Patient Dose Optimization Research Articles

Efficacy and Safety of Naldemedine for Opioid-Induced Constipation in Children.

Background: Naldemedine, a peripherally acting opioid μ receptor antagonist, is effective for prevention of opioid-induced constipation (OIC); however, evidence on its use in children is limited. Objective: To evaluate the efficacy and safety of naldemedine in pediatric patients with OIC. Design, Setting/Subjects: Retrospective analysis of 32 pediatric patients with OIC treated with naldemedine in a single institution in Japan from June 2017 to March 2021. Measurements: Efficacy was evaluated in 13 evaluable patients with bowel movement (BM) response, defined as those with at least three BMs in the first 7 days after naldemedine initiation and an increase of at least one BM from baseline. Safety was evaluated by examining adverse events (AEs) based on the Common Terminology Criteria for AEs (v5.0). Results: BM response was recorded in 11 of the 13 patients (85%), and the number BMs per day significantly increased from 0.43 before naldemedine to 1.00 after naldemedine (p = 0.025). The most common AE was diarrhea, observed in 16 of the 32 patients (50%), and all instances were grade 1 or 2. In three of the 16 patients, naldemedine was discontinued owing to worsening diarrhea. Conclusions: In pediatric patients, naldemedine resulted in a high rate of BM response and increased the BM frequency, indicating its efficacy. In some patients, grade 2 diarrhea required naldemedine discontinuation, suggesting that it should be used with caution in pediatric patients. Further studies are warranted to determine the optimal naldemedine dose in pediatric patients.

Physiologically based pharmacokinetic models for predicting lamotrigine exposure and dose optimization in pediatric patients receiving combination therapy with carbamazepine or valproic acid.

Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug-drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients. Adult and pediatric PBPK models for LTG and VPA were developed using PK-Sim® software in combination with physiological information and drug-specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data. Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2-6 years) and school-aged children (6-12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12-18 years) were similar to those in adults at the same doses. We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population.

Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial

Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer. DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting). Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5). The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both. Daiichi Sankyo and AstraZeneca.

Development of Acceptable Quality Dose (AQD) and image quality-related diagnostic reference levels for common computed tomography investigations in a tertiary care public sector hospital of Khyber Pakhtunkhwa, Pakistan.

To describe the first experience of patient dose optimization in developing AQD, SSDE and image quality-related DRLs for common CT examinations in the adult age group using the concept of AQD. The recent published IQSC from 0 to 4 were used by radiologists for the assessment of image quality. The entire data were collected for five types (brain CT, chest CT, chest HRCT, abdomen KUB CT and abdomen + pelvic CT) CT investigations based on anatomic region (head, chest and abdomen + pelvic). The entire datasets of 264 patients were categorized into three groups based on their weights: group-1 (41-60kg), group-2 (61-80kg) and group-3 (81-100kg). Only score-3 images were considered to assess median and 75th percentile values of CTDIvol and DLP to obtain AQDs and DRLs, respectively. Following the practical training of four radiologists on image quality scoring criteria for CT images, 264 (92%) out of 288 patient images were clinically acceptable as per IQSC for the study. The AQD (median) values in terms of CTDIvol for the mentioned weight groups were 25.8, 2.7, and 30.6mGy, while the median DLP values for these groups were 496, 510 and 557 mGycm, respectively, for brain CT. The 75th percentile values in terms of CTDIvol were 30.2, 35.3 and 36.2mGy, while in terms of DLP, they were 583, 619 and 781 mGycm for brain CT, respectively. Similar results are presented for the above-mentioned procedures, as well as in terms of SSDE. The first ever experience in obtaining AQD, SSDE and DRLs values for specific CT procedures couples image quality with dose indices, showing comparable values with other relevant studies. Hence, it will provide a baseline for comparison within the facility for future studies and facilitate dose optimization for other facilities aiming for improvement.

Impact of relative cisplatin dose to skeletal muscle mass on adverse events in patients with head and neck cancer undergoing chemoradiotherapy.

Chemoradiotherapy (CRT) with high-dose cisplatin (CDDP) is the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC). Although dosing is based on body surface area (BSA), some patients experience CDDP-related adverse events (AEs). We aimed to evaluate the impact of relative CDDP dose to skeletal muscle mass (SMM) on chemotherapy-associated AEs in patients with HNSCC undergoing CRT with high-dose CDDP. We retrospectively analyzed data of patients who underwent CRT with high-dose CDDP (80-100 mg/m2, triweekly) between 2010 and 2023. SMM was measured as the cross-sectional muscle area at the third cervical vertebra (C3-SMM) using computed tomography; the skeletal muscle index (SMI) was defined as SMM normalized by squared height. The CDDP index was defined as the prescribed CDDP dose divided by SMI. CDDP-related AEs were assessed during the first cycle using Common Terminology Criteria for Adverse Events v5.0. Overall, 306 patients were identified. The CDDP index cutoff value best associated with grade ≥ 3 AEs was 10.312. Grade ≥ 3 hematological toxicities exhibited stronger association with high CDDP index value than with low CDDP index value (26.9% vs 16.3%, P = .033). Multivariate analysis revealed that high CDDP index value and creatinine clearance < 70 mL/minute were predictive factors for grade ≥ 3 AEs (odds ratio [OR] 2.55, P = .008; OR 3.68, P = .002, respectively). The CDDP index based on C3-SMM was an independent predictive factor for grade ≥ 3 CDDP-related AEs. C3-SMM is potentially more useful than BSA for determining the optimal CDDP dose in patients with HNSCC.

Combined effect of CYP2C19 and CYP2D6 genotypes on escitalopram serum concentration and its metabolic ratio in a European patient population.

The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population. Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.

Dose optimization and exposure-response analyses to support optimal dose of ABBV-400, a novel C-met–targeting antibody drug conjugate, in patients with metastatic colorectal cancer (mCRC).

3030 Background: ABBV-400 is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody conjugated to a potent inhibitor of topoisomerase 1 (Top1) payload. ABBV-400 has shown encouraging activity and demonstrated tolerability of dosages up to 3.0 mg/kg Q3W as monotherapy in patients with advanced solid tumors in an ongoing phase 1 study (1). Dosage optimization is a critical aspect of oncology drug development and FDA Project Optimus has focused on reformulating the dosage selection paradigm for oncology products. The phase 1 study included a dose optimization phase in mCRC patients in which 3 doses were evaluated (1.6, 2.4 and 3.0 mg/kg Q3W) to determine the optimal dose for further development. Herein, exposure-response analyses are reported to determine optimal monotherapy dose in mCRC patients. Methods: Data across a range of doses (1.6 – 6.0 mg/kg Q3W) from the phase 1 study (NCT05029882) were used. Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to characterize ABBV-400 conjugate and unconjugated payload PK and the relationship between exposures and efficacy (objective response rate [ORR]) and safety (Grade (Gr) ≥ 3 neutropenia, anemia and thrombocytopenia) endpoints. Relative dose intensity (RDI) analysis was performed. Results: ABBV-400 conjugate and payload PK were adequately described by a combined multi-analyte population PK model with first order kinetics (n=204). ABBV-400 conjugate average concentration was a better predictor of response and showed that higher exposure correlated with higher probability of response (n=122 CRC, ORR, p &lt; 0.05) and safety events (n=204, Gr ≥ 3 neutropenia, anemia and thrombocytopenia, p &lt; 0.001). Dose intensity analyses showed greater number of dose reductions for 3 mg/kg Q3W with effective (actual) dose received of 2.6 mg/kg Q3W in mCRC patients. E-R analyses for safety and efficacy and dose intensity analyses in mCRC 3L+ patients indicate that both 2.4 and 3.0 mg/kg doses provided meaningful efficacy (ORR); while the 3.0 mg/kg dose may provide higher response rates, the 2.4 mg/kg Q3W dosing regimen provides an optimal balance of safety and efficacy compared to 3.0 mg/kg Q3W. Conclusions: Population PK, E-R for efficacy and safety and RDI analyses and totality of clinical data supported the selection of 2.4 mg/kg Q3W as optimal ABBV-400 monotherapy dose for further study in mCRC patients. 1. Sharma M, et al. ASCO 2023. Abstract 3015. Clinical trial information: NCT05029882 .

Ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib dose optimization in patients with biomarker-selected advanced solid tumors (TRESR study).

Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects. Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on, 1 week off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating tumor DNA (ctDNA)-based molecular response rate. The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (hazard ratio = 0.23, 2-sided P = .02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity. The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering a substantial reduction in the incidence of anemia without any compromise to efficacy. NCT04497116.

DRL as a common language in patient dose reduction and optimization: A short note from AsiaSafe in 2024 RCRT-RST Annual Congress, Bangkok, Thailand

The AsiaSafe Asian Oceanian Symposium at the 2024 RCRT-RST Annual Congress discussed the situation and role of radiology in patient dose reduction and optimization using Diagnostic Reference Levels (DRLs) as a common language. The scientific committee of the Royal College of Radiologists of Thailand (RCRT) and Radiological Society of Thailand (RST) established the Collaboration Symposia to discuss hot health topics with participated Asian Radiological societies. At the 2024 RCRT-RST Collaboration Symposia, different views, initiatives, and ideas were presented by representatives from societies.

An audit of patient radiation doses during interventional cardiology procedures in Uttarakhand, India, and establishment of local diagnostic reference levels.

The objective of this study was to investigate patient radiation doses by a dose audit of three common interventional cardiology (IC) procedures: coronary angiography (CA), percutaneous transluminal coronary angioplasty (PTCA) and CA-PTCA procedures performed in IC centres in the Uttarakhand state of India, for the establishment of local diagnostic reference levels (DRLs) and the estimation of average effective dose (Eav) for these procedures. For each procedure, the values of kerma-area product (PKA), reference air kerma (Ka,r), fluoroscopy time (FT) and the number of cine images were recorded from 1233 CA, 458 PTCA and 736 CA-PTCA procedures performed over a 12-month period at 13 IC centres of the state. From the recorded dose data, 0.6%, 1.53% and 7.9% patients were identified to have exceeded the PKA trigger level of 500 Gy cm2 for possible skin injury for CA, PTCA and CA-PTCA procedures, respectively. The 3rd quartile of the distribution of the recorded PKA values for each type of procedure was calculated to estimate local DRL values. The estimated values of DRLs and Eav were 37, 153 and 224 Gy cm2, and 6.72, 23.97 and 34.79 mSv for CA, PTCA and CA-PTCA procedures, respectively. For about 77% of the surveyed centres, the recorded patient doses were in agreement with the international standards. The local DRLs proposed in this study may be used to achieve patient dose optimization during IC procedures and the obtained patient dose data may also be archived into national dose database for the establishment of national DRLs.

Multi-institutional study of osimertinib dose-optimization in non-small cell lung cancer patients with EGFR activating mutation aged 70years or older ('MONEY' trial).

Osimertinib is the standard of care for patients with epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer. Dose-toxicity has been previously reported, but no dose-response data within the range of 20-240mg daily (mg/d). Thus, the current 80mg/d dosing might be too high for elderly Japanese patients with an average body weight of only 50kg, resulting in excessive toxicity and cost. We therefore initiated a study to investigate whether osimertinib at 40mg/d is non-inferior to 80mg/d in patients with advanced or recurrent epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer aged ≥70years, using a regression discontinuity design. Osimertinib is administered at 40mg/d for body weight ≤50kg, and 80mg/d for body weight >50kg. The primary endpoint is progression-free survival. Sample size is 550 patients, based on a non-inferiority margin of the progression-free survival hazard ratio 1.333, 0.10 one-sided type I error and 80% power.

First implementation of quality control procedures on selected X-ray machines in South of Benin

Abstract Introduction: The use of X-ray equipment for medical diagnostic radiography procedures has increased due to advances and complexity of radiological procedures. Achieving good image quality while keeping exposure of workers, public and patient exposure to an acceptable level has become a prerequisite for the radiology department in order to comply with best international practices. The aim of this study was to undertake quality control measurement of seven (7) diagnostic radiography equipment in the south of Benin, the first of its kind. Material and methods: Multifunction detector (Piranha) and beam alignment test tool were used to perform quality control tests on seven (7) X-ray units. The method used as well as the interpretation of the results was based on the American Association of Physicists in Medicine (AAPM), United States Food and Drug Administration (FDA), Healing Arts Radiation Protection (HARP), Institute of Physics and Engineering in Medicine (IPEM), International Atomic Energy Agency (IAEA) and Canadian Safety code 35 (S.C 35) recommendations. Results: The quality control results showed that all X-ray equipment investigated were within standard limits for accuracy of exposure time below 10 ms; reproducibility of kVp, exposure time and dose output; specific dose-kVp2 linearity; and specific dose-mAs linearity. Five (5) out of seven (7) diagnostic X-ray machines passed quality control tests such as X-ray beam alignment, exposure time above 10 ms and kVp accuracy. One (1) X-ray machine failed the quality control test of beam filtration at 70 kVp and above. Conclusions: The findings of this study have provided baseline data for other radiology departments to embark on similar QA/QC activities, and also explore options for optimization of patient dose. However, there is a need to extend the study to cover more diagnostic X-ray machines throughout the country. It is anticipated that this would ultimately assist in improving radiation protection and safety during medical diagnostic radiological procedures.

A Comprehensive Physiologically Based Pharmacokinetic Model of Nadolol in Adults with Renal Disease and Pediatrics with Supraventricular Tachycardia.

Nadolol is a long-acting non-selective β-adrenergic antagonist that helps treat angina and hypertension. The current study aimed to develop and validate the physiologically based pharmacokinetic model (PBPK) of nadolol in healthy adults, renal-compromised, and pediatric populations. A comprehensive PBPK model was established by utilizing a PK-Sim simulator. After establishing and validating the model in healthy adults, pathophysiological changes i.e., blood flow, hematocrit, and GFR that occur in renal failure were incorporated in the developed model, and the drug exposure was assessed through Box plots. The pediatric model was also developed and evaluated by considering the renal maturation process. The validation of the models was carried out by visual predictive checks, calculating predicted to observed (Rpre/obs) and the average fold error (AFE) of PK parameters i.e., the area under the concentration-time curve (AUC0-t), the maximum concentration in plasma (Cmax), and CL (clearance). The presented PBPK model successfully simulates the nadolol PK in healthy adults, renal-impaired, and pediatric populations, as the Rpre/obs values of all PK parameters fall within the acceptable range. The established PBPK model can be useful in nadolol dose optimization in patients with renal failure and children with supraventricular tachycardia.

Factors associated with cavity formation after stereotactic body radiation therapy for peripheral early-stage lung cancer.

This retrospective study aimed to identify the factors associated with cavity formation after SBRT in peripheral early-stage lung cancer patients. We analyzed the occurrence of cavity changes after SBRT. We examined 99 cases with T1-T2aN0 peripheral non-small cell lung cancer treated with SBRT from 2004 to 2021. Patients underwent respiratory function tests, including diffusing capacity for carbon monoxide (DLco), before treatment. The median observation period was 35months (IQR 18-47.5months). Treatment involved fixed multi-portal irradiation in 67% of cases and VMAT in 33%. The total radiation doses ranged from 42 to 55Gy, delivered over 4 to 5 fractions. Cavity formation occurred in 14 cases (14.1%), appearing a median of 8months after SBRT. The cavity disappeared in a median of 4months after formation. High DLco and total radiation dose were identified as factors significantly associated with cavity formation. There have been no confirmed recurrences to date, but one patient developed a lung abscess. Although cavity formation after SBRT for peripheral early-stage lung cancer is infrequent, it can occur. This study showed high DLco and total radiation dose to be factors significantly associated with cavity formation. These findings can be applied to optimizing radiation therapy (RT) and improving patient outcomes. Further research is needed to determine the optimal radiation dose for patients with near-normal DLco for whom surgery is an option. This study provides valuable insights into image changes after RT.

Combined pre-treatment and middle-treatment Epstein-Barr virus DNA load contributes to prognostication and treatment modification in nasopharyngeal carcinoma patients.

To investigate whether pre-treatment and middle-treatment plasma Epstein-Barr virus (EBV) DNA loads are useful predictors of prognosis and indicators of therapy modification in nasopharyngeal carcinoma (NPC) patients undergoing radical concurrent chemoradiotherapy (CCRT). Plasma EBV DNA load was measured by quantitative polymerase chain reaction before treatment (pre-DNA) and during the second cycle of DDP (mid-DNA). The primary endpoint was 5-year progression-free survival (PFS). A total of 775 NPC patients treated with CCRT were included. In total, 553 patients with pre-DNA <4000 copies/mL and 222 with ⩾4000 copies/mL. A total of 559 patients had mid-DNA undetectable and 216 had detectable. Multivariate analysis showed that pre- and mid-DNA were independent prognostic predictors of PFS [hazard ratio (HR), 2.035; 95% confidence interval (CI), 1.406-2.944; p < 0.001; HR, 1.597; 95% CI, 1.101-2.316; p = 0.014]. The area under the curve of the combination of pre-DNA and mid-DNA for 5-year PFS was higher than that of pre-DNA, mid-DNA, and tumor node metastasis (TNM) stage (0.679 versus 0.622, 0.608, 0.601). In the low-risk group (pre-DNA <4000 copies/mL and undetectable mid-DNA), patients receiving ⩽200 mg/m2 showed similar efficacy as those receiving >200 mg/m2 cumulative cisplatin dose (CCD) but were associated with fewer all-grade late toxicities. However, in the high-risk group (pre-DNA ⩾4000 copies/mL or detectable mid-DNA), patients receiving >200 mg/m2 CCD showed a higher 5-year PFS (73.1% versus 58.6%, p = 0.027) and locoregional relapse-free survival (88.5% versus 76.1%, p = 0.028) than those receiving ⩽200 mg/m2 CCD. The combination of pre-DNA and mid-DNA could be particularly useful for guiding risk stratification and early treatment modification for NPC treated with CCRT. A total of 200 mg/m2 cisplatin seemed to be the optimal dose for the low-risk patients, while >200 mg/m2 cisplatin may be adequate to achieve satisfactory survival outcomes in the high-risk group.

Current research and future prospects of immunonutrition in gastrointestinal malignancies.

Immune nutrition, as an integral component of nutritional support therapy, has garnered significant attention and research in the treatment of gastrointestinal malignancies. Recent advancements in nutritional formulas containing components such as glutamine, omega-3 polyunsaturated fatty acids, and arginine have led to the development of what is now termed immune nutrition or pharmacological nutrition. These formulations go beyond traditional nutritional support, functioning more like nutritional supplements with pharmacological effects. Patients with gastrointestinal malignancies often experience malnutrition and metabolic disturbances, resulting in immune dysfunction, cytokine dysregulation, and endocrine abnormalities. These issues can compromise intestinal mucosal barrier function, affecting the efficacy and prognosis of anticancer therapies. Recent studies indicate that immune nutrition can modulate specific mechanisms involved in various immune and inflammatory pathways, thereby improving patients' immune status and treatment outcomes. While optimal patient selection, dosing, and timing of immune nutrition are still under investigation, its potential applications in oncology are promising. This article aims to analyze the existing evidence regarding the therapeutic benefits of immune nutrition in gastrointestinal malignancies, offering insights into its clinical standardization and application.

Establishment of an institutional diagnostic reference level for vascular lower extremity computed tomography angiography

About 70% of all collective doses from medical tests come from computed tomography (CT), the primary public radiation exposure source. Patients received higher doses during contrast-enhanced CT procedures (Angiography) than routine CT procedures. The current research aims to quantify the patients' radiation doses, estimate the cancer risk probability, and establish institutional diagnostic reference level (IDRL) during lower extremity angiography. One hundred eleven patients (61.3% male and 38.7% female) underwent contrast-enhanced CT procedures. A 160-Slice CT scanner was used for image acquisition for all patient populations. IDRL values were quantified based on the 3rd quartile value of the CT dose descriptors. All procedures were carried out at Al-Moaallim Medical City, Khartoum, Sudan. A computer software (CT-Expo, ImPACT) was used to extrapolate the effective dosage per extremity CTA examination was estimated. The mean patient age (years) was 56.1 ± 18 (18–82). The patient’s radiation doses was quantified using volume CTDI and dose length product (DLP) to 7.3 ± 2 (2.9–16.8) (mGy) and 3712 ± 126 (279–8374) (mGy.cm), respectively. The average effective doses were 22 mSv (range: 1.7–50) per lower CT angiography for the lower extremity. The proposed IDRL for the VCTA procedure was 3562 mGy cm and 17 mGy for DLP and CTDIvol, respectively. The proposed IDRL is higher than the previously published studies; therefore, patient dose optimization is recommended.

ENTERPRET: A Randomized Controlled Trial of Vedolizumab Dose Optimization in Patients With Ulcerative Colitis Who Have Early Nonresponse

BACKGROUND & AIMSPatients with ulcerative colitis (UC) may experience nonresponse to biologics, possibly due to low drug exposure. This trial assessed the efficacy of dose optimization in patients with UC who have early nonresponse to vedolizumab and high drug clearance. METHODSENTERPRET was a phase 4, open-label, randomized controlled trial that included patients with moderate to severe UC who had high drug clearance at week 5 (serum concentration <50 μg/mL) and nonresponse to standard vedolizumab treatment at week 6. At week 6, eligible patients were randomized 1:1 to receive standard dosing (300 mg every 8 weeks) or dose-optimized vedolizumab (600 mg at week 6, then 300 mg every 4 weeks; or 600 mg at week 6, then 600 mg every 4 weeks [based on week 5 serum concentration]). The primary end point was endoscopic improvement at week 30. RESULTSOf 278 enrolled patients, 132 (47.5%) had a clinical response at week 6. From week 6, 108 patients received standard (n = 53) or dose-optimized vedolizumab (n = 55); among patients with nonresponse at week 6, 86.5% had high drug clearance. At week 30, 10 patients (18.9%) who received standard vedolizumab had endoscopic improvement versus 8 patients (14.5%) who received dose-optimized vedolizumab. Five patients (9.4%) who received standard vedolizumab had clinical remission at week 30 versus 5 patients (9.1%) who received dose-optimized vedolizumab; clinical response was observed in 17 (32.1%) and 17 patients (30.9%), respectively. Safety event rates were similar among treatment groups. CONCLUSIONSIn patients with early nonresponse and high drug clearance, vedolizumab dose optimization is probably not required. A proportion of patients benefited from continued treatment irrespective of the dose received. ClinicalTrials.gov Number: NCT03029143.

OPTIMISASI DOSIS DAN KUALITAS CITRA PADA PEMERIKSAAN PULMONARY ARTERY CATHETER (PAC) DAN PERCUTANEUS CORONARY INTERVENTION (PCI) SEBAGAI UPAYA PROTEKSI RADIASI PASIEN DI CATHLAB RSUP ADAM MALIK MEDAN

The radiation exposure a patient receives during diagnosis and treatment cannot be fully avoided. However, it is crucial to optimize the radiation dose to ensure it is only as much as needed. The purpose of this study is to minimize the patient's radiation exposure during interventions and produce optimal image quality. To accomplish this, dose optimization and image quality were evaluated during PAC and PCI procedures in the Cathlab room at Adam Malik Hospital using Philips Allura Xper FD20. The study was retrospective, using patient dose audits from January 2020 to February 2023, with 250 PACs and 139 PCI mature patients. The median dose value (Q2) was compared to the National diagnostic reference level (NDRL) third quartile (Q3) value to determine optimal patient dose levels. We used a 28 cm PMMA phantom and a 2 cm imaging quality in-house phantom to represent the patient and a solid-state detector to measure surface dose. Medical physicists, radiographers, cardiologists, and nurses worked together in optimization cycles to ensure dose levels were kept to a minimum. Image quality was assessed by calculating the signal difference-to-noise ratio (SDNR), and images were recorded in DICOM format and analyzed using Image J software. Entrance Surface Air Kerma (ESAK) values were recorded to calculate Figure of Merit (FOM) values for each change in physical parameters. The study showed that the distance between the image detector and the object significantly affects the patient's dose. A distance of 14 cm resulted in a higher dose than a distance of 2 cm. The SDNR value varied with the object image distance (OID) factor, and increasing the object's distance to the image detector did not increase the SDNR value. Setting the OID spacing to a minimum is recommended for PAC and PCI procedures to minimize the patient's radiation exposure. The FOM values were affected by both the ESAK and SDNR values. Keywords: Dose Optimization, Image Quality, objek to image distance (OID), Pulmonary Artery Catheter, Percutaneous Coronary Intervention, Cathlab.

Population Pharmacokinetics of Voriconazole and Dose Optimization in Elderly Chinese Patients.

Voriconazole is commonly recommended as a first-line therapy for invasive aspergillosis infections. Elderly patients are susceptible to infectious diseases owing to their decreased physical function and immune system. Our study aims to establish a population pharmacokinetics model for elderly patients receiving intravenous voriconazole, and to optimize dosing protocols through a simulated approach. An accurate fit to the concentration-time profile of voriconazole was achieved by employing a 1-compartment model featuring first-order elimination. The typical clearance rate of voriconazole was found to be 3.22L/h, with a typical volume of distribution of 194L. The covariate analysis revealed that albumin (ALB), gamma-glutamyl transpeptidase, and direct bilirubin had significant impacts on voriconazole clearance. Additionally, body weight was found to be associated with the volume of distribution. Individualized dosing regimens were recommended for different ALB levels based on population pharmacokinetics model prediction. The proposed dosing regimens could provide a rationale for dosage individualization, improve the clinical outcomes, and minimize drug-related toxicities.