Full Dose Research Articles

Fractional Doses of Pneumococcal Conjugate Vaccine - A Noninferiority Trial.

Pneumococcal conjugate vaccines are an expensive component of the routine immunization schedule. Fractional-dose regimens may be one option to increase the sustainability of the vaccine program. We assessed whether the immunogenicity of fractional doses of the 10-valentand 13-valent pneumococcal conjugate vaccines (PCV10 [GSK] and PCV13 [Pfizer], respectively) would be noninferior to that of the full doses and analyzed the prevalence of vaccine-serotype carriage. We randomly assigned healthy infants in Kenya to one of seven equal-sized trial groups. Participants in groups A through F were assigned to receive either a fractional or full dose of PCV10 or PCV13, administered as two primary doses plus one booster dose. In group A, participants received a full dose of PCV13; group B, a 40% dose of PCV13; group C, a 20% dose of PCV13; group D, a full dose of PCV10; group E, a 40% dose of PCV10; and group F, a 20% dose of PCV10. Participants in the seventh group (group G) received a full dose of PCV10 as three primary doses without a booster. Immunogenicity was assessed 4 weeks after the primary series of doses and 4 weeks after the booster dose. Noninferiority could be declared 4 weeks after the primary series if the difference in the percentage of participants with a threshold response was not more than 10% and 4 weeks after administration of the booster if the ratio of the geometric mean concentration (GMC) of IgG was more than 0.5. A vaccine dose was prespecified as noninferior if it met the noninferiority criterion for at least 8 of the 10 vaccine types in the PCV10 groups or at least 10 of the 13 vaccine types in the PCV13 groups. Carriage was assessed when participants were 9 months and 18 months of age. In the per-protocol analysis, 40% of a full dose of PCV13 met the noninferiority criterion for 12 of 13 serotypes after the primary series and for 13 of 13 serotypes after the booster. The immunogenicity of the 20% dose of PCV13 and of the 40% and 20% doses of PCV10 was not noninferior to that of the full doses. Vaccine serotype-type carriage prevalence was similar across the PCV13 groups at 9 months and 18 months of age. In a three-dose schedule (two primary doses and a booster), 40% doses of PCV13 were noninferior to full doses for all included serotypes. Lower doses of PCV13 and PCV10 did not meet the criteria for noninferiority. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03489018; Pan African Clinical Trial Registry number, PACTR202104717648755.).

Identifying risk factors of dose reduction or treatment discontinuation due to fatigue or gastrointestinal symptoms in patients receiving lenvatinib treatment for hepatocellular carcinoma

Introduction Lenvatinib (LEN) is the standard treatment for hepatocellular carcinoma (HCC). In clinical practice, gastrointestinal (GI) symptoms such as fatigue and loss of appetite often lead to dose reduction or treatment discontinuation. This study aimed to identify the predictors of patients who will experience dose reduction or treatment discontinuation owing to fatigue or GI symptoms during LEN treatment for HCC. Methods We retrospectively identified 99 patients who received LEN at the Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and December 2023. To investigate the risk factors for treatment discontinuation or dose reduction due to fatigue or GI symptoms during LEN administration, patients were divided into two groups based on whether treatment discontinuation or dose reduction occurred due to fatigue or GI symptoms during LEN administration (37 patients) or not (62 patients). We compared baseline characteristics between the two groups. Results Multivariate analysis revealed that body weight (odds ratio 4.310, 95% confidence interval 1.380–13.500; P = 0.002) was an independent risk factor that significantly contributed to treatment discontinuation or dose reduction owing to fatigue or GI symptoms during LEN administration. The cut-off value calculated using the body weight curve was 55.0 kg. Using this cutoff value, the sensitivity and specificity of body weight to detect treatment discontinuation or dose reduction due to fatigue or GI symptoms during LEN administration were 83.9% and 56.8%, respectively. Conclusion In clinical practice, patients weighing less than 55 kg who start with a full dose will likely experience weight loss or discontinuation during treatment.

Growth, Development, Yield Attributes and Yield of French Bean (Phaseolus vulgaris L.) as Influenced by Doses and Methods of Nitrogen Application

A field experiment was carried out at School of Natural Resource Management, College of Post Graduate Studies in Agricultural Sciences, CAU, Umiam, Meghalaya during summer season 2021 to study the effect of different doses and application methods of nitrogen on the growth, yield and yield attributes of Frenchbean (Phaseolus vulgaris L.). The experiment comprised of four doses of nitrogen viz.,0, 30, 60, 90 kg ha-1 and two methods of its application i.e., full dose as nitrogen as basal application and 2/3 of nitrogen dose as basal and 1/3 of nitrogen dose split application at active branching stage. The experiments consist of a total of 7 treatments laid out in Randomized Block Design with four replications. Growth parameters such as plant height and number of branches per plant in frenchbean showed a significant increase at all the growth stages with increase in nitrogen doses. Maximum plant height (39.35 cm) and number of branches per plant (3.56) were observed with application of 90 kg N ha-1. The grain yield (762.32 kg ha-1) was observed with application of 90 kg N ha-1 whereas, lowest grain yield was observed in control (146.25 kg ha-1). Yield attributes were observed to follow the same trend with highest number of pods per plant as 5.44, number of seeds per pod as observed significantly more values of all the above said parameters of growth and yield of frenchbeanin comparison to full dose of nitrogen as basal alone. Therefore, the finding of this experiment suggest that the frenchbean should be grown with 90 kg N ha-1 and 2/3 of this dose should be applied as basal application while remaining 1/3 should be applied as top dressing at active branching stage for better growth and yield of frenchbean.

Abstract C013: Racial disparities in Interpersonal Processes of Care (IPC) during early stage breast cancer chemotherapy: Associations with symptoms and the ability to receive dose-intensive chemotherapy

Abstract Purpose: Documented racial disparities exist in the dose intensity of early-stage breast cancer (ESBC) chemotherapy, partly due to chemotherapy symptom toxicity and subsequent dose modifications. Effective communication is crucial for early symptom mitigation. We explored the associations between racial differences in patient-clinician communication, symptom experience, and the ability to receive the full dose of ESBC chemotherapy. Methods - A descriptive, correlational design compared clinician communication, symptoms, and the ability to obtain dose-intensive ESBC chemotherapy by race. Multi-site - large, urban breast cancer outpatient clinics. Patients completed the 18-item Interpersonal Processes of Care (IPC) and 13-item Symptom Distress Scale (SDS) at baseline and each chemotherapy visit. The IPC assesses clarity of communication, elicitation of concerns, explaining results, shared decision-making, compassion, discrimination due to race/ethnicity, and disrespectful office staff. Mean scores for IPC and SDS were calculated for each visit, and average scores across all visits were created for each participant; chemotherapy dose intensity - Receiving 85% or more of the prescribed chemotherapy within the projected timeline, dichotomized to yes or no—Analysis - IBM® SPSS®, version 27. Descriptive statistics were generated for raw data. Pearson’s correlations were used to examine bivariate associations and univariate and multivariate logistic or linear regression models to explore associations further. Results – N = 216 women, 37% - Black and 63% - White. The mean age was 52.99 ± 12.31 years. IPC - Black patients reported significantly higher (worse) IPC scores for "lack of clarity," "discrimination," and "disrespectful office staff" compared to White patients (all ps ≤ 0.01). Associations of SDS and IPC - Patients with higher IPC subscale scores for "lack of clarity," "discrimination," and "disrespectful office staff," and lower scores for "compassion and respect" experienced significantly higher levels of symptom distress (all ps < 0.05). Associations between IPC and Dose Intensity - Patients reporting higher (worse) discrimination scores were less likely to receive 85% of the prescribed chemotherapy. The IPC "discrimination" subdomain score was significantly associated with chemotherapy dose intensity (χ2(1)=6.910, p=0.009). Each one-unit increase in perceived "discrimination" subdomain score increased the likelihood of not receiving prescribed chemotherapy (B=0.985, OR=2.602, p=0.014) by approximately 160.2%. Conclusions - Black patients perceive poorer quality IPC than White patients during ESBC chemotherapy. Specific subdomains of IPC are associated with worse symptom distress and the inability to receive the full dose of ESBC chemotherapy, primarily driven by perceived discrimination. We must understand the relationship between race, communication, symptoms, and the ability to receive appropriate chemotherapy dose intensity. Citation Format: Margaret Q. Rosenzweig, Hiba Q. Abujaradeh. Racial disparities in Interpersonal Processes of Care (IPC) during early stage breast cancer chemotherapy: Associations with symptoms and the ability to receive dose-intensive chemotherapy [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C013.

Control of Cyanobacterial Algal Blooms and Soluble Reactive Phosphorus Using PAK-27 and Phoslock®

Cyanobacterial harmful algal blooms (cHABs) can pose a threat to human health and aquatic ecosystems when they release cyanotoxins in water. This research used samples from two northeastern reservoirs in Ohio and assessed (i) the effectiveness of two PAK-27 dosages, (ii) the potential interference of natural organic matter (NOM) on PAK-27 effectiveness, and (iii) the ability of Phoslock® to adsorb phosphorus released during cell lysis to prevent future bloom formation. PAK-27 was applied in either a quarter (15 mg) or full (58 mg) dose in 1.6 L. Two sets of jars were amended with 200:1 Phoslock®:phosphorus 24 h after PAK-27 application to assess the adsorption of phosphorus released upon cell lysis. A final set of jars was amended with 5 mg NOM to evaluate if NOM would interfere with PAK-27 effectiveness. Quarter and full doses of PAK-27 significantly decreased total phycocyanin content within 2 days of application (p < 0.05). However, the addition of 5 mg NOM influenced nutrient availability and algal response. All jars that received algaecide had increased extracellular microcystin levels (p < 0.05). Although Phoslock® adsorbed soluble reactive phosphorus (SRP), jars treated with only PAK-27 or amended with 5 mg NOM reduced more SRP than Phoslock®.Graphical

Biogas slurry: A potential substance that synergistically enhances rapeseed yield and lodging resistance

Biogas slurry (BS) plays a vital role in improving the efficiency of crop production. On the flip side, the impact of BS on plant lodging factors and yield related traits is still obscure. Hence, we aimed to study the effects of pig and cow BS applications on yield formation, morpho-anatomical, mechanical, physiological properties and transcript expression patterns. The results showed that the yield and lodging resistance of rapeseed were synergistically improved via applying full BS dosage versus nitrogen fertilizer (CK). In addition, the seed yield was significantly increased by 23.9 % by promoting the dry matter accumulation and transport-ability, increasing number of pods by 8.4 % and 1000-seed weight by 5.1 %, respectively. Moreover, BS developed the stem mechanical strength by decreasing lodging index by 34.2 %, which was manifested by an increase in stem thickness and stiffness and a reduction in plant height. Besides, it enhanced the photosynthesis through promoting chlorophyll synthesis, delaying plant senescence, and accumulating N and K concentration. Anatomical observations revealed that BS increased greater number and area of stem vascular bundles, vessels, and maintained a dense microstructure than CK. Also, it boosted pectin, Ca2+ and K+ contents, which were significantly positively correlated with stem mechanical strength and reduced cellulose, lignin and hemicellulose contents. Meanwhile, correlation and structural equation modeling analysis validated the above results. Additionally, the differentially expressed genes were enriched in cell wall formation pathway, especially about the biosynthesis of pectin (PME, PG and PL), cellulose (CesA and CSL), lignin (PAL, POD, CCR, LAC and COMT) and hemicellulose (XTH and Xyl) were identified under BS. The above-mentioned results indicated that BS simultaneously affected lodging behavior by altering structural carbohydrates and modified yield composition by regulating dry-matter accumulation and allocation. This is the first comprehensive strategy on synchronizing rapeseed yield increase and lodging resistance under optimized BS management.

PSXII-18 Nitrogen balance and ruminal bacterial diversity indexes of Nellore cattle fed with amylolytic and fibrolytic enzymes in feedlot

Abstract This study was carried out to evaluate the use of dietary exogenous enzyme (ENZ) products with amylolytic and fibrolytic activity on nitrogen balance and ruminal alpha and beta diversity of Nellore cattle in feedlot. Rumen cannulated Nellore steers [n = 10; body weigh (BW) = 543 kg ± 28.6 kg] were distributed in a replicate 5 × 5 Latin-square design using individual pens. The treatments consisted of a negative control (CON; without ENZ); Amylase [AML, Amaize, Alltech; 0.5 g/kg of diet dry matter (DM); Xylanase (FBL, Fibrozyme, Alltech; 0.9 g/kg of diet DM]; Half dose (HD; AML 0.25 g/kg of diet DM and FBL 0.45 g/kg of diet DM); and Full dose (FD; AML 0.5 g/kg of diet DM and FBL 0.90 g/kg of diet DM; Table 1). The experimental period lasted 19 d (14 d of adaptation and 5 d of collection). Between d 15 and 18, total urine collection was performed to calculate the nitrogen balance. On d 19 a mixed ruminal sample (6 mL of solid and liquid content) was taken 4 h after feeding and stored at -80 ºC until DNA extraction. Total genomic DNA was extracted using the ZymoBIOMICS DNA Miniprep Kit. The library was prepared using primers for the region V3V4 of the16S rRNA gene; 341F (5’-CCTAYGGGRBGCASCAG-3’) x 806R (5’- GGACTACNNGGGTATCTAAT-3’). The amplicons (~ 470 bp) were sequenced with the Illumina NovaSeq 6000 PE 250 platform. The sequences were analyzed using qiime2 with the SILVA database for the taxonomic assignment. Alpha and beta diversities were calculated in Rstudio using phyloseq. All data were analyzed as orthogonal contrasts assuming treatment as a fixed effect: 1) CON vs. ENZ, 2) AML vs. FBL, 3) HD vs. FD, and 4) AML + FBL vs. HD + FD. Animals that received ENZ had reduced fecal nitrogen excretion (FNE, P = 0.014) and greater efficiency of nitrogen utilization (ENU, P = 0.031) than animals in the CON group. The FBL treatment resulted in greater CP/DOM ratio (P = 0.049), nitrogen balance (P = 0.089), and ENU (P = 0.015) compared with AML treatment. No differences were observed between HD and FD for any nitrogen balance variable (P &amp;gt; 0.10). Animals supplemented with both enzymes (HD + FD) had greater values of N intake (P = 0.018), greater CP/DOM ratio (P = 0.006), and greater FNE (P = 0.002) than animals fed either enzyme alone (AML + FBL). The ENZ supplementation did not impact alpha diversity index or beta diversity (P &amp;gt; 0.10). In conclusion, the addition of exogenous enzymes affected nitrogen balance but not ruminal alpha and beta diversity of Nellore cattle in feedlot.

PSXIII-22 Intake, digestibility, and ruminal parameters of Nellore cattle fed with amylolytic and fibrolytic enzymes in feedlot

Abstract This study was carried out to evaluate the use of dietary exogenous enzyme (ENZ) products with amylolytic and fibrolytic activity on nutrient intake, digestibility, and ruminal volatile fatty acids production (VFA) of Nellore cattle in feedlot. Rumen-cannulated Nellore steers [n = 10; body weight (BW) = 543 kg ± 28.6 BW] were distributed in a replicated Latin-square design (5 × 5) in individual pens. The treatments consisted of a negative control (CON; without ENZ); Amylase (AML; Amaize, Alltech, 0.5 g/kg of DM); Xylanase (FBL, Fibrozyme, Alltech, 0.9 g/kg of DM); Half dose (HD; AML 0.25 g/kg of diet DM and FBL 0.45 g/kg of diet DM); and Full dose (FD; AML 0.5 g/kg of diet DM and FBL 0.90 g/kg of diet DM; Table 1). The experimental period lasted 19 d (14 d of adaptation and 5 d of collection). Between d 15 and 18, total fecal collection was performed and on d 19 rumen fluid was collected at 0, 4, 8, 12, and 16 h post-feeding for ammonia, VFA, and pH determination. The data were analyzed as orthogonal contrasts using SAS: (C1) CON vs. ENZ, (C2) AML vs. FBL, (C3) HD vs. FD, and (C4) AML + FBL vs. HD + FD. There were no C1 differences for nutrient digestibility, total VFA, or ruminal pH (P &amp;gt; 0.10). However, a tendency effect in neutral detergent fiber (NDF) intake (P = 0.065) was observed, where animals fed ENZ had reduced values compared with animals kept in CON group. In the same way, ENZ reduced ther extract (EE) intake (P = 0.023), ruminal ammonia (P &amp;lt; 0.001), and isovalerate proportion (P = 0.080) as well as increased proportion of acetate (P &amp;lt; 0.001), valerate (P &amp;lt; 0.001) and acetate:propionate ratio (P = 0.030). No differences were observed in nutrient intake between AML and FBL (P &amp;gt; 0.10), but AML had greater organic matter (OM) digestibility (P = 0.097) and ruminal valerate (P = 0.039) and decreased butyrate proportion (P = 0.068). Animals that received FD had greater values of dry matter (DM; P = 0.009) and OM (P &amp;lt; 0.001) digestibility than HD. The enzyme combination resulted in greater DM (P = 0.026), OM (P = 0.062), crude protein (P = 0.018), EE (P = 0.063) and NDF (P = 0.040) intake and reduced OM digestibility (P = 0.008) compared with AML and FBL alone. The addition of exogenous enzymes in feedlot diets affected nutrient utilization and ruminal fermentation of Nellore cattle fed a feedlot finishing diet.

Evaluation of a novel pediatric asthma inhalation drug delivery device: a focus on patient accessibility, ease of use, dosage feedback, and future directions

Objective Pediatric asthma management faces challenges in medication delivery through oral inhalation devices. While dry powder inhalers (DPIs) are increasingly prescribed to children, many do not receive their prescribed dosage due to insufficient inspiratory flow. This study investigates the utilization of metered-dose inhalers (MDIs) and DPIs among pediatric patients with asthma, focusing on medication delivery challenges. Methods Two survey cohorts comprising a total of 42 caregivers of patients with asthma were conducted. Modifications in the second cohort addressed neutral Likert scale responses to obtain more nuanced feedback. Results Caregivers expressed concerns about uncertainties in their child’s ability to use both MDIs and DPIs and challenges in ensuring proper dosage. Notably, 42% of caregivers in the second cohort rated their child’s inhaler usage as unable, indicating a significant worry about the efficacy of current delivery methods. Additionally, 50% of caregivers across both cohorts expressed uncertainties about their child receiving the full medication dosage. In response to identified challenges with DPIs, an adaptor device emerged as a potential solution, with caregivers exhibiting positive perceptions post-exposure. Features prioritized for the device include ease of use and assurance of dose delivery. Conclusions The study highlights caregiver preferences and the need for innovations to ensure effective medication delivery for pediatric asthma patients. A DPI adaptor device shows promise in addressing technical issues and alleviating caregiver concerns, ultimately contributing to more effective asthma management. Future research should refine these devices based on caregiver feedback to meet the evolving needs of the pediatric asthma population.

New drug combination regimen based on pharmacokinetic characteristics—Erdafitinib combined with sertraline or duloxetine

The aim of this study is to investigate novel strategies for reducing adverse reactions caused by erdafitinib through a drug combination based on its pharmacokinetic characteristics. The spectrum and characterizations of drugs that can inhibit the metabolism of erdafitinib are examined both in vitro and in vivo. The efficacy of combination regimens are then evaluated using subcutaneous xenograft tumor models. The results demonstrated that sertraline and duloxetine, out of more than 100 screened drugs, inhibited the metabolism of erdafitinib through mixed and non-competitive inhibition, respectively. This inhibition primarily occurred via the CYP2C9 and CYP2D6 pathways. The primary alleles of CYP2C9 and CYP2D6 not only determine the metabolic characteristics of erdafitinib but also influence the strength of drug-drug interactions. Co-administration of sertraline or duloxetine with erdafitinib in rats and mice resulted in nearly a three-fold increase in the blood exposure of erdafitinib and its major metabolite M6. When sertraline or duloxetine was combined with 1/3 of the erdafitinib dosage, the anti-proliferative and pro-apoptotic effects on SNU-16 xenografts were comparable to those of the original full dose of erdafitinib. However, the combination regimen significantly mitigated hyperphosphatemia, retinal damage, intestinal villus damage, and gut microbiome dysbiosis. This study utilized pharmacokinetic methods to propose a new formulation of erdafitinib combined with sertraline or duloxetine. The findings suggest that this combination has potential for clinical co-administration based on a database analysis, thereby providing a novel strategy for anti-tumor treatment with fibroblast growth factor receptor (FGFR) inhibitors.

Safety and Immunogenicity of a Carbohydrate Fatty Acid Monosulphate Ester Adjuvant Combined with a Low-Dose Quadrivalent Split-Virion Inactivated Influenza Vaccine: A Randomised, Observer-Blind, Active-Controlled, First-in-Human, Phase 1 Study.

Seasonal influenza vaccine effectiveness is low. Carbohydrate fatty acid monosulphate ester (CMS), a new oil-in-water adjuvant, has proven potency in animal models with suggested capacity for dose-sparing. The objective was to evaluate safety and immunogenicity of CMS when added to a low-dose influenza vaccine (QIV) in humans. In a randomised, double-blind, active-controlled, first-in-human study, sixty participants (18-50 years) received either 0.5 mg CMS or 2 mg CMS with 1/5th dose QIV, or a full dose QIV without CMS. Adverse events (AE) were monitored until 7 days post-vaccination. Haemagglutinin inhibition (HI) titres in serum and CD4+ T cells in PBMCs were determined at day 0, 7, 28, and 180. Mean age was 37.6 (±10.1) years and 42/60 (70.0%) were female. Pain at injection site (42/60, 86.7%) and headache (34/60, 56.7%) were reported most and more frequently in the 2 mg CMS group. HI titres and the frequency of influenza specific CD4+ T cells were equal across strains for the three cohorts on all visits, increased until day 28 and decreased at day 180 to values higher than baseline. CMS was safe in humans. Humoral and cell-mediated immunogenicity was similar across vaccines, even with 1/5th antigen dose. CMS can have beneficial implications in low-resource settings or in a pandemic context.

Prevalence, spatial distribution and determinants of complete childhood pneumococcal conjugate vaccination in Ethiopia: spatial and multilevel analyses

IntroductionPneumococcal disease is a serious global public health concern. The primary causative agent of severe illnesses such as pneumonia, meningitis, acute otitis media, and bacteremia is the pneumococcus bacterium. The pneumococcal conjugate vaccine is a key strategy to reduce the burden of pneumococcal disease. Understanding the spatial distribution of complete childhood pneumococcal conjugate vaccine utilization and its associated factors is crucial for designing strategies to improve vaccination implementation. Therefore, this study aimed to determine the spatial distribution of complete childhood pneumococcal conjugate vaccination coverage and identify its determinants in Ethiopia.MethodA spatial and multilevel analysis was conducted using data from the 2019 Ethiopian Mini Demographic and Health Survey. The analysis included a total of 2,055 weighted children. The association between the outcome variable and the explanatory variables was determined by calculating adjusted odds ratios at a 95% confidence interval. Explanatory variables were considered significantly associated with the outcome if the p-value was less than 0.05.ResultThe prevalence of complete childhood pneumococcal conjugate vaccination in Ethiopia was 53.94% (95% CI: 51.77, 56.08). Higher complete childhood pneumococcal vaccination coverage was observed in the Addis Ababa, Tigray, Amhara, Benishangul-Gumuz, and Oromia regions, while lower coverage was seen in the Afar, Somali, and SNNPR regions of Ethiopia. Factors significantly associated with complete childhood pneumococcal conjugate vaccination included maternal age, antenatal care visits, place of delivery, region, community women’s literacy level, community poverty level, and community antenatal care utilization.ConclusionThe distribution of complete childhood pneumococcal conjugate vaccination exhibited spatial variability across Ethiopia. Approximately half of children aged twelve to thirty-five months received the full dose of the childhood pneumococcal conjugate vaccine in the country. Several factors were identified as statistically significant determinants of complete childhood pneumococcal conjugate vaccination, including maternal age, antenatal care visits, place of delivery, region, community women’s literacy level, community poverty level, and community ANC utilization. Therefore, policies and strategies aimed at combating pneumococcal disease should consider these determinants and address areas with low vaccination coverage.

Rapid Desensitization to Antitumoral Agents. Result from a Retrospective Study, DESARCh

Antitumoral drugs (ADs) can induce drug hypersensitivity reactions (DHRs). Rapid drug desensitization (RDD) protocols represent an important option to mitigate recurrent DHRs thus allowing the safe administration of ADs at therapeutic doses. The aim of this retrospective study was to assess the effectiveness of the RDD protocols performed at our institution. The “DESARCh” study was a retrospective, observational study that included consecutive patients who underwent RDD protocols from January 2011 to December 2022 at IRCCS Ospedale Sacro Cuore Don Calabria in Negrar di Valpolicella, Verona, Italy. The RDD protocol consisted of a 5-step protocol with 5 different concentrations of the drugs at 1:1, 1:10, 1:100, 1:1,000 and 1:10,000 dilution given intravenously over a 1-hour infusion each, with concentrations increasing from the most diluted to the most concentrated form, preceded by a 30-min premedication regimen. A total of 66 RDD protocols were administered to 25 female patients with ovarian (64%; n = 16/25), breast (12%; n = 3/25), endometrium (8%; n = 2/25), cervix (8%; n = 2/25), uterine (4%; n = 1/25) and fallopian tubes (4%; n = 1/25) cancers. A known history of atopy/allergy was reported by 36% (n = 9/25) of patients. Patients received RDD protocols because of DHRs to carboplatin (n = 23/66, 34.85%), paclitaxel (n = 18/66, 27.27%), pegylated liposomal doxorubicin (n = 3/66, 4.55%), and trastuzumab (n = 22/66, 33.33%). DHRs were mild-moderate, severe and life-threatening in 60.72%, 28.57% and 10.71% of cases, respectively. The success rate of RDD protocols, defined as the rate of complete administration of full target dose with no breakthrough reactions, was 81.82% (n = 54/66). Success rate was lower for carboplatin compared to other drugs (65.22% vs 90.7%; P = .017678). The RDD protocol used in our institution was found to be safe, with a meaningful success rate. However, further research is needed to better understand the underlying mechanisms of DHRs and to enhance effectiveness, particularly for patients experiencing DHRs to platinum compounds. This study was approved by the ethics committee of Verona and Rovigo (Italy) with approval number 15476 on 10/03/2023 and it was registered with the Register of Observational Studies of the Italian Medicines Agency (AIFA) (available since 31 January 2023), with ID n. 109, on 28/02/2023 ( https://www.aifa.gov.it/en/registro-studi-osservazionali ).

Evaluating nephrotoxicity reduction in a novel polymyxin B formulation: insights from a 3D kidney-on-a-chip model.

This study aimed to assess the nephrotoxicity associated with VRP-034 (novel formulation of polymyxin B [PMB]) compared to marketed PMB in a three-dimensional (3D) kidney-on-a-chip model. To model the human kidney proximal tubule for analysis, tubular structures were established using 23 triple-channel chips seeded with RPTEC/hTERT1 cells. These cells were exposed to VRP-034 or PMB at seven concentrations (1-200 µM) over 12, 24, and 48 h. A suite of novel kidney injury biomarkers, cell health, and inflammatory markers were quantitatively assessed in the effluent. Additionally, caspase and cytochrome C levels were measured, and cell viability was evaluated using calcein AM and ethidium homodimer-1 (EthD-1). Exposure to marketed PMB resulted in significantly elevated levels (P < 0.05) of four key biomarkers (KIM-1, cystatin C, clusterin, and OPN) compared to VRP-034, particularly at clinically relevant concentrations of ≥10 µM. At 25 µM, all biomarkers demonstrated a significant increase (P < 0.05) with marketed PMB exposure compared to VRP-034. Inflammatory markers (interleukin-6 and interleukin-8) increased significantly (P < 0.05) with marketed PMB at concentrations of ≥5 µM, relative to VRP-034. VRP-034 displayed superior cell health outcomes, exhibiting lower lactate dehydrogenase release, while ATP levels remained comparable. Morphological analysis revealed that marketed PMB induced more severe damage, disrupting tubular integrity. Both treatments activated cytochrome C, caspase-3, caspase-8, caspase-9, and caspase-12 in a concentration-dependent manner; however, caspase activation was significantly reduced (P < 0.05) with VRP-034. This study demonstrates that VRP-034 significantly reduces nephrotoxicity compared to marketed PMB within a 3D microphysiological system, suggesting its potential to enable the use of full therapeutic doses of PMB with an improved safety profile, addressing the need for less nephrotoxic polymyxin antibiotics.

625. PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY CHEMORADIATION AND MINIMALLY INVASIVE SURGERY FOR LOCALLY ADVANCED CARCINOMA OF THE ESOPHAGUS

Abstract Background Most patients with esophageal cancer (EC) present locally advanced disease. Currently, multimodal strategies as neoadjuvant chemoradiotherapy or perioperative chemotherapy are employed, but still have high local and distant failures rates. This study evaluated the results of a phase II protocol with induction chemotherapy (IC) and concurrent chemoradiation (CR) before surgery for locally advanced carcinoma of the esophagus and esophagogastric junction (EGJ). The primary end point was to evaluate pathological complete remission (PCR) rate at surgical specimen. A PCR ≥ 30% was considered promising for further study. Methods Patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus and JEG, clinical stage T1b-3, N0-2, M0, PS 0-2, underwent two cycles of IC with carboplatin and paclitaxel followed by CR with the same agents and minimally invasive esophagectomy. At the screening, 14 days after the first cycle of IC and 6-8 weeks after the CR, metabolic responses were accessed by PET-CT and classified according the PERCIST criteria. Results One hundred and twenty-nine patients were accrued from January 2017 to April 2023. Forty-seven patients started the trial and 45 completed the neoadjuvant part of the protocol. Most patients were male (73.3%), the median age of was 55 years and AC was the most prevalent histological subtype (53.3%). Grade 3/4 toxicity during IC were infrequent and included neutropenia (12.5%), anemia (6.2%) and dysphagia (10.4%). Lymphopenia (10.7%) and dysphagia (6.5%) were the most common grade 3/4 toxicity during CR. All cases received the full radiotherapy dose of 45 Gy by IMRT technique. Thirty-seven patients underwent surgery and 31 had minimally invasive MacKeown esophagectomy with complete tumor resection (R0). Sixty-four percent of all included patients completed the neoadjuvant therapy and survived for 30 days after surgery. The most prevalent postoperative complications were anastomotic fistula (29%) and pneumonia (19%). Median hospital stay was 12 (7-56) days. Six patients (19.3%) had major postoperative morbidity (Clavien-Dindo ≥ IIIb), 4 were reoperated and one (3.2%) died during hospitalization. The median number of lymph nodes retrieved was 24. Eleven patients (33.5%) had pathological positive lymph nodes. The overall pathological complete response rate was 25.8%, 41.8% for SCC and 15.8% for AC. The early metabolic evaluation by PERCIST showed that 2 cases (4.4%) had progressive disease (PD), 26 (57.7%) stable disease (SD), 15 (33.3%) partial response (PR) and 2 (4.4%) complete response (CR). All the CR were SCC. The late metabolic response analysis showed that 1 (2.4%) patient had PD, 6 (14.6%) SD, 23 (56%) PR and 11 (27%) CR. On the basis of an intention-to-treat analysis, the median overall survival was 31.4 months, whereas the five-year overall survival was 31.2%. After curative surgery, 12 patients had recurrence disease. Six (19%) patients had recurrences at distant sites, 4 (12.9%) had loco-regional recurrence and 2 (6.4%) had both patterns. Conclusion This intensified neoadjuvant regimen was efficacious and safe in patients with locally advanced EC, but failed to reach the defined efficacy goal for further investigation, especially for AC.

Dosing Strategies and Quantitative Clinical Pharmacology for Bispecific T-Cell Engagers Development in Oncology.

Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first-in-human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model-based adaptive design; (3) virtual testing of different step-up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step-up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit-risk profile for cancer patients.

523. FIVE YEARS OF FLOT THERAPY. RANDOMIZED CONTROLLED TRIAL EVIDENCE IN PRACTICE

Abstract Introduction The combination of 5-flurouracil, oxaliplatin, leucovorin and docetaxel (FLOT) is an effective chemotherapy regime in locally advanced, resectable gastro-oesophageal adenocarcinoma. Since the FLOT4-AIO randomised controlled trial demonstrated superiority over ECF/ECX it has been standard of care at many centres and European Society of Medical Oncology’s recommended perioperative regimen. After over five years of offering this treatment to patients we assessed how this evidence had translated into practice; identifying factors that predict dose reduction or incomplete therapy and overall survival. Method Patients who had the combination of neoadjuvant FLOT chemotherapy and oesophagectomy for adenocarcinoma of the oesophagus or gastro-oesophageal junction between February 2018 and September 2023 were identified from a prospectively collected database. Data on completion of chemotherapy, perioperative outcomes and long-term survival were collected. Pathological regression was assessed using Mandard tumour regression grade (TRG). The peri-operative, pathological, and long-term outcomes of patients who completed four cycles of neoadjuvant FLOT was compared with those who had reduced dose or early cessation. Statistical analysis used IBM SPSS, with Mann-Whitney U and Chi squared for variable analysis and univariate cox regression for survival. Results Eighty patients were included with a median age of 66 (47-79), 84% were male. Full dose completion was achieved by 57 (71%) patients, 20 (25%) had dose reduction and 7(8%) did not complete four cycles. Age, anaerobic threshold and VO2 max were not significantly different between those completing or not completing neoadjuvant chemotherapy (p=0.460, p=0.624, p=0.104 respectively); or requiring dose reductions (p=0.317, p=0.587, p=0.82). Median TRG across all three groups was 3. Median follow up was 55.4 months and mean overall survival was 53.4 months. No difference in survival was observed between those who completed or did not complete neoadjuvant FLOT (p=0.45). Conclusion Completion of neoadjuvant chemotherapy was lower in this cohort of patients than FLOT4-AIO. Rates of pathological complete response were similar. This translated into similar mean overall survival. Median survival was unable to be calculated as survival exceeds 50% at the time of our study. The use of FLOT has translated well into the routine neoadjuvant clinical setting with acceptable short- and long-term outcomes.

Low dose optimization for total-body 2-[18F]FDG PET/CT imaging: a single-center study on feasibility based on body mass index stratification.

Implementing personalization protocol in clinical routine necessitates diverse low-dose PET/CT scan protocols. This study explores the clinical feasibility of one-third (1/3) dose regimen and evaluates the diagnostic image quality and lesion detectability of BMI-based 1/3-injection doses for 2-[18F]FDG PET/CT imaging. Seventy-four cancer patients underwent total-body 2-[18F]FDG PET/CT examination, with 37 retrospectively enrolled as full-dose group (3.7 MBq/kg) and 37 prospectively enrolled as the 1/3-dose group (1.23 MBq/kg). The 1/3-dose group was stratified by BMI, with an acquisition time of 5 min (G5), 6 min (G6), and 8 min (G8) for BMI < 25, 25 ≤ BMI ≤ 29, and BMI > 29, respectively. Image quality was subjectively and objectively assessed, and lesion detectability was quantitatively analyzed. Subjective assessments of 1/3-dose and full-dose PET images showed strong agreement among readers (κ > 0.88). In the 1/3-dose group, the Likert scores were above 4. G5, G6, and G8 showed comparable image quality, with G5 demonstrating higher lesion conspicuity than G6 and G8 (p = 0.045). Objective evaluation showed no significant differences in SUVmax, liver SUVmean and TBR between 1/3- and full-dose groups (p > 0.05). No statistical differences were observed in the SUVmax of primary tumor, SUVmean of liver and TBR across all BMI categories between the 1/3-dose and full-dose groups. Lesion detection rates showed no significant difference between the 1/3-dose (93.24%, 193/207) and full-dose groups (94.73%, 198/209) (p = 0.520). A BMI-stratified 1/3-dose regimen is a feasible low-dose alternative with clinically acceptable lesion detectability equivalent to full-dose protocol, potentially expanding the applicability of personalized protocols. This study demonstrated that BMI-stratified 1/3-dose regimens for [18F]FDG total-body PET/CT yielded equivalent outputs compared to the full-dose regimen, which aligns with clinical needs for personalization in dose and BMI. Currently, limited personalized low-dose total-body PET/CT protocols are available, particularly for patients with varied BMI. Reducing the radiotracer dose to 1/3 the standard demonstrated comparable image quality and lesion detectability equivalent to full dose. BMI-stratified 1/3-dose regimen is a clinically feasible low-dose alternative.

Anti-OJ antibody-positive anti-synthetase syndrome following SARS-CoV-2 infection: a case report and literature review

BackgroundCOVID-19 can induce a systemic inflammatory response with variable clinical manifestations. Similar to various viruses, COVID-19 has been implicated in the pathogenesis of autoimmune diseases. This article highlights the potential for infections including the SARS-CoV-2 virus to induce exacerbations of pre-existing autoimmune diseases or even potentially unmask de novo autoimmune diseases in particular anti-synthetase syndrome (ASSD) in predisposed individuals. Although there are other case reports of ASSD following SARS-CoV-2 infection, here we present the first reported case of a gentleman with a newly diagnosed anti-OJ positive anti-synthetase syndrome following SARS-CoV-2 infection.Case presentationDescribed is a case of a 70-year-old man presenting to the emergency department with worsening dyspnea in the context of a recent COVID-19 infection. CT-chest revealed changes suggestive of fibrotic lung disease, consistent with usual interstitial pneumonitis (UIP) pattern. Despite recovery from his COVID-19 illness, the patient subsequently developed proximal myopathy with cervical flexion weakness on further assessment with persistently elevated creatinine kinase (CK). Myositis autoantibodies found a strongly positive anti-OJ autoantibody with MRI-STIR and muscle biopsy performed to further confirm the diagnosis. The patient received pulse methylprednisolone 1 g for 3 days with a long oral prednisolone wean and in view of multiple end-organ manifestations, loading immunoglobulin at 2 g/kg administered over two days was given. In addition, he was then commenced and escalated to a full dose of azathioprine given a normal purine metabolism where he remains in clinical remission to this date. At least 267 cases of rheumatic diseases has been associated with SARS-CoV-2 infection as well as COVID-19 vaccination. A literature search on PubMed was made to determine the amount of case reports describing myositis associated with SARS-CoV-2 infection. We found 3 case reports that fit into our inclusion criteria. Further literature searches on diagnostic approach and treatment of ASSD were done.ConclusionAlthough SARS-CoV-2 infection itself can cause a directly mediated viral myositis, this case report highlights the possibility of developing virus-triggered inflammatory myositis through multiple aforementioned proposed mechanisms. Therefore, further studies are required to explore the relationship and pathophysiology of SARS-CoV-2 infection and the incidence of inflammatory myopathies.

Wide cone beam CT dosimetry: Analysis of results and uncertainty evaluation

ObjectiveTo investigate the consistency of the recommended methodology, we analyzed the dosimetric results obtained for each setup beam shaping filter and tube voltage and evaluated the uncertainty associated with the full dose measurement process. MethodsA 300-mm PTIC was used to validate the results obtained with the 100-mm PTIC. Considering the other dosimetric parts, a cylindrical 160-mm diameter PMMA phantom and a cylindrical 320-mm diameter PMMA phantom were also used in the experimental protocol. ResultsFor the lowest and highest tube voltages available, the CTDIair,160 values obtained by 1-step dosimetry with the 300-mm PTIC were greater than the respective values obtained by 2- and 3-step dosimetry with the 100-mm PTIC. ConclusionThis study established that careful positioning of the 100-mm PTIC in 2 or 3 steps, as well as proper execution of the other dosimetric parts recommended by the IAEA, represents a validated approach within up to 20% uncertainty for wide cone beam CT dosimetry.