Patient Dose Research Articles

Median effective dosage of midazolam oral solution for preschool children in preoperative sedation

AbstractThis study aimed to detect median effective dosage (ED50) of midazolam oral solution (MOS) for preschool children in preoperative sedation. Thirty children (3–6 years old, with a body mass index (BMI) of 18–28 kg/m2, American Society of Anesthesiologists status (ASA) I‐II) scheduled for the hidden penis correction surgery under general anesthesia were selected. The effective dosage of MOS for preschool children in preoperative sedation was measured by sequential method. The initial dose was set at 0.5 mg/kg, with a concentration gradient of 0.1 mg/kg. Sedation was deemed successful if the patients’ Ramsay sedation scores were ≥4 and Frankl treatment compliance rating scale was ≥3, without any grade III or higher adverse events during anesthesia. If these criteria were met, the dosage for the next patient was reduced by one gradient based on the last patient's dosage, otherwise, the dosage for the next patient was increased by one gradient. This process was repeated until the 7th inflection point from unsuccessful to successful sedation was reached, at which point the trial was terminated. Probit regression analysis was used to calculate the ED50, 95% effective doses (ED95) and 95% confidence interval (CI) of MOS. Adverse reactions such as bradycardia, nausea, vomiting, and blurred vision were recorded during sedation. This study revealed that the ED50 and ED95 of MOS for preschool children preoperative sedation are 0.627 mg/kg (95% CI 0.582–0.669 mg/kg) and 0.795 mg/kg (95% CI 0.712–1.211 mg/kg), respectively, providing a reference for the administration of MOS in this population.

Oral versus intravenous empirical antibiotics in children and adolescents with uncomplicated bone and joint infections: a nationwide, randomised, controlled, non-inferiority trial in Denmark

Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs. From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325. 248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI -2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups. In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship. Innovation Fund Denmark and Rigshospitalets Forskningsfond.

Radiogenic cancer risk from contrast enhanced computed tomography during pediatric abdomen and pelvis examinations in Saudi Arabia

The sensitivity to ionizing radiation is increasing by age of development for some malignant tumors. Therefore, children have higher risk to radiation induced tumors due the high cellular rate of proliferation and long lifespan probability. The risk is also increase with increase the effective and organ doses. Computed tomography (CT) exposed pediatric patients to higher radiation dose during multiphase image acquisition, repeated exams, for follow-up procedures. This research intended to estimate the radiogenic risks and effective radiation doses resulted from CT enhanced contrast for abdomen and pelvis. 126 (66 (62.3%) males, 60 (47.7%) females) pediatric patients underwent CT enhanced abdominal examination at Medical Imaging Department at King Khalid Hospital and Prince Sultan Center for Health Services, Alkharj, Saudi Arabia. The average and range of pediatric age (years) is 11.6 ± 5.0 (0.1–17). The mean, standard deviation, and range of the volume CT air kerma index (CVOL (mGy) and the air kerma length product (PKL, mGy.cm) were 9.8 ± 9.4 (2.1–45.8) and 1795 (221–3150) per abdominopelvic procedure, respectively. The mean and range of the effective dose (mSv) per procedure are 26.9 (2.4–59.1). The effective dose is higher compared to the most previously published studies. The effective dose per pediatric abdomen and pelvis with contrast procedure suggest that the patient dose is not optimized yet. Because the chest and pelvis region contain sensitive organs that are irradiated repeatedly, dose optimization is crucial.

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i. p.) 1 h prior to ketamine or HNKs (10 mg/kg, i. p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 h post-injection (t24 h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

Can We Harvest More Mature Oocytes by Repeating Gonadotropin-Releasing Hormone Agonist Doses in Polycystic Ovarian Syndrome Patients at Risk of OHSS in Antagonist Cycles? A Randomised Clinical Trial.

There is an ongoing debate about the optimal dosage of gonadotropin-releasing hormone (GnRH) agonist for oocyte triggering in polycystic ovarian syndrome (PCOS) patients at risk for ovarian hyperstimulation syndrome (OHSS). In this study, we intend to ascertain whether the use of repeated doses of a GnRH agonist for oocyte triggering in these patients can enhance the outcomes of controlled ovarian stimulation (COS) for in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI) cycles. This randomised clinical trial enrolled 70 PCOS women candidates for IVF/ICSI with the standard antagonist protocol at Royan Institute (Tehran, Iran) from May 2020 to June 2022. Patients at risk of OHSS with oestradiol (E2) levels >3000 pg/ml on the day of trigger were randomly assigned to a control or experimental group. Group A (control group) patients received 0.2 mg triptorelin (Decapeptyl®) for final oocyte maturation. Group B (experimental group) patients received a second dose of 0.1 mg Decapeptyl®12 hours after their first dose, for a total dose of 0.3 mg. IVF/ICSI outcomes were compared between the groups. Ultimately, 35 women from the study group and 33 from the control group completed the treatment cycle. Both groups were comparable in terms of demographic characteristics, baseline hormonal profiles, and PCOS phenotypes. The dosage of gonadotropin, stimulation duration, number of retrieved oocytes, oocyte maturation rate, and oocyte recovery ratio did not significantly differ between the groups. No significant differences were found in terms of the number of blastocyst and cleavage embryos, nor the quality of obtained embryos between the groups. The mild to moderate OHSS rate was significantly lower in the study group (P=0.038). A second dose of GnRH agonist 12 hours after the first dose did not improve the number and maturity of oocytes, or pregnancy outcomes in PCOS patients (registration number: NCT04600986).

Pharmacogenomics: An Update Review

Pharmacogenomics studies how genetics affects how drugs affect the human body. The terms genomics and pharmacology are the sources of the field's name, which represents the intersection of genetics and medicine. The discovery of the laws of heredity in 1866 marked the beginning of the area of pharmacogenetics (PGx). The FDA has established PGx testing recommendations, so whenever these 250+ drugs are being reviewed, testing should be considered. Physicians in the fields of pain management, mental health, and cardiovascular health are among those who provide PGx recommendations. Antidepressant medications offer several therapeutic options that are similar, which makes them a prime candidate for the use of PGx. It makes sense that pharmaceutical companies are hesitant to use pharmacogenomics in clinical investigations given its relative youth. Clinical trials and pharmacogenomic testing together have many advantages. Finding populations with risk factors unrelated to the medication itself may also be facilitated by pharmacogenetics. Oral anticoagulants and chemotherapy treatment regimens are now recommended based on a patient's pharmacogenetic condition. When it comes to patient dosing, pharmacogenetic techniques are gradually replacing the traditional method of depending solely on trial and error. The present therapeutic application of pharmacogenetics can also be applied to drug research and development.

Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation

In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data. To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin. The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023. Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin. Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component. The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable. In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria. ClinicalTrials.gov Identifier: NCT00781391.

Safety, Pharmacokinetics, and Pharmacodynamics of the New Aldose Reductase Inhibitor Govorestat (AT-007) After a Single and Multiple Doses in Participants in a Phase 1/2 Study.

In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo-controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5-40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose-1-phosphate (Gal-1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2-compartment model with sequential zero- and first-order absorption, and no effect of demographic factors. Multiple-dose PK of govorestat was linear in the 0.5-40 mg/kg range, and CSF levels increased dose dependently. Elimination half-life was ∼10 h. PK/PD modeling supported once-daily dosing. Change from baseline in galactitol was -15% ± 9% with placebo and -19% ± 10%, -46% ± 4%, and -51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal-1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes.

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.

New Predictive Equation for the Estimation of Plasma Concentrations of Formed Colistin in Patients Treated With Colistimethate Sodium for Multidrug-Resistant Gram-Negative Bacterial Infections.

The clinical use of colistin methanesulphonate (CMS) is limited by potential nephrotoxicity. The selection of an efficient and safe CMS dose for individual patients is complicated by the narrow therapeutic window and high interpatient pharmacokinetic variability. In this study, a simple predictive equation for estimating the plasma concentration of formed colistin in patients with multidrug and extremely drug-resistant gram-negative bacterial infections was developed. The equation was derived from the largest clinical cohort of patients undergoing therapeutic drug monitoring (TDM) of colistin for over 8 years in a tertiary Spanish hospital. All variables associated with C ss,avg were selected in a multiple linear regression model that was validated in a second cohort of 40 patients. Measured C ss,avg values were compared with those predicted by our model and a previous published algorithm for critically ill patients. In total, 276 patients were enrolled [the mean age was 67.2 (13.7) years, 203 (73.6%)] were male, and the mean (SD) C ss,avg was 1.12 (0.98) mg/L. Age, gender, estimated glomerular filtration rate, CMS dose and frequency, and concomitant drugs were included in the model. In the external validation, the previous algorithm appeared to yield more optimized colistin plasma concentrations when all types of C ss,avg values (high and low) were considered, while our equation yielded a more optimized prediction in the subgroup of patients with low colistin plasma concentrations (C ss,avg <1.5 mg/L). The proposed equation may help clinicians to better use CMS among a wide variety of patients, to maximize efficacy and prevent nephrotoxicity. A further prospective PK study is warranted to externally validate this algorithm.

Prediction of personalised postprandial glycaemic response in type 1 diabetes mellitus.

Patients with type 1 diabetes (T1D) face unique challenges in glycaemic control due to the complexity and uniqueness of the dietary structure in China, especially in terms of postprandial glycaemic response (PPGR). This study aimed to establish a personalized model for predicting PPGR in patients with T1D. Data provided by the First People's Hospital of Yunnan Province, 13 patients with T1D, were recruited and provided with an intervention for at least two weeks. All patients were asked to wear a continuous glucose monitoring (CGM) device under free-living conditions during the study period. To tackle the challenge of incomplete data from wearable devices for CGM measurements, the GAIN method was used in this paper to achieve a more rational interpolation process. In this study, patients' PPGRs were calculated, and a LightGBM prediction model was constructed based on a Bayesian hyperparameter optimisation algorithm and a random search algorithm, which integrated glucose measurement, insulin dose, dietary nutrient content, blood measurement and anthropometry as inputs. The experimental outcomes revealed that the PPGR prediction model presented in this paper demonstrated superior accuracy (R=0.63) compared to both the carbohydrate content only model (R=0.14) and the baseline model emulating the standard of care for insulin administration (R=0.43). In addition, the interpretation of the model using the SHAP method showed that blood glucose levels at meals and blood glucose trends 30 minutes before meals were the most important features of the model. The proposed model offers a heightened precision in predicting PPGR in patients with T1D, so it can better guide the diet plan and insulin intake dose of patients with T1D.

Pharmacokinetics of Briquilimab as a Conditioning Agent for Hematopoietic Stem Cell Transplantation in Patients With Severe Combined Immunodeficiency, Myelodysplastic Syndrome, or Acute Myeloid Leukemia

For successful engraftment of donor hematopoietic stem cells (HSC), conditioning with chemotherapy and/or radiation prior to hematopoietic cell transplantation (HCT) has been required to open marrow niche space and minimize the risk of immune rejection. Briquilimab, a humanized IgG1 monoclonal antibody that blocks the interaction between the c-Kit receptor and stem cell factor on various C-Kit expressing tissues including HSC, is a potential nonmyeloablative conditioning agent in clinical development for patients with severe combined immunodeficiency (SCID), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). This study aimed to characterize pharmacokinetics (PK) and develop a population PK model of briquilimab after single intravenous infusions of 4 different doses in patients with SCID, MDS, or AML receiving HCT. The PK data was collected from 2 different studies: JAS-BMT-CP-001 and JSP-CP-003. JAS-BMT-CP-001 is a phase 1/2 open-label study of briquilimab as a conditioning agent prior to allogenic HCT in SCID patients. The participants received single intravenous infusions of 0.1, 0.3, 0.6, or 1.0 mg/kg. JSP-CP-003 was a phase 1a/b open-label study of briquilimab in combination with a standard conditioning regimen of low dose total body irradiation and fludarabine in MDS or AML subjects undergoing HCT. The participants received a single intravenous dose of 0.6 mg/kg briquilimab. In both studies, briquilimab PK samples were obtained at pre-treatment, 5 minutes post-end of infusion, 4- and 24-hours post-start of infusion, any time between 2 days and 30 days postinfusion, and on the day of HCT prior to donor cell infusion.The population PK model was developed using the PK data from these 2 clinical studies, and the effect of participants’ baseline characteristics on the briquilimab PK was evaluated. PK simulations were performed using the developed PK model to calculate the time to reach target concentrations for HCT. A total of 49 participants (21 SCID adult and pediatric participants with a median age of 12 yr and 28 MDS/AML adult participants with a median age of 70 yr) were included in the PK analysis. A 2-compartment model with combined linear and non-linear elimination best described the PK of briquilimab. Body weight was determined as the sole covariate of the PK parameters among the explored covariates. For a typical subject with a body weight 70 kg, the estimated parameters for clearance, maximum metabolic rate of Michaelis Menten elimination, Michaelis Menten constant, central volume, peripheral volume, and intercompartmental clearance were 17.6 mL/h, 51,434.8 ng/h, 71.5 ng/mL, 3444.0 mL, 1613.3 mL, and 21.2 mL/h, respectively. The median time to reach target concentrations of 500, 1000, and 2000 ng/mL after a single dose of 0.6 mg/kg was calculated as 12.3, 10.4, and 7.7 days, respectively. The PK of intravenous briquilimab was characterized in subjects with SCID, MDS, or AML receiving HCT, and a population PK model was developed to estimate briquilimab clearance to use as a guide to the timing of donor cell infusion post-briquilimab. Body weight was identified as a significant covariate on elimination and volume of distribution of briquilimab.

Antimicrobial management of dental infections: Updated review.

Dental infections, which include anything from severe periodontal illnesses and abscess forms to routine tooth caries, are a major public health risk. This review article focuses on the pathophysiology and treatment of dental infections. A narrative review was conducted based on several published articles, relevant journals, and books in Google Scholar PubMed using the keywords dental caries, periodontal disease, gingivitis, and related diseases; we excluded duplicated information. Our review illustrated the types of dental infections and the proper antimicrobial drug that is suitable for this disease. Drawing from recent research findings and clinical evidence, we explore the spectrum of bacteria commonly associated with dental infections and their susceptibility profiles to various antibiotics. Emphasis is placed on understanding the mechanisms of antibiotic action and resistance in the context of dental pathogens, shedding light on optimal treatment regimens and potential challenges in clinical management. Additionally, we go over the clinical consequences of antibiotic therapy in dentistry, taking into account factors like patient selection, dose guidelines, and side effects. The management of dental infections through antimicrobial strategies has undergone significant advancements, as evidenced by this updated review. Besides the normal methods, emerging technologies such as 3D printing for drug delivery of antibiotics and disinfectants hold promise in enhancing treatment efficacy and patient outcomes. By leveraging the precision and customization afforded by 3D printing, dentistry can tailor antimicrobial interventions to individual patient needs, optimizing therapeutic outcomes while minimizing adverse effects.

Dose optimization of pancreatic enzyme replacement therapy is essential to mitigate muscle loss in patients with advanced pancreatic cancer and exocrine pancreatic insufficiency

Background & AimsExocrine pancreatic insufficiency (EPI) contributes to malnutrition, marked by muscle loss during chemotherapy for advanced pancreatic cancer (aPC). Pancreatic enzyme replacement therapy (PERT) is recommended for patients with EPI; however, it’s efficacy for attenuating muscle loss has not been demonstrated. We aimed to delineate the impact of PERT dose on muscle loss using a 7-year population-based cohort with aPC who were provided PERT at the discretion of their oncologist or dietitian according to clinical indications of EPI. MethodsAll patients treated with chemotherapy for aPC from 2013-2019 in Alberta, Canada (population ∼4.3 million) were included if they had computed tomography (CT) scans both prior to and 12 ± 4 weeks after chemotherapy initiation. Change in muscle area (cm2) was measured at 3rd lumbar level on repeated CT scans. Muscle loss was defined by measurement error (loss >2.3 cm2). Clinical and pharmaceutical data were retrieved from provincial registries. For patients who were dispensed PERT -8 to +6 weeks from chemo start (PERT users), estimated dose consumed per day was calculated as: (total dose dispensed)/(days, first to last dispensation). PERT users were categorized as high dose or low dose users according to the median estimated dose consumed. Non-users were classified as No PERT. Association between PERT use and muscle loss was analyzed with multivariable logistic regression. ResultsAmong 210 patients, 81 (39%) were PERT users. Median estimated dose consumed per day of 75 000 USP lipase units defined the cutoff between low dose and high dose uses. There were no significant differences in baseline characteristics between high dose and low dose groups. Muscle loss was more prevalent among low dose compared to both high dose and No PERT groups (88% vs. 58% and 67%, p < .05). In the multivariable model predicting muscle loss, low dose PERT was independently associated with greater odds of muscle loss (OR 5.4, p=.004) vs. high dose, independent of tumour response, disease stage, and chemotherapy regimen. ConclusionIn patients with clinical indications of EPI during chemotherapy for aPC, low doses of PERT were insufficient to prevent muscle loss. Patients with EPI consuming higher doses of PERT had similar odds of muscle maintenance to patients without clinical indications of EPI. Provider education for optimal PERT dosing in patients with EPI should be prioritized, and resources must be allocated to support dose titration.

Optimized high-dose granulocyte transfusions for the treatment of infections in neutropenic patients: A single-center retrospective analysis.

Granulocyte transfusions for patients with prolonged neutropenia and severe infections has been a controversial practice. Previous studies suggest a benefit of high-dose granulocyte transfusions (≥0.6 × 109/kg), although, until recently, the consistent production of high-dose units has been challenging. Here, we present our experience and results utilizing high-dose granulocyte transfusions at a large, tertiary academic medical center for the treatment of infections in adult, neutropenic patients. A retrospective chart review (2018-2021) was conducted for all patients who received high-dose granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. Gathered parameters included patient demographics, clinical history, infection status, dose, clinical outcomes, pre- and post-absolute neutrophil count (ANC), and transfusion times including time between granulocyte collection, administration, and posttransfusion ANC count. Gathered parameters were summarized using descriptive statistics, outcomes were assessed utilizing Kaplan-Meier curves/log-rank/regression testing. Totally 28 adult, neutropenic patients refractory to antimicrobial agents and/or G-CSF received a total of 173 granulocyte concentrates. Median ANC increased from 0.7 × 109/L pre-transfusion to 1.6 × 109/L posttransfusion. The mean granulocyte yield was 77.4 × 109 resulting in an average dose per kilogram of 0.90 × 109 ± 0.30 × 109 granulocytes. Composite day 42 survival and microbial response was 42.9% (n = 12/28) without significant adverse reactions. Here, we demonstrate the successful and safe implementation of high-dose granulocyte transfusions for neutropenic patients. Given the rapid and consistent production, distribution, and improved granulocyte quality, further investigations to determine the clinical efficacy of G-CSF primed granulocyte transfusions is now possible.

P-605 Effectiveness of follitropin delta in patients with potential poor response: A post hoc analysis from the ESTHER-1 trial

Abstract Study question What is the effectiveness of individualised follitropin delta dosing compared to conventional follitropin alfa dosing in patients with potential poor response undergoing ovarian stimulation? Summary answer Individualised follitropin delta dosing provides a favourable efficacy and safety balance and is as good as follitropin alfa in patients with potential poor ovarian response. What is known already Poor ovarian response to controlled ovarian stimulation constitutes a challenge in in-vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) treatment. The dosing algorithm of follitropin delta incorporates the prediction of ovarian response based on anti-Müllerian hormone (AMH), an accurate marker of ovarian reserve, and body weight, for an individualised dosing. In the general IVF/ICSI population and potential high responders, individualised follitropin delta reduces the risk of ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions for OHSS, with sustained efficacy compared to conventional follitropin alfa. However, the performance of follitropin delta in the subpopulation of patients with potential poor response has not been evaluated. Study design, size, duration Post hoc analysis of 332 patients with potential poor response from the ESTHER-1 trial (determined by AMH level at screening &amp;lt;9 pmol/L). Patients received the maximum daily dose of 12 µg follitropin delta (fixed dosing throughout stimulation) as stipulated by the dosing algorithm for patients with AMH &amp;lt;15 pmol/l, or follitropin alfa at a starting dose of 150 IU, with potential dose adjustments from stimulation day 6 and onwards (maximum daily dose of 450 IU). Participants/materials, setting, methods Participants were women, 18–40 years, undergoing their first IVF/ICSI cycle in a GnRH antagonist protocol, including triggering with human chorionic gonadotrophin, IVF/ICSI insemination, and single or double blastocyst transfer on Day 5. Ultrasound was performed 10–11 weeks after transfer to confirm ongoing pregnancy. All pregnancies were followed until birth. Study outcomes include number of oocytes retrieved and number of good quality blastocysts, ongoing pregnancy and live birth rates, cycle cancellation and OHSS rates. Main results and the role of chance A total of 332 patients (25.0% of the overall ESTHER-1 population) had serum AMH at screening of &amp;lt; 9 pmol/l and were included in the analysis: 168 were treated with follitropin delta and 164 were treated with follitropin alfa. Baseline characteristics were similar between the treatment groups, with a mean age of 34.8 years, a median AMH of 5.7 pmol/l and a mean weight of 64.5 kg. With follitropin delta, the mean daily dose was 12.0 µg and with follitropin alfa 12.4 µg, resulting in mean total doses of 104.6 µg and 112.3 µg, respectively. The mean number of oocytes retrieved was 5.8 ± 3.5 with follitropin delta and 5.5 ± 3.6 with follitropin alfa and the mean number of good-quality blastocysts was 1.2 ± 1.4 with both treatments. The ongoing pregnancy rate was 29.8% with follitropin delta and 29.3% with follitropin alfa and the live birth rates were 29.2% and 28.7%, respectively. Thirteen patients (7.7%) treated with follitropin delta and 14 (8.5%) treated with follitropin alfa had their cycles cancelled due to poor response. One case of OHSS (0.6%) was observed in the follitropin delta group, and 3 cases (1.8%) were observed in the follitropin alfa group. Limitations, reasons for caution The main limitation of the study is its post hoc nature. Furthermore, the study is based on a relatively small number of patients. Wider implications of the findings This subgroup analysis, alongside the normoresponder and the potential hyperresponder subgroup of the ESTHER-1 trial, adds evidence for the effectiveness of follitropin delta across all ovarian reserve subgroups of the infertile population. Trial registration number NCT01956110

Effect of Omega-3 Fatty Acids Supplementation in Pediatric Patients with Type 1 Diabetes Mellitus

Abstract Background Omega-3 fatty acids (O3FAs) are polyunsaturated fatty acids derived from fish oil. Beneficial effects of O3FA supplementation in a wide range of disease condition have been well studied. However; the role of O3FA in management of type 1 diabetes mellitus (T1DM) remains unclear and controversial. Objectives Therefore, we performed a randomized-controlled trial to assess the effect of oral O3FAssupplementation on glycemic control and lipid profile in pediatric patients with T1DM. Methods This study included 70 children and adolescents with T1DM. Patients were randomly assigned into two groups; intervention group and received oral O3FAs capsules (1 gram daily). The other group did not receive any supplementation and served as a control group. Both groups were followed-up for 6 months with assessment of fasting blood glucose (FBG), HbA1c and fasting lipids. Results Supplementation with O3FAs was safe and well-tolerated. After 6 months, O3FAs adjuvant therapy for the intervention group resulted in a significant decrease of systolic blood pressure, insulin dose, FBG, HbA1c, triglycerides, total cholesterol and LDL-cholesterol compared with baseline levels and compared with the control group (p &amp;lt; 0.05). On the other hand, T1DM patients without O3FAs adjuvant therapy (control group) had higher blood glucose levels and HbA1c at study end compared with baseline levels (p &amp;lt; 0.001). Conclusions O3FAs as an adjuvant therapy to insulin improved blood glucose levels, glycemic control and dyslipidemia leading to reduction in insulin dose in pediatric patients with T1DM.

Feasibility and predictive factors on the completion of docetaxel plus S‐1 adjuvant chemotherapy in pathological stage III gastric cancer

AbstractBackgroundThe standard adjuvant chemotherapy regimen for stage III gastric cancer is docetaxel plus S‐1 (DS) based on the results of the START‐II trials. However, in clinical practice some patients could not continue this intensive doublet chemotherapy because of limited tolerability. This study aimed to assess the practical feasibility of DS and elucidate the predictive factors for the completion of adjuvant DS therapy.MethodsData from consecutive patients who underwent radical gastrectomy between 2018 and 2021 and were diagnosed with histopathologically confirmed stage III gastric cancer were retrospectively collected. First, the completion rate and adverse effects of DS were assessed. Second, the association between DS incompletion and patient backgrounds including body weight, skeletal muscle index (SMI), and intramuscular adipose content (IMAC) were examined.ResultsOf 87 patients, 59 patients (67.8%) completed DS and dose reduction was required in 18 patients (20.6%). Neutropenia of grade 3 or higher was the most common hematological toxicity observed (17.2%). The most frequent nonhematological toxicity of grade 3 or higher was fatigue (6.9%), followed by diarrhea (5.7%), nausea (4.5%), and anorexia (4.5%). In a multivariate analysis, low SMI (p = 0.005) and high IMAC (p = 0.004) were significant risk factors for DS incompletion.ConclusionsDS adjuvant chemotherapy after radical gastrectomy for pathological stage III gastric cancer is acceptable, even in clinical practice, with respect to completion and toxicity. Additionally, the body composition factors such as SMI and IMAC might be useful in predicting incompletion of DS. These findings will help us to preoperatively select patients for DS.

Pediatrics organ dose and lifetime attributable cancer risk estimates in routine computed tomography

ObjectivesEvaluating organ doses received by pediatric patients and estimating lifetime attributable risk (LAR) in Riyadh, Saudi Arabia from chest and abdominal pelvic Computed Tomography (CT) scans. MethodsA total of 155 patients under the age of 15 were divided into four age groups: under 1, 1–5, 5–10, and 10–15. The organ dose was determined using the National Cancer Institute dosimetry system for (NCICT) software, and the LAR if cancer incident was measured according to the BEIR VII report. The 1st, 2nd, and 3rd quartiles were calculated for organs received primary X-ray beams. ResultsThe highest and lowest median doses were for the kidney in the 10-15-year-old group 4.84 mGy (Cl95%, 0.15–9.54) and the prostate in the >1-year-old group 0.02 mGy (Cl95%, −0.01 – 0.05), respectively. Furthermore, there was a correlation between age and breast doses in chest scans, as median doses increased from 0.08 mGy to 3.70 mGy. Breast cancer in females had a highest LAR from chest CT and colon cancer in abdomen-pelvic CT. The group 1–5 years old had the highest risk of breast cancer, followed by chest CT (LAR = 25.94). However, colon cancer (LAR = 10.39), followed by an abdomen-pelvic CT, had the highest risk in the same group in both genders. Colon and breast cancers had the highest LAR among males and females in all groups. ConclusionThe study found that older patients received higher median organ doses for the same examination than younger patients. Females have greater organ doses in the thorax compared to males, resulting in a higher mean LAR. While CT scans are useful tools for diagnosis, it's essential to consider the patient's dose, particularly in pediatric cases.

Decreased Rates of Radiation-induced Trismus and Lowered Mastication Structure Doses in Patients Treated for Head and Neck Cancer During the Last Two Decades

AimsTo investigate how absorbed doses to mastication structures in modern radiotherapy (RT) technique for head and neck cancer (HNC) compared with earlier RT techniques and with published trismus tolerance doses. To compare the incidence of radiation-induced trismus by earlier and newer RT techniques. Materials and methodsThis study investigated two HNC patient cohorts treated with RT in 2007–2012 (three-dimensional conformal radiotherapy [3DCRT] and/or intensity-modulated radiotherapy [IMRT]; n =121 [Cohort 1]) and 2017–2020 (volumetric-modulated arc therapy [VMAT]; n =124 [Cohort 2]). All patients underwent RT without mastication structure–sparing intent, had normal mouth-opening ability before RT, and were prospectively assessed. Trismus was defined as the maximal interincisal opening ≤35 mm at any follow-up (3-, 6-, and 12-months post-RT). The temporomandibular joints (TMJs), masseter, and medial/lateral pterygoid muscles were delineated on the planning CT:s. Mean doses were compared between cohorts, and evaluated with respect to published trismus tolerance doses. P values ≤ 0.05 indicated statistical significance. ResultsWithin 12 months post RT, 74/121 (61%) of patients in Cohort 1 had experienced trismus compared to 11/124 (9%) in Cohort 2. Averaged mean doses (±S.D.) for the masseter muscles were 35.2±8.3 Gy in Cohort 1 and 20.2±8.7 Gy in Cohort 2 (P <0.001). Corresponding numbers were 19.1±16.2 and 4.3±4.3 Gy for the TMJs, 53.7±10.1 and 40.2±16.8 Gy for the medial pterygoid muscles, and 29.2±18.7 and 9.2±8.4 Gy for the lateral pterygoid muscles (all P <0.001). Masseter muscle doses were below tolerance doses in 23% of patients in Cohort 1 compared with 90% in Cohort 2. The corresponding numbers were 52% and 96% for the TMJs, 8% and 36% for the medial pterygoid muscles and 72% and 100% for the lateral pterygoid muscles. ConclusionMastication structure mean doses by more recent RT techniques were generally below proposed tolerance doses, with dose reductions of 10–20 Gy compared with earlier techniques. Modern RT without mastication-structure-sparing intent resulted in below 10% of HNC patients experiencing trismus compared with 60% treated with earlier techniques.