3.6), non-melanoma skin cancer (0-0.8) and elevations in creatine phosphokinase levels (4.4-7.9) were higher with upadacitinib than with active comparators in the RA and PsA populations. Deaths (0-0.8), serious infections (0-3.9), major adverse cardiovascular events (0-0.4), venous thromboembolism (<0.1-0.4) and malignancies (0.3-1.4) were observed, with rates generally lowest in AS and AD. Increased rates of acne were observed in patients with AD only. CONCLUSIONS Findings from this analysis demonstrate that upadacitinib is generally well tolerated with observed differences in safety profiles likely reflective of varying patient characteristics across RA, PsA, AS and AD populations. TRIAL REGISTRATION NUMBERS NCT02675426, NCT02706951, NCT02706847, NCT02629159, NCT02706873, NCT03086343, NCT03104374, NCT03104400, NCT03178487, NCT03569293, NCT03568318 and NCT03607422.
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Improvement of inflammatory response and gastrointestinal function in perioperative of cholelithiasis by Modified Xiao-Cheng-Qi decoction.
Sun, BF, Zhang, F, Chen, QP, Wei, Q, Zhu, WT, Ji, HB, Zhang, XY
World journal of clinical cases. 2023;(4):830-843
Abstract
BACKGROUND In the perioperative period of biliary surgery, various factors can induce the release of a large number of inflammatory factors, leading to an imbalance in pro-inflammatory and anti-inflammatory responses and resulting in gastrointestinal (GI) dysfunction. Enhanced Recovery After Surgery protocols in biliary surgery have been shown to reduce the stress response and accelerate postoperative recovery. It is crucial to reduce the inflammatory response and promote the recovery of GI function after biliary surgery, both of which are the basis and key for perioperative care and postoperative recovery. AIM: To better understand the effects of Modified Xiao-Cheng-Qi decoction (MXD) on inflammatory response and GI function in the perioperative management of cholelithiasis and their correlation. METHODS This was a prospective randomized placebo-controlled trial, in which 162 patients who received biliary tract surgery were randomly assigned to three groups: MXD group, XD group, and placebo-control group. The observed parameters included frequency of bowel sounds, time of first flatus and defecation, time of diet, and amount of activity after surgery. The serum levels of C-reactive protein (CRP), interleukin (IL)-6, IL-10, serum amyloid A protein (SAA), and substance P were measured by the enzyme-linked immunosorbent assay. Then, the spearman correlation coefficient was used to analyze the relationship between the indicators of GI function and inflammation. RESULTS Compared to the placebo-control, improvements in GI function were observed in the MXD groups including reduced incidence of nausea, vomiting, and bloating; and earlier first exhaust time, first defecation time, and feeding time after surgery (P < 0.05). On the 1st and 2nd d after surgery, IL-6, CRP and SAA levels in MXD group were lower than that in placebo control, but substance P level was higher, compared to the control (P < 0.05). Functional diarrhea occurred in both MXD and XD groups without any other adverse effects, toxic reactions, and allergic reactions. Diarrhea was relieved after the discontinuation of the investigational remedies. Bowel sounds at 12 h after surgery, the occurring time of the first flatus, first defecation, postoperative liquid diet and semi-liquid diet were significantly correlated with levels of IL-6, CRP, SAA and substance P on second day after surgery (P < 0.05). CONCLUSION Treatment with MXD can relieve inflammatory response and improve GI function after surgery. Moreover, there are significant correlations between them. Furthermore, it does not cause serious adverse reactions.
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Severity of coeliac disease and clinical management study when using a non-metabolised medication: a phase I pharmacokinetic study.
Chretien, ML, Bailey, DG, Asher, L, Parfitt, J, Driman, D, Gregor, J, Dresser, GK
BMJ open. 2023;(2):e057151
Abstract
OBJECTIVE The non-metabolised antihistamine fexofenadine has oral absorption resulting from transporter activity. Uptake by enterocyte organic anion transporting polypeptides and efflux by an ATP-binding cassette transporter (P-glycoprotein) are primary determinants. Coeliac disease-mediated lesions to the small intestinal mucosa may alter oral absorption of the drug probe, fexofenadine. DESIGN A phase I, open-label, single-dose, pharmacokinetic study SETTING London, Ontario, Canada PARTICIPANTS Patients with coeliac disease (n=41) with positive serology and healthy individuals (n=48). MAIN OUTCOME MEASURES Patients with coeliac disease-duodenal histology and oral fexofenadine pharmacokinetics within a 3-week period. Healthy individuals-oral fexofenadine pharmacokinetics with water and grapefruit juice. RESULTS Patients with coeliac disease were stratified by disease severity: Group A (n=15, normal), B+C (n=14, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=12, moderate to severe villous blunting). Patients with coeliac disease in groups A, B+C and D and healthy individuals receiving water had similar fexofenadine AUC0-8 (2038±304, 2259±367, 2128±410, 1954±138 ng.h/mL; p>0.05; mean±SEM) and Cmax (440±73, 513±96, 523±104, 453±32 ng/mL; p>0.05), respectively. These four groups all had higher fexofenadine AUC0-8 (1063±59; p<0.01) and Cmax (253±18; p<0.05) compared with those for healthy individuals receiving grapefruit juice. Coeliac groups had a positive linear trend between disease severity and fexofenadine Tmax (2.0±0.3, 2.7±0.4, 3.1±0.5 hours; p<0.05). CONCLUSIONS Coeliac disease severity based on duodenal histopathology did not affect oral fexofenadine bioavailability. Increased Tmax suggested absorption distal to the duodenum (jejunum + ileum), where histology seems more normal which may be the key determinant. Patients with coeliac disease may not require consideration for alternative clinical drug management for a number of non-metabolised and transport-mediated medications.
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Effects of food and race on the pharmacokinetics of lazertinib in healthy subjects and patients with EGFR mutation-positive advanced non-small cell lung cancer.
Huh, KY, Lim, Y, Yoon, DY, Hwang, JG, Sim, S, Kang, J, Wang, J, Kim, M, Jang, SB, Shreeve, SM, et al
Lung cancer (Amsterdam, Netherlands). 2023;:112-120
Abstract
OBJECTIVES Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild type-sparing third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for advanced non-small cell lung cancer (NSCLC). The study aimed to evaluate the effects of food and race on the pharmacokinetics (PK) of lazertinib from a healthy volunteer trial and PK data from NSCLC patients with EGFR mutation. MATERIALS AND METHODS An open-label, single-dose, two-period, single-sequence crossover study was conducted in healthy subjects with two race groups (non-Asian and Asian). Subjects orally received a single dose of lazertinib 240 mg in fasted and fed state (high-fat meal) in each period separated by a 21-day washout. An open-label, multicenter, phase 1/2 study was conducted in Asian and non-Asian patients with NSCLC. Patients were given oral lazertinib 20-320 mg once daily in fasted state continuously in 21-day cycles. PK parameters were evaluated using non-compartmental analysis. RESULTS A total of 24 healthy subjects (12 non-Asians and 12 Asians) and 52 NSCLC patients (22 non-Asians and 30 Asians) were evaluated. The change in the overall systemic exposure of lazertinib at fed state was less than 15%. Non-Asians showed 58-76% of the systemic exposure than Asians in healthy subjects. In contrast, there were no significant differences in systemic exposure by race both after single and multiple doses among NSCLC patients. CONCLUSION Lazertinib can be taken with or without food considering the comparable systemic exposures related to food. Although effect of race was not consistent across studies, there was no evidence for dose adjustment based on race.
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Impact of a Comprehensive Intervention Bundle Including the Drug Burden Index on Deprescribing Anticholinergic and Sedative Drugs in Older Acute Inpatients: A Non-randomised Controlled Before-and-After Pilot Study.
Fujita, K, Hooper, P, Masnoon, N, Lo, S, Gnjidic, D, Etherton-Beer, C, Reeve, E, Magin, P, Bell, JS, Rockwood, K, et al
Drugs & aging. 2023;(7):633-642
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Abstract
INTRODUCTION Implementation of the Drug Burden Index (DBI) as a risk assessment tool in clinical practice may facilitate deprescribing. OBJECTIVE The purpose of this study is to evaluate how a comprehensive intervention bundle using the DBI impacts (i) the proportion of older inpatients with at least one DBI-contributing medication stopped or dose reduced on discharge, compared with admission; and (ii) the changes in deprescribing of different DBI-contributing medication classes during hospitalisation. METHODS This before-and-after study was conducted in an Australian metropolitan tertiary referral hospital. Patients aged ≥ 75 years admitted to the acute aged care service for ≥ 48 h from December 2020 to October 2021 and prescribed DBI-contributing medication were included. During the control period, usual care was provided. During the intervention, access to the intervention bundle was added, including a clinician interface displaying DBI score in the electronic medical record. In a subsequent 'stewardship' period, a stewardship pharmacist used the bundle to provide clinicians with patient-specific recommendations on deprescribing of DBI-contributing medications. RESULTS Overall, 457 hospitalisations were included. The proportion of patients with at least one DBI-contributing medication stopped/reduced on discharge increased from 29.9% (control period) to 37.5% [intervention; adjusted risk difference (aRD) 6.5%, 95% confidence intervals (CI) -3.2 to 17.5%] and 43.1% (stewardship; aRD 12.1%, 95% CI 1.0-24.0%). The proportion of opioid prescriptions stopped/reduced rose from 17.9% during control to 45.7% during stewardship (p = 0.04). CONCLUSION Integrating a comprehensive intervention bundle and accompanying stewardship program is a promising strategy to facilitate deprescribing of sedative and anticholinergic medications in older inpatients.
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Effect of Magnesium on Deterioration and Symptomatic Hemorrhagic Transformation in Cerebral Ischemia: An Ancillary Analysis of the FAST-MAG Trial.
Fan, S, Jang, M, Kim-Tenser, M, Shkirkova, K, Liebeskind, DS, Starkman, S, Villablanca, JP, Hamilton, S, Naidech, A, Saver, JL, et al
Cerebrovascular diseases (Basel, Switzerland). 2023;(5):539-542
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Abstract
BACKGROUND Magnesium (Mg) is a neuroprotectant in preclinical models. Lower serum Mg levels have been associated with symptomatic hemorrhagic transformation (HT) in patients with ischemic stroke. Early treatment of acute ischemic stroke with Mg may reduce rates of symptomatic HT. METHODS In this post hoc study of the Field Administration of Stroke Therapy Magnesium (FAST-MAG) trial, 1,245 participants with a diagnosis of cerebral ischemia received 20 g of Mg or placebo initiated in the prehospital setting. Posttreatment serum Mg level was measured for 809 participants. Cases of clinical deterioration, defined as worsening by ≥4 points on the National Institute of Health Stroke Scale (NIHSS), were imaged and evaluated for etiology. Symptomatic HT was defined as deterioration with imaging showing new hemorrhage. RESULTS Clinical deterioration occurred in 187 and symptomatic HT in 46 of 1,245 cases of cerebral ischemia. Rates of deterioration and symptomatic HT were not significantly lower in those who received Mg (15.7% vs. 14.4%, p = 0.591; 2.8% vs. 4.6%, p = 0.281). In cases where serum Mg level was obtained posttreatment, lower serum Mg level (<1.7 mg/dL) was associated with significantly higher rates of deterioration and symptomatic HT (27.5% vs. 15.5%, p = 0.0261; 11.6% vs. 3.65%, p = 0.00819). CONCLUSIONS Treatment with Mg did not significantly reduce rates of clinical deterioration or symptomatic HT. Future analysis should address whether treatment with Mg could have influenced the subgroup with low serum Mg at baseline.