Dose Reduction Research Articles

Serum creatine kinase elevation following tyrosine kinase inhibitor treatment in cancer patients: Symptoms, mechanism, and clinical management.

Molecular targeted tyrosine kinase inhibitors (TKIs) have produced unprecedented treatment response in cancer therapy for patients harboring specific oncogenic mutations. While the TKIs are mostly well tolerated, they were reported to increase serum levels of creatine kinase (CK) and cause muscle metabolism-related toxicity. CK is an essential enzyme involved in cellular energy metabolism and muscle function. Elevated serum CK levels can arise from both physiological and pathological factors, as well as triggered by specific drug classes. The incidence of serum CK elevation induced by a few approved TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib combination [Food and Drug Administration, United States]; aumolertinib, and sunvozertinib [only approved by National Medical Products Administration, China]) were over 35%. CK elevation-related symptoms include myopathy, myositis, inclusion body myositis (IBM), cardiotoxicity, rhabdomyolysis, rash, and acneiform dermatitis. High-level or severe symptomatic CK elevation may necessitate dose reduction and indirectly dampen TKI efficacy. This review presents an updated summary about the prevalence rate and recent research about mechanisms leading to TKI-induced serum CK elevation in cancer patients. The utility of monitoring serum CK levels for predicting TKI-induced adverse effects and their management will also be discussed.

Treatment approaches and survival outcomes in elderly colorectal cancer patients: a single-center comparative study.

Geriatric patients account for nearly half of new colorectal cancer (CRC) cases. This study compares clinicopathological features, treatments, outcomes, and frailty in elderly (≥ 70) and younger (< 70) CRC patients at our center. Patients diagnosed with non-metastatic or de novo metastatic CRC between January 2015 and April 2024 were included. Demographic, pathological, and survival data were retrospectively collected. Analyses were performed using SPSS version 25, with statistical significance set at P < 0.05. Of the 414 non-metastatic CRC patients, 26.6% were aged ≥ 70. Elderly patients received less perioperative chemotherapy (60% vs. 81.6%, P < 0.001) and had more dose reductions (41.6% vs. 19.2%, P < 0.001). Frailty reduced perioperative chemotherapy in elderly non-metastatic patients (54.5% vs. 92.1%, P < 0.001) but did not affect dose reduction (37.9% vs. 33.3%, P = 0.764) or treatment duration (median 24weeks for both groups, P = 0.909). In metastatic patients, frailty shortened chemotherapy duration (9.5 vs. 15.5weeks, P = 0.129). Elderly patients had lower 5- and 8-year overall survival (OS) rates (64.7%, 60.1% vs. 83.0%, 78.8%, P = 0.004). In the de novo metastatic cohort (135 patients), age did not affect OS (19.4 vs. 17.3months, P = 0.590) or PFS (9.8 vs. 7.5months, P = 0.209). Rectal cancer (HR: 2.751, P = 0.005) and early chemotherapy termination (HR: 4.138, P < 0.001) worsened OS in non-metastatic CRC, while absence of RAS (HR: 2.043, P = 0.047), BRAF mutations (HR: 8.263, P = 0.010), and metastasectomy (HR: 3.650, P = 0.036) improved OS in metastatic CRC. Age does not independently worsen CRC survival, though early chemotherapy discontinuation impacts outcomes. Reduced-dose chemotherapy or monotherapy can help minimize adverse effects in elderly patients.

Estimated glomerular filtration rate versus creatinine clearance to determine anticoagulant dosage after lower-limb orthopedic surgery.

Anticoagulation is recommended for thromboprophylaxis after lower-limb orthopedic surgery. The suggested dosage is based on creatinine clearance (CCr) in the labels. However, most facilities only provide estimated glomerular filtration rate (eGFR) as laboratory data. Because the eGFR equation adjusts for a body surface area (BSA) of 1.73 m2, it may overestimate renal function in patients with a small BSA. This retrospective study aimed to determine whether different renal function estimation formulas affect the incidences of venous thromboembolism (VTE) and bleeding when determining anticoagulant dosages. This study included patients who underwent lower-limb orthopedic surgery and received anticoagulants (edoxaban, enoxaparin, and fondaparinux) between 2017 and 2020 at Yaizu City Hospital. Anticoagulant dosing was evaluated using CCr, eGFR, and de-indexed eGFR (without correction for BSA), and the incidences of VTE and bleeding were compared among these formulas. The median values for BSA, CCr, eGFR, and de-indexed eGFR were 1.40 m2, 56.0mL/min, 73.0mL/min/1.73m2, and 60.9mL/min, respectively. There was no significant difference in the VTE incidence among these formulas. However, when dose reduction or contraindication threshold was determined by eGFR vs. CCr, the bleeding incidence was significantly higher in the group that was overdosed by CCr (6.0% vs. 25.7%, p < 0.05). Similarly, using de-indexed eGFR vs. CCr, the bleeding incidence was significantly higher in the group that was overdosed by CCr (7.5% vs. 28.6%, p < 0.05). In orthopedic surgery, anticoagulant dosages should be based on CCr for patients with a small BSA to avoid bleeding risks.

Aficamten in patients with obstructive hypertrophic cardiomyopathy: an integrated safety analysis

Abstract Background Aficamten is a next-in-class, oral, selective cardiac myosin inhibitor targeting the hypercontractility underlying hypertrophic cardiomyopathy (HCM). It relieves left ventricular outflow tract obstruction, improves exercise capacity, symptoms, quality of life, and cardiac biomarkers with a modest effect on left ventricular ejection fraction (LVEF). Purpose To present an integrated safety analysis from all aficamten trials to date. Methods Patients with obstructive HCM (oHCM) who received ≥1 dose of aficamten or placebo [PBO] in the phase 2 REDWOOD-HCM trial, phase 3 SEQUOIA-HCM trial, or the open-label extension FOREST-HCM were included. Results In the PBO-controlled pool of REDWOOD-HCM and SEQUOIA-HCM, 170 patients received aficamten and 153 PBO. In the cumulative (parent+extension) aficamten treated pool, 283 patients were analyzed from initial dose of aficamten or after enrollment in FOREST-HCM (100 PBO-to-aficamten). Overall, mean age was 59 years, 42% were female. In the PBO-controlled pool the mean cumulative follow up was 70.8 patient-years (py) on aficamten, and 66.3 py on PBO, and the total cumulative exposure period to aficamten was 205.2 py. The mean dose of aficamten in the cumulative pool was 12.6 mg/day. Treatment emergent serious adverse events (TESAE) occurred in 10 (5.9%) aficamten patients vs 14 (9.2%) PBO patients in the PBO-controlled pool, and in 24 (8.5%) aficamten patients in the cumulative pool. In the blinded phase, reported AEs were dizziness in 11 (6.5%) aficamten vs 3 (2%) PBO patients, syncope in 3 (1.8%) vs 4 (2.6%), dyspnea in 11 (6.5%) vs 8 (5.2%) and hypertension in 11 (6.5%) vs 4 (2.6%). Site-read LVEF &amp;lt;50%, all resulting in down-titration occurred in 9 (5.3%) aficamten patients [exposure adjusted incidence rate (EAIR) 11.2 per 100 py] and 1 (0.7%) PBO patient (EAIR: 1.3 per 100 py), and in 11 (3.9%) aficamten patients in the cumulative pool (EAIR: 5.3 per 100 py). None of the LVEF &amp;lt;50% events in aficamten patients were associated with heart failure symptoms; 1 PBO patient with a low LVEF had an AE of peripheral edema. During the maintenance phase of the cumulative exposure pool, 1588 echocardiograms were performed, of which 11 (0.7%) led to dose reduction due to LVEF &amp;lt;50%, none resulted in discontinuation or treatment interruption. In the cumulative pool, 6 (2.1%) patients terminated treatment early, none due to aficamten-related AEs. New onset atrial fibrillation occurred in 4 (2.4%) aficamten (EAIR: 4.9 per 100 py) and 5 (3.3%) PBO patients (EAIR: 6.5 per 100 py). There were no deaths during the study period. Conclusions In this integrated safety analysis, aficamten had a safety profile similar to PBO and was consistent over an extended treatment period. There was a low incidence of LVEF &amp;lt;50%, none of which were associated with clinical sequalae, and all were successfully managed by dose reduction. Monitoring echocardiography in the maintenance phase yielded very few actionable results.

Real-world experience with mavacamten in obstructive hypertrophic cardiomyopathy: observations from a tertiary care center

Abstract Background In symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, mavacamten is commercially approved to help improve left ventricular (LV) outflow tract (LVOT) gradients, symptoms, and reduce eligibility for septal reduction therapy (SRT) under the risk evaluation and mitigation strategy (REMS) program. We sought to prospectively report the initial real-world clinical experience with the use of commercially available mavacamten in a multi-hospital tertiary healthcare system. Methods We studied the first 150 consecutive oHCM patients (mean age 65 years, 53% women, 83% on betablockers and 61% in New York Heart Association [NYHA] class III) who were initiated on 5 mg of mavacamten with dose titrations using symptom assessment and echocardiographic measurements of LVOT gradient and LV ejection fraction (LVEF) measurements. We measured changes in NYHA class, LVEF, LVOT gradients (resting and Valsalva) at baseline, 4, 8 and 12 weeks. Results At 261±143 days (range of 31-571 days), 69 (46%) patients had ≥1 NYHA class, 27 (18%) additional patients had ≥2 NYHA class improvement and 40 (27%) reported a no change in symptoms. The mean LVOT gradient at rest decreased from 41±33 mmHg at baseline to 16±17 mmHg at 4 weeks, 16±16 mmHg at 8 weeks and 15±16 mmHg at 12 weeks. The mean drop in resting LVOT gradient from baseline to last follow-up was 26±3 mmHg (p&amp;lt;0.0001). The mean Valsalva LVOT gradient decreased from 72±43 mmHg at baseline to 29±31 mmHg at 4 weeks, 29±28 mmHg at 8 weeks and 30±29 mmHg at 12 weeks (p&amp;lt;0.001). The mean reduction in post Valsalva LVOT gradient from baseline to last follow-up was 43±4 mmHg (p&amp;lt;0.0001). At baseline, 100% patients had Valsalva LVOT gradients ≥ 30 mm Hg and 142 (95%) had ≥ 50 mm Hg. After initiation of mavacamten therapy, Valsalva LVOT gradient ≥ 30 mm Hg was observed in 44/150 (29%) at 4 weeks, 40/141 (28%) at 8 weeks and 41/136 (30%) at 12 weeks. In 40 patients who reported no symptomatic improvement, the mean Valsalva LVOT gradient decreased from 73±39 mmHg at baseline to 34± 27 mmHg at 4 weeks, 35±28 mmHg at 8 weeks and 30±24 mmHg at 12 weeks (P&amp;lt;0.001). The mean LVEF at baseline was 66±6% and changed to 64±5% at 4 weeks, 63±5% at 8 weeks and 62±7% at 12 weeks (p&amp;lt;0.0001). No patient underwent SRT, developed LVEF ≤30% or developed heart failure requiring admission. Three (2%) patients needed temporary interruption of mavacamten due to LVEF&amp;lt;50. During follow up, dose reduction or discontinuation of background HCM therapy (betablockers, calcium channel blockers and disopyramide) occurred in 33 (22%) patients. The breakdown of various drug doses of mavacamten, at last follow-up, is as follows: 2.5 mg (n=29, 19%), 5 mg (n=80, 53%), 10 mg (n=37, 25%) and 15 mg (n=3, 2%). Conclusions In a real-world study in symptomatic oHCM patients at a multi-hospital tertiary care referral center, we demonstrate the efficacy and safety of prescribing mavacamten under the REMS program.

Synergistic effect of antibiotics, α-linolenic acid and solvent type against Staphylococcus aureus biofilm formation.

A promising approach to the treatment of bacterial infections involves inhibiting the quorum sensing (QS) mechanism to prevent the formation and growth of bacterial biofilm. While antibiotics are used to kill remaining bacteria, QS inhibitors (QSIs) allow for antibiotic doses to be reduced. This study focuses on evaluating the synergy between gentamicin sulphate (GEN), tobramycin (TOB), or azithromycin (AZM) with linolenic acid (LNA) against the formation of an early Staphylococcus aureus biofilm. Minimum biofilm inhibitory concentration (MBIC) was determined using the resazurin reduction assay for all antibiotics and LNA. The reduction of biofilm mass was assessed using the crystal violet (CV) assay. We have also evaluated the effect of dimethyl sulfoxide with TWEEN (DMSO_T) on early biofilm formation. Synergy was determined by metabolic activity assay and fractional biofilm inhibitory concentration (FBIC). DMSO_T at a concentration of 1% enhanced early biofilm formation, but also decreased the doses of antibiotic needed to reduce the biofilm by up to 8 times. Adding LNA at a concentration of 32µg/ml or 64µg/ml allowed up to a 32-fold reduction of antibiotic doses for GEN and TOB and a 4-fold reduction for AZM. LNA's use in combination with various antibiotics could reduce their doses and help fight drug-resistant bacteria in the biofilm.

Preliminary results of the non-invasive cardiac radioablation for ventricular tachycardia study; an in silico dosimetric comparison of photon vs proton radiotherapy for ventricular arrhythmias

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has been proposed as an alternative treatment for refractory ventricular arrhythmias (VA) in patients who are unsuitable or refractory to standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. Most of the STAR treatments performed so far used photon radiotherapy. As compared to photons, particle therapy with protons, based on its finite penetration depth in tissue, might have the potential to reduce the dose to surrounding healthy tissues thus lowering the risk of side effects. Purpose The purpose of this in silico simulation study was to evaluate the feasibility of STAR with protons in patients with VA and to compare the doses of the organs at risk (OARs) in photon and proton treatment plans. Methods 14 patients (11 males) candidates to standard CA for VA were enrolled. ECG gated CT scans in expiratory breath-hold, and standard electroanatomical mapping were performed in each patients to reconstruct a 3D bipolar voltage map and identify the ablation target. Based on the information obtained by the contouring of the ablation target three treatment plans were simulated: one with photons, and two with protons - with and without cardiac gating- to assess the doses at the OARs. Results The median age was 68.5 (63.25-71.5), all patients had a history of recurrent VA and the indication for treatment with CA. 7 patients had an ischemic cardiomyopathy, 4 an idiopathic cardiomyopathy and 3 ventricular ectopic beats without structural heart disease. The mean left ventricular ejection fraction was 40±11% and 8 out of 14 patients were ICD carriers. Both photons and protons treatment plans reached the goals for target coverage (25 Gy on 98% of the target volume). A statistically significant reduction in the mean maximum dose (Dmax) to some OARs was observed in proton compared to photon plans (see table 1). Specifically, the Dmax delivered to the mitral valve, vena cava, descending aorta, esophagus and to the lungs have been largely reduced with the proton plans. However, in some specific cases, a higher maximum dose was observed for protons in structures close or overlapping with the target, mainly due to the need of an additional margin in the treatment plan to account for proton range uncertainty. The use of cardiac gating did not show a significant dose reduction to OARs compared to the non-gated proton plan. Conclusion The preliminary results of our in silico simulation study suggest that STAR therapy with the use of protons might be associated with a significant dose reduction to the surrounding organs. Nevertheless, the choice of the best treatment should be evaluated on a case by-case strategy since some specific cases may be better suitable for photon treatment.Table 1

Analyzing the economic ramifications of the broad implementation of generic prasugrel

Abstract Introduction The 2023 European Acute Coronary Syndrome (ACS) guidelines state that prasugrel (PRG) should be considered in preference to ticagrelor (TCG) in patients (pts) who proceed to percutaneous coronary angioplasty (PCI). In Portugal, PRG is less available due to earlier evidence considering pretreatment and contraindications for each drug. PRG (10mg) is currently a generic drug, while TCG is not. We aimed to evaluate the proportion of pts that could be switched from TCG to PRG, and the economic impact of a widespread national adoption. Methods To determine eligibility for generic PRG 10mg, we examined a single center prospective database of consecutive ACS pts undergoing PCI in a full year. Eligibility for TCG and PRG was based on drug specific contraindications, previous stroke for PRG and chronic liver disease (CLD) for TCG, and indication for PRG dose reduction (≤60 kg and ≥75 years). To estimate hospital costs we used the price per pill indicated by the pharmacy (0.98€ TCG, 0.67€ PRG). To obtain post-discharge and NHS savings we used the INFARMED public information. We estimated 3500 PCIs per year on a national level, based on published data. Results A total of 780 pts were included, median age 68±10.4years, 523 (67.1%) were male, 51.9% (n=406) had non-ST elevation ACS. Mean admission time was 8.36 days. Considering PRG and TCG contraindications, 157 pts (20.3%) had a previous history of stroke and 20pts (2.6%) had CLD. 150 pts (19.2%) had PRG dose reduction criteria. Eligible for PRG 10mg and TCG 90mg were 434 pts (57.8% of total PCI pts). Cost per admission would be 33 697.35€ for TCG and 17 617.28€ for PRG. At a national level, hospital costs can be reduced by 16080.07€. Considering the 1-year outpatient setting and a widespread generic PRG 10mg adoption, NHS savings are estimated in 898 323.59€, and patient savings in 401248.25€ (198.38€ per patient). Conclusions ACS pts in real-world scenarios exhibit both eligibility for PRG and TCG. Considering the lower cost, the NHS can potentially save 914 403,66€ (figure 1) annually through the widespread adoption of generic PRG 10mg.

Plasma apixaban levels and thrombin generation assay in patients with atrial fibrillation with dose reduction criteria of apixaban

Abstract Background Off-label reduced-dose apixaban is commonly prescribed in patients with atrial fibrillation (AF). However, the pharmacokinetic data of apixaban according to the dosage and label is limited especially in those with dose reduction criteria of apixaban. Purpose We investigated the apixaban plasma concentration (PC) and thrombin generation assay (TGA) parameters across different apixaban dose settings. Methods We enrolled 398 non-valvular AF patients with more than single-dose reduction criteria of apixaban and divided them into three groups: (1) on-label standard dose (single dose-reduction criterion with standard-dose of apixaban 5mg twice daily, n=173); (2) off-label reduced-dose (single dose-reduction criterion with apixaban 2.5mg twice daily, n=61); and (3) on-label reduced-dose (two or more dose-reduction criteria with apixaban 2.5mg twice daily, n=164). Apixaban PC by anti-Xa assay and TGA parameters of these three groups were compared at the trough level. Results The on-label standard dose group showed a higher PC than the on-label reduced dose (124.7 vs. 80.3 ng/mL, p&amp;lt;0.001), and the on-label reduced dose exhibited a higher PC than the off-label reduced dose (80.3 vs. 53.2 ng/mL, p=0.031) (Figure). The TGA parameters displayed a similar pattern of differences, with the on-label standard dose group tends to show the least thrombogenic profiles (Figure). Lower creatinine clearance (CrCl), older age, and female sex were statistically significant predictors for a higher apixaban PC by multivariable regression model (p&amp;lt;0.001, p=0.043, and 0.023, respectively), and CrCl was the most influential variable to dichotomize apixaban PC in all three groups (Figure). Conclusions Off-label reduced-dose apixaban group exhibited significantly lower apixaban level than both on-label standard dose and on-label reduced-dose apixaban groups, suggesting the importance of adhering to current dose-reduction criteria for maintaining appropriate apixaban levels. Caution is particularly advised in off-label under-dosing for patients with high creatinine clearance. Further investigation into the impact of off-label under-dosing on clinical outcomes is essential to guide optimal therapeutic strategies.

Clinical Outcomes of Poly(ADP–Ribose) Polymerase Inhibitors as Maintenance Therapy in Patients with Ovarian Cancer in the Southeastern Region of Korea

Purpose: In this study, we aimed to retrospectively investigate the real-world clinical efficacy and adverse events of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in real-world clinical practice among patients with newly diagnosed epithelial ovarian cancer. Methods: We retrospectively reviewed the medical records from hospitals. Patients with epithelial ovarian cancer treated with olaparib or niraparib as frontline maintenance treatment between 1 January 2014 and 31 December 2022 were included. Progression-free survival (PFS) was analyzed using the Kaplan–Meier method, and adverse events associated with PARP inhibitor treatment were investigated. Results: Ninety-six patients treated with PARP inhibitors were identified. The median follow-up period was 21.8 months (95% confidence interval [CI] 19.4–24.0). Twenty (20.1%) patients experienced disease progression, and two patients died. The median PFS was 45.3 months (95% CI 39.4–NA). BRCA1 or BRCA2 gene mutations and primary cytoreductive surgery were associated with better PFS. Adverse events of any grade occurred in 74 (77.1%) patients. Nineteen (19.8%) patients experienced PARP inhibitor therapy interruptions, and 35 (36.5%) patients experienced dose reductions. Only three patients discontinued the drug due to adverse events. Conclusions: In a real-world setting, PARP inhibitors showed efficacy comparable to that reported in published randomized controlled trials and had acceptable safety profiles.

Efficacy and safety of long-term edoxaban treatment for low body weight cancer patients with isolated distal deep vein thrombosis: a post-hoc subgroup analysis of the ONCO DVT study

Abstract Background Low body weight is known to be a bleeding risk in the anticoagulation treatment. ONCO DVT study revealed that 12-month edoxaban treatment for cancer patients with isolated distal deep vein thrombosis (DVT) reduced a composite outcome of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death compared with 3-month edoxaban treatment. However, the efficacy and safety of long-term edoxaban treatment for cancer patients with low body weight is unclear. Purpose In this subgroup analysis, we assessed the efficacy and safety of 12-month edoxaban treatment for low body weight cancer patients with isolated distal DVT. Methods We conducted a post-hoc subgroup analysis of the ONCO DVT study in the low body weight patients. ONCO DVT study was a multicenter, open-label, adjudicator-blinded, randomized clinical trial. Cancer patients with isolated distal DVT were assigned to 12-month or 3-month edoxaban treatment. The primary endpoint was a composite outcome of a symptomatic recurrent VTE or VTE-related death at 12 months. The major secondary endpoint was major bleeding at 12 months. We enrolled patients who met low body weight defined in Japanese Version of High Bleeding Risk criteria (&amp;lt;55 kg for men, &amp;lt;50 kg for women) and evaluated the efficacy and safety of 12-month edoxaban treatment using logistic regression models and log-rank test. Results Among 601 patients in the intention-to-treat population of ONCO DVT study, 322 patients (53.6%) met low body weight: 151 patients were in 12-month edoxaban group and 171 patients were in 3-month edoxaban group. The body weight was similar between two group (47.1±5.2 kg in 12-month edoxaban group vs. 46.9±5.4 kg in 3-month edoxaban group; P=0.77). All of them used a lower dose edoxaban (30 mg once daily) following the dose reduction criteria. 12-month edoxaban group had lower rates of the primary endpoint compared with 3-month edoxaban group (2 patients (1.3%) vs. 10 patients (5.8%); Odds ratio 0.22 [95% CI, 0.05–1.00]; Log-rank P=0.036). There was no significant difference in the major secondary endpoint of major bleeding (12 patients (7.9%) in 12-month edoxaban group vs. 16 patients (9.4%) in 3-month edoxaban group; Odds ratio 0.83 [95% CI, 0.38–1.83]; Log-rank P=0.65). All clinically relevant bleeding events occurred in 22 patients (14.6%) in 12-month edoxaban group and in 27 patients (15.8%) in 3-month edoxaban group (Odds ratio 1.40 [0.90–2.19]; Log rank P=0.13), resulting in the comparable risk of bleeding in the 12-month edoxaban group. Conclusions Our study suggests that 12-month edoxaban treatment for low body weight cancer patients with isolated distal DVT prevents recurrent VTE or VTE-related death without increasing the risk of bleeding compared to 3-month edoxaban treatment.primary endpointsecondary endpoint

Angiotensin receptor-neprilysin inhibitor (Sacubitril/Valsartan) in cancer therapy-related cardiac dysfunction: real-world experience from a nurse-led cardio-oncology clinic

Abstract Introduction Cancer therapy-related cardiac dysfunction (CTRCD) is a common toxicity amongst patients receiving anti-cancer treatment1. Angiotensin receptor-neprilysin inhibitor (ARNI) Sacubitril/Valsartan is recommended to reduce Heart Failure (HF) admissions and cardiovascular mortality2. However, patients with active cancer were excluded from the key trials of ARNI. This study aims to provide a real-world experience of ARNI prescription and management from the perspective of a nurse-led Cardio-Oncology clinic. Methods This is a single centre, retrospective, observational cohort study performed at a Cardio-Oncology specialist centre between the period of 2021 to 2024. Adult cancer patients receiving anti-cancer therapy were included if they had symptomatic HF or asymptomatic CTRCD, were initiated on ARNI and followed up in the nurse-led Cardio-Oncology clinic. Results Twenty-nine patients were started on ARNI (see Figure 1). The mean age of the patients was 66+11 years and 17 (59%) were male. Cardiovascular risk factors were common: hypertension (45%), hyperlipidaemia (35%), diabetes mellitus (21%), and smoking (17%). Haematological and breast malignancies were most common (31% and 21% respectively), followed by gynaecological malignancies (14%). Twenty-one (72%) were treated with cytotoxic chemotherapy including 10 (35%) received anthracyclines. Five (17%) patients received human epidermal growth factor receptor 2 (HER2) targeted therapies, 3 (10%) were on tyrosine kinase inhibitors, and 2 (7%) received immunotherapy. Twenty-five (86%) patients presented with symptomatic HF while 4 (14%) had asymptomatic CTRCD. The median N-terminal-pro B-type natriuretic peptide (NTproBNP) level was elevated at 1325(806-4330)ng/L. Thirteen (45%) patients tolerated the maximum dose of 200mg twice daily, while 16 (56%) could only tolerate middle and lowest dosages. ARNI dose up titration to the maximum tolerated dose took 26 (15-79) days. Twenty-eight (97%) patients were on beta blockers, 26 (90%) received SGLT2 inhibitors, 25 (86%) on mineralocorticoid receptor antagonists, and 10 (35%) patients required diuretics. The most common side effect was symptomatic hypotension in 11 (38%) patients. Two (7%) had hyperkalemia, 1 (3%) acute kidney injury following initiation, and 1 (3%) had dizziness without significant hypotension. Nine (31%) required dose reduction allowing ARNI to be continued, while 3 (10%) patients had to permanently discontinue ARNI. There were no cardiovascular deaths, cancer deaths or HF admissions. Conclusion The Cardio-Oncology nurse-led clinic permits rapid up-titration of ARNI to target dosages in patients with CTRCD, resulting in significant improvements in cardiac function. The nurse lead clinic education, support and side effect management allowed uninterrupted continuation of cancer treatment. Whether this approach translates into be better cardiac and cancer outcomes requires further study.

The Impact of Reduced Immunosuppression on Alloimmunity: A Retrospective Study of Pediatric Kidney Transplant Recipients.

Kidney transplantation is the best treatment for end-stage kidney disease but requires immunosuppressive medications, which have significant side effects. Many pediatric recipients experience these side effects, leading to dosage reductions, which potentially increase the risk of alloimmunity. We aimed to describe the alteration in immunosuppressive medication, explore the reasons for the reductions, and assess the potential impact on alloimmunity. Data from 49 pediatric kidney transplant recipients receiving an allograft from 2009 to 2020 were retrospectively studied. The recipients were screened for HLA antibodies after the transplantation. The median age of recipients was 11 years (IQR 8), with a median follow-up of 5 years (IQR 5). Eighty percent of the transplantations were corticosteroid-free. During follow-up, 11% developed de novo donor-specific antibodies (dnDSA), and 60% had detectable HLA antibodies. The 1-year rejection rate was 4%. Immunosuppressive medication was altered substantially in most recipients, resulting in 72% being on mono- or dual therapy with a reduced mycophenolate mofetil (MMF) dosage by the end of the first posttransplant year. The median MMF dose was nearly half of the intended. Tacrolimus levels were maintained close to the target of 5 ng/mL. No association was found between reduced immunosuppression and dnDSA or rejections. Reductions were primarily due to MMF-related side effects: leukopenia in 77%, gastrointestinal issues in 34%, and infections with Epstein-Barr virus, cytomegalovirus, and BK polyomavirus in 49%. Reduced MMF with a sufficient trough tacrolimus level in a population of mainly corticosteroid-free pediatric kidney transplant recipients did not lead to unacceptable alloimmunity.

Dosimetric optimization for dynamic mixed beam arc therapy (DYMBARC).

Non-coplanarity and mixed beam modality could be combined to further enhance dosimetric treatment plan quality. We introduce dynamic mixed beam arc therapy (DYMBARC) as an innovative technique that combines non-coplanar photon and electron arcs, dynamic gantry and collimator rotations, and intensity modulation with photon multileaf collimator (MLC). However, finding favorable beam directions for DYMBARC is challenging due to the large solution space, machine component constraints, and optimization parameters, posing a highly non-convex optimization problem. To establish DYMBARC and solve the pathfinding challenge by employing direct aperture optimization (DAO) to determine the table angles and gantry angle ranges of photon and electron arcs for different clinically motivated cases. The method starts by generating a grid of beam directions based on user-defined resolutions along the gantry and table angle axes for each beam quality considered. Beam directions causing collisions or entering through the end of CT are excluded. For electrons, a fixed source-to-surface distance of 80cm is used to reduce in-air scatter. Electron beam energies with insufficient range to reach the target or beam directions impinging on the table before reaching the patient are excluded. The remaining beam directions form the pathfinding solution space. Promising photon and electron MLC-defined apertures, with associated monitor unit (MU) weights, are iteratively added using a hybrid-DAO algorithm. This algorithm combines column generation to add apertures and simulated annealing to further refine aperture shapes and weights. Apertures are added until the requested number of paths are formed and the user-defined maximum total gantry angle range is reached. Paths are resampled to a finer gantry angle resolution and subject to DAO for simultaneous optimization of beam intensities along the photon/electron arcs. Subsequent final dose calculation and MU weight reoptimization result in a deliverable DYMBARC plan. DYMBARC plans are created for three clinically motivated cases (brain, breast, and pelvis) and compared to DYMBARC variants: colli-DTRT (dynamic collimator trajectory radiotherapy) using non-coplanar photon arcs; and Arc-MBRT (mixed beam radiotherapy) using photons and electrons but restricted to coplanar setup. Additionally, a manually defined volumetric modulated arc therapy (VMAT) setup serves as a reference clinical technique. Dose distributions, dose-volume histograms, and dosimetric endpoints are evaluated. Dosimetric validation with radiochromic film measurements (gamma evaluation, 3% / 2mm (global), 10% dose threshold) is performed on a TrueBeam system in developer mode for one case. While maintaining similar target coverage and homogeneity, DYMBARC reduced mean doses to organs-at-risk compared to VMAT by an average of 3.2, 0.5, and 2.9Gy for the brain, breast, and pelvis cases, respectively. Similar or smaller mean dose reductions were observed for Arc-MBRT or colli-DTRT, compared to VMAT. Electron contributions to the mean planning target volume dose ranged from 2% to 34% for DYMBARC and from 11% to 40% for Arc-MBRT. Measurement validation showed>99.7% gamma passing rate. DYMBARC was successfully established using a dosimetrically optimized pathfinding approach, combining non-coplanarity with mixed beam modality. DYMBARC facilitated the determination of photon and electron contributions on a case-by-case basis, enhancing more personalized treatment modalities.

Mid-term efficacy of single anastomosis duodenal-ileal bypass with sleeve gastrectomy in the treatment of obesity and type 2 diabetes mellitus

Objective: To evaluate the mid-term efficacy of single anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S) in the treatment of obesity and type 2 diabetes mellitus. Methods: The cohort of this retrospective observational study comprised 118 obese patients with body mass index (BMI) ≥40 kg/m2 with or without other related metabolic diseases and BMI of (27.5-40.0) kg/m2 with type 2 diabetes mellitus (T2DM) who had been treated with SADI-S. Patients who had undergone modified surgery or been followed up for less than 1 year were excluded. Clinical data of the included patients [56 men and 62 women aged (34.5±9.7) years], who had undergone SADI-S in China-Japan Union Hospital, Jilin University from October 2018 to August 2022, were collected. Their mean preoperative body mass was (125.9±25.0) kg and BMI (42.8±6.8) kg/m2. The 60 patients with T2DM had a mean fasting blood glucose of (9.9±3.2) mmol/L and HBA1c of (8.4±1.7) % before surgery. The main outcome measures were mid-term weight loss after surgery (body mass, BMI, excess weight loss, and total weight loss) 1, 2, 3, and 4 years after surgery and efficacy regarding diabetes mellitus (fasting blood glucose, glycated hemoglobin and diabetes remission rate at 1, 2, and 3 years after surgery). Outcomes were defined as follows. Complete remission: HbA1c <6% or fasting blood glucose <6 mmol/L without hypoglycemic medication; partial remission: HBA1c <6.5% or fasting blood glucose <7 mmol/L without hypoglycemic medication; significant improvement: HBA1c <7.0%, stable decrease of at least 1% compared with preoperative HBA1c, and postoperative dose of hypoglycemic medication significantly less; ineffective: no change in HBA1c and no reduction in dosage of hypoglycemic medication. Other outcome measures included intraoperative and postoperative adverse effects and postoperative nutritional indexes. Results: SADI-S was successful in all patients. There was no significant bleeding, conversion to open surgery, or perioperative death. The operation time was (186.1±41.5) minutes, and the postoperative hospital stay 6 (5-7) days. Surgical complications occurred in four patients, comprising peritoneal effusion, internal jugular vein thrombosis, anastomotic leakage, and gastric fistula. Body weight and BMI 1, 2, 3 and 4 years were significantly lower post- than pre-operatively (all P<0.05). Excess weight loss was (81.9±16.2) %, (82.2±15.5) %, (88.3±20.1) %, and (83.2±18.1) % at 1, 2, 3, and 4 years postoperatively, respectively. Total weight loss was (39.7±8.7) %, (40.6±10.6) %, (42.2±11.5) % and (45.4±10.2) %, respectively. The mean fasting blood glucose concentrations of the 60 patients with T2DM were (5.1±1.0) mmol/L, (5.0±0.7) mmol/L, and (5.4±0.9) mmol/L 1, 2 and 3 years postoperatively, respectively. The values for glycosylated hemoglobin were (4.9±0.6) %, (4.8±0.5) %, and (5.1±0.8) %, respectively, all of which are significantly lower than preoperatively (all P<0.05). The complete remission rate of diabetes was 95.0% (38/40), 90.0% (36/40), and 9/13 1, 2, and 3 years postoperatively, respectively. Additionally, the partial remission rate and significant improvement rate were both 100%. Two years postoperatively, the incidence of anemia was 27.8% (10/36), of hypoproteinemia 11.8% (4/34), and of ferritin deficiency 25.8% (8/31), all of which were improved by conservative treatment such as blood transfusion, iron supplementation, and adjustment of diet. Conclusion: SADI-S has a significant mid-term beneficial effect on weight loss and diabetes remission status in patients with obesity and type 2 diabetes.

Research on Catalytic Pyrolysis Process of Coconut Coat of Tropical Agricultural and Forestry Wastes

The effects of reaction temperature, reaction time, heating rate, nitrogen flow rate, and catalyst quality on the oil yield and oxygen content in oil were investigated by using the single-factor principle. Too high and too low reaction temperature, nitrogen flow rate, heating rate, and reaction time improved the yield of bio-oil, but the oxygen content in bio-oil was higher. The reduction in catalytic dose is beneficial to the increase in oil yield but not conducive to the increase in aromatic compound content. The optimal reaction conditions were observed as a reaction temperature of 500 °C, a nitrogen flow rate of 110 mL/min, a heating rate of 20 °C/min, a reaction time of 15 min, a mass ratio of catalyst to coconut coat powder of 1, an oil yield of 4.97%, a water yield of 35.80%, and a solid yield of 30.78%. The gas yield was 28.45%, the oxygen content was 10.3%, and the aromatic compound content was 89.7%. The analysis of the catalytic cracking mechanism shows that most of the oxygen-containing compounds in bio-oil are generated into water and aromatic compounds by a catalytic cracking reaction at high temperature, thus removing oxygen.

Outcomes of Radiation Dose Reduction Protocol in Electrophysiologic and Cardiac Device Procedures

Background: Exposure to radiation has been demonstrated to be associated with adverse short- and long-term health outcomes. Objective: To presented outcomes before and after the implementation of a radiation dose reduction protocol in electrophysiologic (EP) and cardiac device procedures. Materials and Methods: The present study was a retrospective comparative study, conducted at Chiang Mai University Hospital in Thailand using 2017 and 2019 data, including all patients who underwent EP and cardiac implantable electronic device (CIED) procedures. Exclusion criteria involved patients with incomplete radiation dose records. The authors compared fluoroscopic time, radiation exposure, and complication rates before and after the protocol. Results: Among the 458 cases, with 214 Eps and 244 devices, the mean age was 58 years. For device implantation procedures, there was no significant change in fluoroscopic time as median (P₂₅, P₇₅) before and after protocol implementation were 3.1 (0.4, 5.8) versus 4.4 (1.2,7.6) minutes, respectively (p=0.117). However, there was a decreasing trend in dose area product (DAP) at 242.0 (119.2, 766.0) versus 197.9 (71.5, 494.5) cGy.cm² (p=0.073). The reduction in DAP was more pronounced in cardiac resynchronization therapy (CRT) implantation when comparing 2017 to 2019 were 1,933.6 (1,039.4, 7,683.8) versus 1,074.6 (427.2, 2,890.7) cGy.cm² (p=0.020). In EP procedures, fluoroscopic time significantly decreased from 8.1 (3.0, 14.3) minutes in 2017 to 1.0 (0.0, 3.6) minute in 2019 (p&lt;0.001), accompanied by a significant reduction in exposure dose of 45.0 (10.8, 153.3) versus 1.7 (0.0, 31.6) mGy (p&lt;0.001) and DAP of 1,022.9 (247.2, 2,660.3) versus 38.5 (0.0, 566.9) cGy.cm² (p&lt;0.001). There was no difference in the complication rate between the two periods. Conclusion: The implementation of the radiation dose reduction protocol resulted in a significant decrease in radiation exposure during EP procedures and showed a trend towards reduction in CIED procedures.

Assessing causality in deprescribing studies: A focus on adverse drug events and adverse drug withdrawal events.

Generating real-world evidence about the effect of medication discontinuation or dose reduction on outcomes, such as reduction of adverse drug effects (ADE; intended benefit) and occurrence of adverse drug withdrawal events (ADWE; unintended harm), is crucial to informing deprescribing decisions. Determining the causal effects of deprescribing is difficult for many reasons, including lack of randomization in real-world study designs and other design and measurement issues that pose threats to internal validity. The inherent challenge is how to identify the effects, both intended benefits and unintended harms, of a new medication stoppage or reduction when implemented in patients with many potential clinical and social risks that may influence the likelihood of deprescribing as well as outcomes. We discuss methodological issues of estimating the effect of medication discontinuation or reduction on risk of ADEs and ADWEs considering: (1) sampling study populations of sufficient size with the potential to demonstrate clinically meaningful and quantifiable outcomes, (2) accurate and appropriately timed measurement of covariates, outcomes, and discontinuation, and (3) statistical approaches to managing confounding and other biases inherent in long-term medication use by individuals with multiple morbidities. Designing rigorous deprescribing studies that address internal validity threats will support evidence generation by improving the ability to assess benefits and harms when the exposure of interest is the absence of a medication. Iterative learnings about data quality, variable definition, variable measurement, and exposure-outcome associations will inform strategies to improve the causal inferences possible in real-world deprescribing studies.

Low-dose radiographic inspection of welding by a novel aperiodic reverse stochastic resonance method

Abstract Low-dose radiographic inspection is a growing trend in industry to minimize radiation risks to humans and the environment. However, reduction in radiation dose often introduces significant noise, which affects image quality and hinders accurate identification of subtle defects. This study addresses this issue by introducing a novel phenomenon called aperiodic reverse stochastic resonance (ARSR), observed in nonlinear systems excited by aperiodic binary signals. ARSR enables simultaneous amplitude amplification and reversal of signals under specific noise conditions. Leveraging ARSR, we propose an image denoising framework for low-dose radiographic inspections. First, a set of projection data is obtained by using Radon transform to reduce the dimensionality of X-ray images from different angles. Then, the projection data is modulated based on the ARSR system. Finally, the image is reconstructed based on the inverse Radon transform. Simulations and experimental comparison results in welding applications validate the effectiveness of the framework, demonstrating significant improvements in image quality for low-dose radiographic defect detection. Unlike advanced methods such as Gaussian filtering, BM3D, and DnCNN, which operate at the pixel level, ARSR performs denoising at the projection data stage, reducing noise impact, preserving original information, and focusing on physical data processing during imaging. This approach enhances the detection of subtle defects, highlighting the potential of stochastic resonance in image processing.

Burosumab in adults with X-linked hypophosphatemia: real-world experience from a retrospective study in Sydney

Abstract X-linked hypophosphatemia (XLH) is a chronic disabling hereditary musculoskeletal disorder associated with inactivating PHEX mutations and elevated circulating FGF-23 concentrations. In a placebo-controlled trial of adults with XLH, burosumab (anti-FGF-23 antibody) demonstrated durable improvements in phosphate concentrations, and self-reported stiffness and physical limitation. However, real-world data regarding burosumab efficacy and tolerability in adults with XLH is lacking. A retrospective audit was performed of patients (age ≥ 18-years) who commenced four-weekly subcutaneous burosumab for XLH at Royal North Shore and Westmead Hospitals, Sydney, between January 2021 and June 2024. Patients were managed per standard clinical care and burosumab dose adjusted as necessary according to manufacturer instructions. Electronic medical records were reviewed to collate data regarding patient demographics, XLH-related complications and prior treatment, burosumab dosage and side effects, and pre- and post-burosumab biochemistry and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores. Of thirteen adults with XLH, all had hypophosphatemia before commencing burosumab (mean 0.64 ± 0.08 mmol/L). Mean WOMAC scores demonstrated baseline impairments in stiffness, pain and physical limitation. Burosumab was administered for median 15 months during follow-up (median dose 70 mg). Hypophosphatemia resolved in all patients within three months of burosumab (mean 1.03 ± 0.38 mmol/L). Two patients developed hyperphosphatemia two weeks after commencing burosumab requiring dose reduction. One patient ceased burosumab in the setting of hypercalcaemia and constipation secondary to pre-existing tertiary hyperparathyroidism. Adverse events were mild, including transient musculoskeletal discomfort (n = 4), restless legs (n = 2), injection site reaction (n = 2) and headache (n = 1). Repeat WOMAC within 12 months of commencing burosumab (n = 9) demonstrated clinically meaningful improvements in stiffness (-33.3 ± 12.5, P&amp;lt;.001) and physical function (-14.3 ± 16.2, P=.029). This study reports real-world outcomes of adults with XLH treated with burosumab. Clinical experience from two centres in Sydney support trial findings that burosumab is well-tolerated and associated with improved serum phosphate concentrations and self-reported stiffness and physical function.