Patient Dose Research Articles

National Diagnostic Reference Levels for Standard Descending Thoracic Endovascular Aortic Repair and Optimisation Strategies

The International Commission on Radiological Protection has highlighted the large number of medical specialties that use fluoroscopy outside diagnostic imaging departments without radiation protection programmes for patients and staff. Vascular surgery is one of these specialties. Thoracic endovascular aortic repair (TEVAR) is a complicated procedure requiring radiation protection guidance and optimisation. The recent EU Basic Safety Standards Directive requires the use and periodic updating of diagnostic reference levels (DRLs) for interventional procedures. The aim of this study was to determine doses for patients undergoing TEVAR with mobile Xray systems and hybrid rooms (fixed Xray systems) to obtain national DRLs and to suggest optimisation actions. This was a retrospective cross sectional study. The Spanish Chapter of Endovascular Surgery conducted a national survey in 11 autonomous communities representing around 77.6% of the Spanish population (47.33 million inhabitants). A total of 266 TEVAR procedures from 17 Spanish centres were analysed, of which 53.0% were performed in hybrid operating rooms. National DRLs were obtained and defined as the third quartile of the median values from the different participating centres. The proposed national DRLs are: for kerma area product (KAP), 113.81 Gy·cm2 for mobile Xray systems and 282.59 Gy·cm2 for hybrid rooms; and for cumulative air kerma (CAK) at the patient entry reference point, 228.38 mGy for mobile systems and 910.64 mGy for hybrid rooms. Based on the requirement to know radiation doses for standard endovascular procedures, this study of TEVARs demonstrated that there is an increased factor of 2.48 in DRLs for KAP when the procedure is performed in a hybrid room compared with mobile C-arm systems, and an increased factor of 3.98 in DRLs for CAK when the procedure is performed with hybrid equipment. These results will help to optimise strategies to reduce radiation doses during TEVAR procedures.

Evaluation of the four mg warfarin initiation dose in patients with cardiovascular disease

Background: Warfarin is the most widely used oral anticoagulant for the prevention of stroke in patients with cardiovascular disease. In Indonesia, validation of the initiation dose of warfarin has never been carried out. Objective: To evaluate the efficacy and safety of 4 mg warfarin initiation dose in achieving therapeutic targets. Methods: It was a prospective observational study involving hospitalised and ambulatory patients administered a 4 mg warfarin initiation dose between days one and three. On day four, the INR was measured for three to seven days. Subsequently, the initiation dose was adjusted to the therapeutic INR. The INR level was measured every seven days until patients achieved therapeutic INR twice. Results: A total of 14 patients were included in this study, with a mean age of 62 years. The most common indication for using warfarin was non-valvular atrial fibrillation (85.7%), with a CHA2DS2-VASc score between one and three and a HAS-BLED score ranging from zero to two. The median time to achieve therapeutic INR was 22.2 days, and the predictive value of the day four INR for determining the maintenance dose had an r2= 0.77. Conclusions: The initiation dose of 4 mg warfarin effectively achieved therapeutic INR within an acceptable time.

A novel method for rapid estimation of active bone marrow dose for radiotherapy patients in epidemiological studies.

In a dedicated effort to improve the assessment of clonal hematopoiesis (CH) and study leukemia risk following radiotherapy, we are developing a large-scale cohort study among cancer patients who received radiation. To that end, it will be critical to analyze dosimetric parameters of red bone marrow (ABM) exposure in relation to CH and its progression to myeloid neoplasms, requiring reconstruction method for ABM doses of a large-scale patients rapidly and accurately. To support a large-scale cohort study on the assessment of clonal hematopoiesis and leukemia risk following radiotherapy, we present a new method for the rapid reconstruction of ABM doses of radiotherapy among cancer patients. The key idea of the presented method is to segment patient bones rapidly and automatically by matching a whole-body computational human phantom, in which the skeletal system is divided into 34 bone sites, to patient CT images via 3D skeletal registration. The automatic approach was used to segment site-specific bones for 40 radiotherapy patients. Also, we segmented the bones manually. The bones segmented both manually and automatically were then combined with the patient dose matrix calculated by the treatment planning system (TPS) to derive patient ABM dose. We evaluated the performance of the automatic method in geometric and dosimetric accuracy by comparison with the manual approach. The pelvis showed the best geometric performance [volume overlap fraction (VOF): 52% (mean) with 23% (σ) and average distance (AD): 0.8cm (mean) with 0.5cm (σ)]. The pelvis also showed the best dosimetry performance [absorbed dose difference (ADD): 0.7Gy (mean) with 1.0Gy (σ)]. Some bones showed unsatisfactory performances such as the cervical vertebrae [ADD: 5.2Gy (mean) with 10.8Gy (σ)]. This impact on the total ABM dose, however, was not significant. An excellent agreement for the total ABM dose was indeed observed [ADD: 0.4Gy (mean) with 0.4Gy (σ)]. The computation time required for dose calculation using our method was robust (about one minute per patient). We confirmed that our method estimates ABM doses across treatment sites accurately, while providing high computational efficiency. The method will be used to reconstruct patient-specific ABM doses for dose-response assessment in a large cohort study. The method can also be applied to prospective dose calculation within a clinical TPS to support clinical decision making at the point of care.

Utility of a Third Heplisav-B Dose in Patients With Inflammatory Bowel Disease Without Immunity After 2-Dose Heplisav-B Vaccination.

Hepatitis B virus (HBV) vaccination is recommended in patients with inflammatory bowel disease (IBD). Although the 2-dose Heplisav-B vaccine has proven effective, more than 20% of patients with IBD do not seroconvert. We prospectively evaluated the effectiveness of a third Heplisav-B dose in patients with IBD lacking HBV immunity despite 2-dose vaccination. Adults with IBD who had received 2-dose Heplisav-B vaccination between 2018 and 2023 were identified. Seroconversion was defined as hepatitis B surface antibody (HBsAb) ≥ 10 IU/L measured at ≥4 weeks after vaccination. Patients who did not seroconvert were prospectively offered a third Heplisav-B dose, followed by repeat HBsAb measurement. Demographic, clinical, medication, and vaccination data were compared between those who did and did not seroconvert. Of 192 patients identified, 71.9% (138/192) seroconverted after 2-dose Heplisav-B vaccination. The 54 patients (28.1%) who did not seroconvert were more likely to be male, have diabetes, chronic kidney disease, or elevated Charlson Comorbidity Index. Of the 54 patients, 30 (55.6%) elected to receive a third Heplisav-B dose, with 56.7% (17/30) achieving seroconversion (median HBsAb titer 376 IU/L, IQR 47-1,000 IU/L) despite a median intervaccination time of 416 days (IQR 90.8-667.8). No differences were noted between patients who did vs did not seroconvert after third-dose vaccination. In patients with IBD lacking HBV immunity despite 2-dose Heplisav-B vaccination, administration of a third dose resulted in a 56.7% seroconversion rate. Our results suggest that administration of an additional Heplisav-B dose may be an effective strategy in patients lacking immunity despite primary 2-dose vaccination.

Exposure-response relationship of guselkumab and the potential of serum proteomics in identifying predictive biomarker candidates in psoriasis.

Response to biologics in psoriasis varies in real-world settings. Serum biomarkers could aid biologic selection and dose modifications to improve patient outcomes while encouraging cost-effective care. To explore the exposure-response relationship for guselkumab (GUS), to define a GUS concentration target for optimal response and to evaluate the potential of serum protein levels as predictive biomarker candidates. This is a prospective, multicentric, cohort study in psoriasis patients treated with GUS. Serum GUS trough concentrations (TCs) collected at multiple timepoints were measured using an in-house immunoassay. Next, proximity extension assay technology (Target 96 Inflammation Panel Olink®) was used to measure serum protein levels in a subcohort including 38 GUS patients (week 0 and week 4), six psoriasis patients naive for systemic treatment and four healthy controls. Seventy-five patients participated and 400 samples were collected. Guselkumab TCs and clinical response were correlated at week 4, week 12 and in steady-state (≥20 weeks). Optimal responders (Psoriasis Area and Severity Index [PASI] ≤ 2) had significantly higher TCs than suboptimal responders from week 4 onwards in treatment. An optimal steady-state TC of 1.6 μg/mL was defined. Although TC and absolute PASI were lower and worse, respectively, in patients weighing ≥90 kg, clinical outcomes referred to desirable to excellent PASI ranges. Therefore, we do not recommend systematically higher GUS doses in obese patients. We could not reveal early differentially expressed proteins to distinguish future optimal from suboptimal responders. We demonstrated an exposure-response relationship for GUS and an optimal steady-state TC of 1.6 μg/mL in real-world psoriasis patients. Hereby, we deliver more evidence that therapeutic drug monitoring poses a promising strategy in optimizing GUS treatment. No biomarker candidates were identified through serum proteomics. We propose protein screening should be repeated in larger cohorts to continue the quest for predictive biomarkers.

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial

Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200mg/day for patients with bodyweight <77kg and/or platelet count <150×103/μL at baseline and 300mg/day otherwise. OS was a secondary endpoint. Totally, 265 patients were randomised to receive niraparib (n=177) or placebo (n=88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Increasing the Use of Enteral Antibiotics in Hospitalized Children With Uncomplicated Infections.

Route of administration is an important component of antimicrobial stewardship. Early transition from intravenous to enteral antibiotics in hospitalized children is associated with fewer catheter-related adverse events, as well as decreased costs and length of stay. Our aim was to increase the percentage of enteral antibiotic doses for hospital medicine patients with uncomplicated common bacterial infections (community-acquired pneumonia, skin and soft tissue infection, urinary tract infection, neck infection) from 50% to 80% in 6 months. We formed a multidisciplinary team to evaluate key drivers and design plan-do-study-act cycles. Interventions included provider education, structured discussion at existing team huddles, and pocket-sized printed information. Our primary measure was the percentage of antibiotic doses given enterally to patients receiving other enteral medications. Secondary measures included antibiotic cost, number of peripheral intravenous catheters, length of stay, and 7-day readmission. We used statistical process control charts to track our measures. Over a 6-month baseline period and 12 months of improvement work, we observed 3183 antibiotic doses (888 in the baseline period, 2295 doses during improvement work). We observed an increase in the percentage of antibiotic doses given enterally per week for eligible patients from 50% to 67%. We observed decreased antibiotic costs and fewer peripheral intravenous catheters per encounter after the interventions. There was no change in length of stay or readmissions. We observed increased enteral antibiotic doses for children hospitalized with common bacterial infections. Interventions targeting culture change and communication were associated with sustained improvement.

A novel method for accurate and real-time quantification of radiopharmaceutical activity in automated dose dispensers

In recent years, there has been a rapid growth in new technologies within nuclear medicine and PET diagnostics, particularly in the field of radiopharmaceutical dose preparation. These advancements are driven by the integration of automatic algorithms into the process. This evolution has brought about significant improvements in the efficiency and accuracy of radiopharmaceutical dose preparation. These automatic algorithms utilize state-of-the-art technologies to streamline the process and ensure precise and tailored doses for patients. The integration of these advanced technologies has revolutionized the field, allowing for more effective and personalized treatment options in nuclear medicine and PET diagnostics. By employing automatic radiopharmaceutical dose dispensers (ARDDs), radiation exposure to technologists is minimized while also mitigating the risk of potential infections for patients. Ionization chambers are currently the most used detectors to measure the activity of radiopharmaceuticals in ARDDs. However, they present certain limitations, including size constraints. This study is part of an international endeavor to develop a new approach for evaluating radiopharmaceutical activity in an ARDD named KARl 100. A new approach was used to develop a scintillation detector by linking a PVT detector to a SiPMs array consisting of four elements, each having an active surface of 6 × 6 mm with a bias voltage of 30 V. The detection system's amplified output was then fed to a single-channel analyzer called Enviro, developed by Tema Sinergie S.p.A in Italy. The counts per second (CPS) detected by the detector were studied using WinTAM software allowing for the radionuclide’s activity concentration to be read out at run-time. Three widely used medical radioisotopes, 18F, 11C and 68Ga, were used to evaluate the performance of the detector in terms of linearity and repeatability of the measurements. Half-life and linear response were evaluated over a wide range of activities with different decay schemes. Data analysis was conducted, resulting in half-lives of the 18F, 11C and 68Ga radioisotopes of 109.75 ± 0.35, 20.62 ± 0.34 and 67.82 ± 0.25 min, respectively, with calculated deviations of 0.0167%, 1.00% and 0.29% from expected values. The linear response of the detector over the entire range of desired activity concentrations was confirmed after data correction for the detector dead time. Calibration of the detector combined with the dispenser system was carried out in parallel investigations to provide the required device properties for reference applications in nuclear medicine. Furthermore, Monte Carlo simulations using FLUKA code were performed to investigate the contribution of beta particles in addition to gamma radiations to assess the influence of beta particles on the calibration factors. For better accuracy, a shielding was designed to prevent any beta particles from reaching the detector.

Abstract PO4-13-01: A randomised trial comparing 6-monthly dosing of adjuvant zoledronate with a single one-time dose in patients with early breast cancer (REaCT-ZOL): Quality of life and toxicity outcomes

Abstract Background: While adjuvant 6-monthly zoledronate is widely used in patients with early-stage breast cancer (EBC), questions remain around optimal scheduling of adjuvant bisphosphonates. We reviewed quality of life and bisphosphonate-related toxicities observed within a prospective randomised trial. Methods: Patients with EBC were randomised to either a single infusion of adjuvant zoledronate (4mg IV) or to 6-monthly treatment for 3 years. Quality of life was measured using the EQ-5D-5L questionnaire (before and after each infusion and 6-monthly thereafter in the single infusion arm). Acute phase reaction (APRs) data was collected after each infusion and data on other bisphosphonate-related toxicities (hypocalcaemia, renal impairment, ONJ and atypical fractures) was collected 6-monthly for 3 years. Results: Between 21-Nov-2018 and 02-Apr-2020, 211 patients were randomized to either a single infusion (n=107) or 6-monthly (n=104) adjuvant zoledronate. While each zoledronate infusion was associated with a worsening QoL, the overall QoL was the same in the two study arms. APRs occurred in 75% of patients after receiving zoledronate. Other bisphosphonate-related toxicities were uncommon in either arm. Significantly more patients discontinued study treatment in the 6-monthly arm (30/104, 28.8%) compared with the single infusion arm (3/107, 2.8%) (p &amp;lt; 0.001). The most common reason for study discontinuation was the occurrence of APRs, pain and malaise. Disease-free and overall survival rates were not significantly different in the study arms. Discussion: A single infusion of adjuvant zoledronate may offer patients a more convenient and better tolerate regimen than repeat infusions. APRs remain an important toxicity with repeat infusions of zoledronate, leading to increased rates of treatment discontinuation. Larger, definitive, trials comparing a single infusion with repeat treatments are required. Citation Format: Igor Machado, Lucas Clemons, Carol Stober, Gregory Pond, Arif Awan, Henry Conter, Demetrios Simos, Sukhbinder Dhesy-Thind, Mihaela Mates, Vikaash Kumar, John Hilton, Lisa Vandermeer, Mark Clemons. A randomised trial comparing 6-monthly dosing of adjuvant zoledronate with a single one-time dose in patients with early breast cancer (REaCT-ZOL): Quality of life and toxicity outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-01.

Abstract PO1-07-05: Preliminary Evaluation in Breast Cancer of PointCheck: a Noninvasive AI-Based Neutropenia Monitoring Device

Abstract Background Febrile neutropenia (FN) is a common complication that can arise in breast cancer patients receiving myelosuppressive chemotherapy and increases the risk of fatal infections. Despite better preventive strategies there are between 140,000 to 200,000 FN-related hospitalizations yearly. Quick detection and awareness of grade III neutropenia (Absolute Neutrophil Count [ANC] &amp;lt; 1,000/µL) or greater can be critical to managing FN and treatment scheduling and dosing in patients with breast cancer. The current gold standard for neutropenia detection is a peripheral blood collection that requires patients to come into the clinic. PointCheck™ is a novel, noninvasive technology that can monitor for grade III neutropenia or greater and enable prompt detection in the home by acquiring microscopy videos of superficial capillaries through the nailfold skin and analyzing those videos with computer vision AI algorithms. To evaluate the usability, diagnostic performance, and preliminary clinical utility of PointCheck™ on FN detection we conducted a multi-center observational usability and diagnostic study. Methods The present study included an overall cohort of 175 diverse cancer patients, with 70 breast cancer patients. The primary endpoint was to achieve a score over 80.8 on a standardized System Usability Scale (SUS). Secondary endpoint was achievement of diagnostic performance with an area under the curve (AUC) above 0.80. We also performed an exploratory analysis on the device's clinical utility. Eligible participants were introduced to the device, watched a tutorial video and were given a user manual. They used the device autonomously under the supervision of the clinical team. Usability data was collected using the SUS, the scoring system that has a scale between 0-100. PointCheck™ measurements were analyzed using AI algorithms and compared to same-day Complete Blood Counts (CBCs) collected within 90 minutes of the measurement to assess accuracy in classifying patients as grade III neutropenic or greater (&amp;lt; 1,000/µL), or non-grade III neutropenic (≥1,000/µL). In the exploratory clinical utility analysis, clinicians provided narrative insights by completing a Likert survey assessing how PointCheck™ would support or impact their clinical decisions. Results 81.4% of breast cancer patients scored above 80.8 on the SUS scale across all sites, with a mean SUS score of 87.7 (SD=13.2). Furthermore, the AI-based PointCheck™ classifier accurately discriminated neutropenia patients with an AUC = 0.90 in the overall cohort. In the exploratory analysis, a majority of clinicians (65.2%) agreed that the device could have helped better evaluate their patients (Table 1). Whereas almost 3 out of 4 clinicians (72.4%), described that the use of PointCheck™ could have avoided preparing a chemotherapy infusion if the patient was not ready due to grade III neutropenia or greater. Conclusions The present study showed that there is a high perception of usability of PointCheck™, indicating an above average user experience and falling within the top 10% of systems. Furthermore, we found that PointCheck™ can accurately detect grade III neutropenia or greater in a large cohort of patients including breast cancer patients. Application of PointCheck™ to clinical practice as a monitoring system can contribute to the early detection of FN and antineoplastic therapy management. Table 1: Clinical Utility Survey Results Citation Format: Juan Garcia-Mosquera, Manuel Alva, Toshiaki Iwase, Ganimete Lamaj, Pablo Tolosa, Rodrigo Sánchez-Bayona, José Pelaez-Escobar, Alberto Pablo-Trinidad, Ryan Benasutti, Aurélien Bourquard, Ian Butterworth, Alvaro Sánchez-Ferro, Carlos Castro-González, José Manuel Pérez-García, Alejandro Martínez-Bueno, Eva Ciruelos, Azadeh Nasrazadani. Preliminary Evaluation in Breast Cancer of PointCheck: a Noninvasive AI-Based Neutropenia Monitoring Device [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-07-05.

Optimal Strategies to Select Warfarin Dose for Thai Patients with Atrial Fibrillation.

Background: Warfarin has been the mainstay treatment for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation (AF). The optimal starting dose of warfarin remains unclear. Objective: To investigate the most optimal dosing strategies for warfarin starting dose in Thai patients with AF. Material and Methods: We enrolled consecutive AF patients who were starting on warfarin and resulting in a stable INR of 2.0-3.0 at two consecutive time points. We measured the dose of warfarin at which INR achieved the target range. The optimal dosage was defined as the difference from the actual dose within 20%. We compared strategies of warfarin dosing, including warfarin dosing formula, 2.5 mg, 3 mg and 5 mg doses. The primary endpoints were the proportions of patients in optimal, underdosing, and overdosing categories. Results: Among 1207 patients visiting the Outpatient Clinic between October 2011 and September 2021, 531 patients were identified with AF and INR in the therapeutic range of 2.0-3.0 on at least two consecutive visits. The mean age of participants was 68 ± 11 years, and men accounted for 44.4% of the population. The warfarin dosing formula resulted in optimal dosing in 37% and overdosing in 24% of cases, whereas the 2.5 mg, 3 mg and 5 mg doses resulted in optimal dosing in 36%, 39%, and 11%, and overdosing in 33%, 44% and 88% of patients, respectively (p < 0.01). Conclusions: In Thai patients with AF, the optimal warfarin starting dose may be 2.5 mg, 3 mg or a simplified warfarin dosing formula, whereas the 5 mg dose should be avoided due to the high risk of overdosing.

Abstract PS16-09: Analysis of the Radiosensitivity Index/Genomic-Adjusted Radiation Dose (RSI-GARD) in Paired Pre- and Post-Treatment TNBC Samples: Implications for Biomarker-Guided Radiotherapy

Abstract Objectives: Adjuvant radiotherapy is an important component of curative treatment for triple-negative breast cancer (TNBC). While there are several accepted variations in nominal dose and fractionation, these regimens are generally felt to be radiobiologically equivalent. Molecular radiosensitivity biomarkers have the potential to allow tailoring of physical radiotherapy dose for individual patients. The Radiosensitivity Index (RSI)/Genomic-Adjusted Radiation Dose (GARD) is a gene expression signature that predicts intrinsic radiosensitivity across multiple malignancies, with initial studies demonstrating clinical utility of RSI-GARD in TNBC. Since most TNBC patients will receive neoadjuvant systemic therapy, we sought to understand how neoadjuvant therapy-induced molecular adaptations could alter intrinsic radiosensitivity and RSI-GARD. Methods: Total RNA was isolated from pre-treatment and paired surgical specimens (for patients with residual disease (RD)) from TNBC patients treated with chemotherapy on the NeoSTOP (NCT02413320) or chemoimmunotherapy on the NeoPACT (NCT03639948) neoadjuvant trials and was subjected to RNA exome sequencing. The RSI was calculated according to the published algorithm using normalized expression of the 10 genes in this signature (AR, JUN1, STAT1, PRKCB, RELA, ABL1, SUMO1, PAK2, HDAC1, and IRF1). The resulting RSI score was substituted as the surviving fraction (SF) using the linear quadratic model of radiation-induced cellular lethality assuming a fractional dose of 2.0 Gy and a constant β=0.05 Gy−2 to derive a patient-specific α, which is a coefficient modifying dose-dependent cellular lethality resulting from binary mis-repair of double-strand breaks (DSBs) arising from a single particle track. Results: Pre-treatment sequencing data were available for N=200 patients and the overall pathologic complete response (pCR) rate was 56.5%. Paired pre- and post-treatment sequencing data were available for N=58 patients (N=27 from NeoSTOP and N=31 from NeoPACT). One NeoPACT patient had a negative RSI, which led to an undefined α. Under the assumptions of the RSI-substituted LQ model, the median α/β ratio (reflecting sensitivity to fractionation) for all pre-treatment samples was 11.7 Gy. TNBC patients who achieved pCR had a significantly higher pre-treatment α (i.e., higher intrinsic radiosensitivity) compared to patients who had residual disease (P=0.04), and this trend was the same for patients treated with chemotherapy (P=0.31) or chemoimmunotherapy (P=0.05). Importantly, α did not change significantly between paired pre- and post-treatment samples (median change post- vs. pre-treatment=0.03 Gy−1 (range -0.25 to +0.24 Gy−1; P=0.26) in patients with RD, with no difference in subgroups treated with chemotherapy (P=0.99) or chemoimmunotherapy (P=0.10). Conclusions: We found that predicted intrinsic radiosensitivity using the RSI-GARD is associated with pathologic response to neoadjuvant systemic therapy, suggesting that this signature also predicts intrinsic chemosensitivity in TNBC patients. The modeled α/β ratio for all pre-treatment samples was 11.7 Gy, which is substantially higher than empirically determined α/β ratios in studies that were enriched for HR+/HER2- breast cancers. Globally, the RSI-GARD score was not impacted by neoadjuvant systemic therapy, with no significant change in the score in paired pre- and post-treatment samples. These results can inform future testing and implementation of RSI-GARD into prospective trials. Citation Format: Shane Stecklein, Julia White, Rachel Yoder, Joshua Staley, Zachary Schmitt, Anne O'Dea, Lauren Nye, Deepti Satelli, Gregory Crane, Rashna Madan, Maura O'Neil, Andrew Godwin, Harsh Pathak, Qamar Khan, Joyce O'Shaughnessy, Priyanka Sharma. Analysis of the Radiosensitivity Index/Genomic-Adjusted Radiation Dose (RSI-GARD) in Paired Pre- and Post-Treatment TNBC Samples: Implications for Biomarker-Guided Radiotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-09.

Respiratory Effects of Benzodiazepine in Patients with Advanced-Stage Cancer Receiving Opioid Analgesics: A Prospective Observational Study.

Despite the risk of respiratory depression, benzodiazepines are often prescribed to patients receiving palliative care owing to their efficacy in symptom control. Opioids, which also cause respiratory depression, are often administered to patients with advanced-stage cancer. However, the additive effect of the two drugs has not been systematically analyzed. This prospective observational study aimed to determine the respiratory effects of coadministration of benzodiazepines and opioids in terminally ill patients with cancer. The respiratory variables (primary endpoint) and activity index (ACI) (secondary endpoint) of 24 patients were assessed using a continuous noncontact, nonrestraining vital sign monitor placed under the legs of the bed. The respiratory rate (RR) changed from 12.0 ± 3.9/min to 10.3 ± 3.3/min (n = 24, p = 0.0005) following administration of the first dose of benzodiazepine in addition to regular opioid treatment, indicating no difference (p > 0.83) from the decrease in the RR observed on the previous day at the same time (12.1 ± 3.3/min to 10.3 ± 3.4/min). No increase in apnea-hypopnea frequency and respiratory irregularity or no decrease in respiratory size was observed. The ACI showed a significant decrease following the administration of benzodiazepine, suggesting remission of the symptoms. The effect of five repeated doses of benzodiazepines in nine patients showed no significant change in the respiratory variables compared with the first dose. Addition of single or consecutive benzodiazepine-type drugs at clinically useful dose in patients receiving palliative care for cancer with opioid analgesics, readily exposed to respiratory depression, was observed with a decreased RR similar to the decrease observed during sleep with opioid alone.

PRECLINICAL AND CLINICAL EFFICACY AND SAFETY OF A NOVEL MULTI-TARGET SMALL MOLECULE MT-1207 FOR HYPERTENSION

Objective: To develop a novel multi-target small molecule agent for the treatment of hypertension with potential renal protection. Design and method: Part I (preclinical): MT-1207 was tested in the in vitro and in vivo preclinical models to evaluate mechanisms of action, hypertension efficacy, and renal protection. The in vitro activity of MT-1207 was evaluated in enzyme and radioligand binding assays. In vivo Spontaneously Hypertensive Rats (SHR) and two-kidney two-clip (2K2C) rat models were used to evaluate antihypertensive effects and renal protection of MT-1207. Preclinical safety evaluation of MT-1207 was conducted in rats and dogs following ICH guidelines. Part II (clinical): MT-1207 in clinical phases I and II were completed based on the clinical protocols. Phase Ia was a single center, randomized, double-blind, placebo-controlled, dose escalation study to evaluate safety, tolerability, pharmacokinetic of single oral dose of MT-1207 in healthy adult subjects. Phase Ia doses were 5, 10, 20, 40, 60, 90 mg. Similarly, Phase Ib study was conducted in patients with hypertension at 10 and 20 mg (BID) for 10 days. Clinical phase II was a multi-center, randomized, double-blind, placebo- and active-controlled, multiple-dose study to evaluate safety and pharmacodynamics of MT-1207 in patients with hypertension for 8 weeks. Results: Preclinical (part I): MT-1207 showed potent selective inhibitions of Adrenergic 1alpha and Serotonin (5-HT2A) receptors with IC50 &lt; 1 nM. The efficacy of antihypertension of MT-1207 in SHR model was evident with a well-defined dose-response relationship at 2.5, 5, and 10 mpk. In 2K2C rat model, both blood pressure and serum uric acid decreased post-dose at 4-week and 9-week, indicating antihypertensive effects and potential kidney protection, respectively. Clinical (part II): in Phase I, healthy volunteers had good tolerability at 40 mg and below. Rapid blood pressure decreases were observed 1-2 hr post dose in patients with 10 and 20 mg doses. Results from Phase II (10 and 20 mg (BID)) with placebo and active drug (amlodipine) study will be presented including summary of adverse effects (AE) and efficacy data. Conclusions: Clinical data (phases I and II) demonstrated antihypertensive effects of MT-1207 with mild adverse effects.

Validation of the Elekta iBEAM Evo couchtop modeling in the Monaco treatment planning system

IntroductionRecently, carbon fiber (CF) has prevailed as the primary material used in radiotherapy couchtops. Modern couchtops incorporate the CF sandwich design, in which two thin CF plates sandwich an air-equivalent polymeric foam. Developments in radiotherapy necessitate irradiation from posterior angles through the couchtop. However, the presence of the couchtop needs proper modeling in the Treatment Planning System (TPS) due to attenuation; otherwise, the tumor dose is reduced. In the current study, an effort was made with the intent of finding the optimum electron density (ED) values for Elekta's iBEAM Evo couchtop components (CF and Foam Core (FC)) for its proper modeling in Monaco TPS. Also, the attenuation of the beam due to the couchtop's presence was investigated. Materials and MethodsA cylindrical phantom with an ionization chamber positioned at the isocenter was utilized for the measurements. The phantom was placed centrally on the iBEAM Evo couchtop and was irradiated with an Elekta Infinity linear accelerator's 6, 10, and 15 MV photon beams. The gantry angle was set at 0o and from 120o to 180o with an increment of 10o. The same procedure was designed and followed in Monaco TPS. Measured and calculated dose values were compared by calculating percentage deviation (PD). Attenuation has also been calculated using the measurements of the experimental setup and the Monaco calculations. ResultsThe values of ED that provided the optimum agreement between measured and Monaco-calculated dose values while minimizing PD were 0.55 g/cm3 for CF, and 0.1 g/cm3 for FC. The maximum values of PD for the beams of 6, 10, and 15 MV were -0.62%, +1,78%, and +2.35% , respectively, for a 5x5 cm2 field size. Furthermore, Monaco predicted attenuation from 1.83% to 6.26% (calculated values), while from the measurements, an attenuation from 1.44% to 5.75% (measured values) regarding the posterior angles was found. Thus, good agreement was verified between the TPS calculations and experimental measurements. ConclusionsElekta's iBEAM Evo couchtop modeling was successfully validated in Monaco TPS. The couchtop's presence alters the patient's dose regarding irradiation from the posterior angles. Due to the attenuation of the beam, proper incorporation, modeling, and validation of the couchtop are necessary to improve the radiotherapy outcome and ensure that each patient receives the optimal treatment.

EFFECT OF HIGH DOSE APROCITENTAN IN PATIENTS WITH RESISTANT HYPERTENSION NOT CONTROLLED BY LOW DOSE

Objective: The phase 3 PRECISION study in patients with resistant hypertension tested 12.5 mg and 25 mg aprocitentan during the 4-week DB placebo-controlled part, in addition to a fixed-dose combination of amlodipine, valsartan, hydrochlorothiazide. No differences in primary endpoint (SiSBP) were observed between the two doses. This post-hoc exploratory analysis evaluates the observed long-term benefit of increasing to a higher dose (25 mg) in patients not achieving a blood pressure control after 4 weeks on the lower dose (12.5 mg). Design and method: In PRECISION, after completion of the 4-week DB part 1, all randomized patients received 25 mg aprocitentan during the 32-week SB part 2. This subgroup analysis includes 93 subjects who were still uncontrolled at week 4 (SiSBP &gt; 140 mm/Hg) in the 12.5 mg aprocitentan group (n=223). The % of patients achieving control (&lt;140 or &lt; 130 for SiSBP and &lt; 90 or &lt; 85 mm/Hg for SiDBP) or showing a response of &gt;/= -10 or &gt;/= -15 mmHg in SiSBP or &gt;/= -5 or &gt;/= -10 mm/Hg in SiDBP vs week 4 at week 6, 12 and 36 (i.e., after 2 to 32 weeks of treatment with 25 mg) were calculated. Results: Among the patients in the aprocitentan 12.5 mg group with uncontrolled SiSBP at 4 weeks, after 2 weeks of treatment with 25 mg (at study Week 6), 39.8% (37/93) of subjects achieved SiSBP &lt; 140 mmHg. This increased to 49.3% (37/73) after 32 weeks of aprocitentan 25 mg treatment, at study week 36. The control rate set at the 130 mm Hg threshold and the response rates also increased over time. Also, for SiDBP the increase in the dose of aprocitentan resulted in a high proportion of patients being controlled (45% to 68% depending on the threshold) and responders (45 to 68%) after 32 weeks of treatment. Conclusions: These additional exploratory analyses show that switching from 12.5 mg to 25 mg aprocitentan can achieve further BP control or response not obtained with the lower dose.

Bone morphogenetic protein in subaxial cervical arthrodesis: a meta-analysis of 5828 patients.

Use of bone morphogenetic protein (BMP)-an osteoinductive agent commonly used in lumbar arthrodesis-is off-label for cervical arthrodesis. This study aimed to identify the effect of BMP use on clinical and radiological outcomes in instrumented cervical arthrodesis. A comprehensive systematic review of the literature was performed to identify studies directly comparing outcomes between cervical arthrodeses with and without using BMP. Outcomes were analyzed separately for cases of anterior cervical discectomy and fusion (ACDF) and posterior cervical fusion (PCF). A total of 20 studies with 5828 patients (1948 with BMP and 3880 without BMP) were included. In the ACDF cases, BMP use was associated with higher fusion rates (98.9% vs 93.6%, risk difference [RD] 8%; risk ratio [RR] 1.12, p = 0.02), lower reoperation rates (2.2% vs 3.1%, RD 3%; RR 0.48, p = 0.04), and higher risk of dysphagia (24.7% vs 8.1%, RD 11%; RR 1.93, p = 0.02). No significant differences in the Neck Disability Index, neck pain, or arm pain scores were associated with the use of BMP. On subgroup meta-analysis of ACDF cases, older age (≥ 50 years) and higher BMP dose (≥ 0.9 mg/level) were associated with significantly higher fusion rates and relatively lower risk for dysphagia, whereas arthrodesis of fewer segments (< 2 levels) showed significantly higher dysphagia rates without a significant increase in fusion rates. In the PCF cases, the use of BMP was not associated with significant differences in fusion (p = 0.38) or reoperation (p = 0.61) rates but was associated with significantly higher blood loss during surgery (mean difference 146.7 ml, p ≤ 0.01). Use of BMP in ACDF offers higher rates of augmented fusion and lower rates of all-cause reoperation but with an increased risk of dysphagia. The benefit of fusion outweighs the risk of dysphagia with a higher BMP dose in older patients being operated on for < 2 levels. The use of BMP in PCF seems to have a less important effect on clinical and radiological outcomes.

A Quality Initiative to Improve Appropriate Medication Dosing in Pediatric Patients with Obesity.

Emerging evidence supports the use of alternative dosing weights for medications in patients with obesity. Pediatric obesity presents a particular challenge because most medications are dosed based on patient weight. Additionally, building system-wide pediatric obesity safeguards is difficult due to pediatric obesity definitions of body mass index-percentile-for-age via the Center for Disease Control growth charts. We describe a quality initiative to increase appropriate medication dosing in inpatients with obesity. The specific aim was to increase appropriate dosing for 7 high-risk medications in inpatients with obesity ≥2 years old from 37% to >74% and to sustain for 1 year. The Institute for Healthcare Improvement model for improvement was used to plan interventions and track outcomes progress. Interventions included a literature review to establish internal dosing guidance, electronic health record (EHR) functionality to identify pediatric patients with obesity, a default selection for medication weight with an opt-out, and obtaining patient heights in the emergency department. Appropriate dosing weight use in medication ordered for patients with obesity increased from 37% to 83.4% and was sustained above the goal of 74% for 12 months. Implementation of EHR-based clinical decision support has increased appropriate evidence-based dosing of medications in pediatric and adult inpatients with obesity. Future studies should investigate the clinical and safety implications of using alternative dosing weights in pediatric patients.

Anti-SARS-CoV-2 Spike Antibody Response to the Fourth Dose of BNT162b2 mRNA COVID-19 Vaccine and Associated Factors in Japanese Hemodialysis Patients.

We assessed the anti-SARS-CoV-2 spike antibody response to four doses of BNT162b2 mRNA COVID-19 vaccine in Japanese hemodialysis patients and determined factors associated with the anti-SARS-CoV-2 spike antibody titer after the fourth dose. Fifty-one patients were enrolled in this single-center, prospective, longitudinal study. Change in anti-SARS-CoV-2 spike antibody titers between after the second and fourth doses were evaluated. Multiple linear regression analysis was used to identify factors associated with the anti-SARS-CoV-2 spike antibody titer after the fourth dose. The anti-SARS-CoV-2 spike antibody titer was higher 4 weeks after the fourth dose compared with 4 weeks after the third dose (30,000 [interquartile range (IQR), 14,000-56,000] vs 18,000 [IQR, 11,000-32,500] AU/mL, p<0.001) and 4 weeks after the second dose (vs 2896 [IQR, 1110-4358] AU/mL, p<0.001). Hypoxia-inducible factor prolyl hydroxylase inhibitor use (standard coefficient [β]=0.217, p=0.011), and the log-anti-SARS-CoV-2 spike antibody titer 1 week before the fourth dose (β=0.810, p<0.001) were correlated with the log-anti-SARS-CoV-2 spike antibody titer 4 weeks after the fourth dose, whereas only the log-anti-SARS-CoV-2 spike antibody titer 1 week before the fourth dose (β=0.677, p<0.001) was correlated with the log-anti-SARS-CoV-2 spike antibody titer 12 weeks after the fourth dose. Hypoxia-inducible factor prolyl hydroxylase inhibitor use and the anti-SARS-CoV-2 spike antibody titer before the fourth dose were associated with the anti-SARS-CoV-2 spike antibody titer after the fourth dose in Japanese hemodialysis patients.

Data-driven gating (DDG)-based motion match for improved CTAC registration

BackgroundRespiratory motion artefacts are a pitfall in thoracic PET/CT imaging. A source of these motion artefacts within PET images is the CT used for attenuation correction of the images. The arbitrary respiratory phase in which the helical CT (CThelical\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\hbox{CT}_{\ ext{helical}}$$\\end{document}) is acquired often causes misregistration between PET and CT images, leading to inaccurate attenuation correction of the PET image. As a result, errors in tumour delineation or lesion uptake values can occur. To minimise the effect of motion in PET/CT imaging, a data-driven gating (DDG)-based motion match (MM) algorithm has been developed that estimates the phase of the CThelical\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\hbox{CT}_{\ ext{helical}}$$\\end{document}, and subsequently warps this CT to a given phase of the respiratory cycle, allowing it to be phase-matched to the PET. A set of data was used which had four-dimensional CT (4DCT) acquired alongside PET/CT. The 4DCT allowed ground truth CT phases to be generated and compared to the algorithm-generated motion match CT (MMCT). Measurements of liver and lesion margin positions were taken across CT images to determine any differences and establish how well the algorithm performed concerning warping the CThelical\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\hbox{CT}_{\ ext{helical}}$$\\end{document} to a given phase (end-of-expiration, EE).ResultsWhilst there was a minor significance in the liver measurement between the 4DCT and MMCT (p=0.045\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p = 0.045$$\\end{document}), no significant differences were found between the 4DCT or MMCT for lesion measurements (p=1.0\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p = 1.0$$\\end{document}). In all instances, the CThelical\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\hbox{CT}_{\ ext{helical}}$$\\end{document} was found to be significantly different from the 4DCT (p<0.001\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p < 0.001$$\\end{document}). Consequently, the 4DCT and MMCT can be considered equivalent with respect to warped CT generation, showing the DDG-based MM algorithm to be successful.ConclusionThe MM algorithm successfully enables the phase-matching of a CThelical\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\hbox{CT}_{\ ext{helical}}$$\\end{document} to the EE of a ground truth 4DCT. This would reduce the motion artefacts caused by PET/CT registration without requiring additional patient dose (required for a 4DCT).