Dose Of Therapy Research Articles

Abstract 7374: Mathematical modeling of targeted radionuclide therapy and CAR-T cell immunotherapy for maximizing therapeutic efficacy in multiple myeloma

Abstract Background: Resistance of cancer cells to monotherapies has led to the development of sequential or combination therapy regimens. However, dosing and scheduling of these therapies is challenging due to the numerous dosing and scheduling combinations that can be given. Mathematical models are thus critical tools for addressing this challenge as multiple therapy combinations can be tested in silico to finalize a patient-specific therapeutic regimen in vivo. Here we develop a mathematical framework for combining targeted radiation therapy (TRT) with Chimeric Antigen Receptor (CAR)-T cell immunotherapy and demonstrate the use of in silico techniques to schedule these therapies for maximizing survival. Methods: In the mathematical framework tumor growth is assumed to be exponential and the effect of radiation on both tumor cells and CAR-T cells is modeled using the linear-quadratic model of cell survival to radiation. A predator-prey model is used to characterize the dynamics of tumor and CAR-T cells. Using a preclinical disseminated mouse model of multiple myeloma (MM1S), we evaluate tumor response to 200 nCi of 225Ac-DOTA-Daratumumab (TRT) and 1 million cells of CS1 CAR-T cell therapy both as monotherapies as well as in combination. Tumor burden tracked using bioluminescence imaging from six groups of mice is used to calibrate model parameters: (a) No treatment. (b) Day 7 TRT. (c) Day 7 CAR-T cell therapy. (d) Day 7 TRT + Day 18 CAR-T cell therapy. (e) Day 7 TRT + Day 25 CAR-T cell therapy. (f) Day 7 TRT + Day 32 CAR-T cell therapy. Response to therapy is evaluated using progression-free survival (PFS), overall survival (OS) and time to minimum tumor burden (tmin), all of which are calculated using the predicted in silico tumor burden dynamics and the tumor burden at the start of first therapy. We evaluate these response metrics for various dosing and scheduling regimens. Results: Therapy intervals that were too short or too long are shown to be detrimental for therapeutic efficacy. TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing, while the interval being too long results in tumor regrowth, negatively impacting tumor control and survival. If a single dose is split into multiple doses, the splitting is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Based on the model parameters we estimate the minimum required TRT activity and CAR-T cell dose to demonstrate an improvement in PFS. Conclusions: The proposed model demonstrates the impact of different dosing and scheduling regimens of TRT and CAR-T therapy on survival metrics. It is a potent tool for translating preclinical results to the clinic and eventually tailor therapy regimens for patients. Citation Format: Vikram Adhikarla, Dennis Awuah, Enrico Caserta, Megan Minnix, Maxim Kuznetsov, Amrita Krishnan, Jeffrey Y. Wong, John E. Shively, Xiuli Wang, Flavia Pichiorri, Russell C. Rockne. Mathematical modeling of targeted radionuclide therapy and CAR-T cell immunotherapy for maximizing therapeutic efficacy in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7374.

Abstract 697: Enhanced tumor control and survival in solid tumor models following combined low dose radiotherapy and T cell therapy

Abstract Background: Solid tumors remain a significant challenge in cancer therapy due to their resistance to conventional treatments. Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising approach for treating solid tumors, but its effectiveness is often limited by the poor infiltration of CAR-T cells into the tumor microenvironment. Thus, enhancing a robust infiltration of chimeric antigen receptor T cells into solid tumors is essential for an effective antitumor response and therapeutic success. Methods: In this study, we investigated the combined effects of multiple doses of low-dose radiotherapy (LD-RT) and CAR T-cell therapy on tumor growth and survival using two models of NSG mice implanted with gastric carcinoma (GSU) or pancreatic adenocarcinoma (CAPAN-2) cells. The engineered CAR-T cells were designed to target guanyl cyclase-C (GCC) or mesothelin, respectively. Furthermore, our study employed atomic force microscopy (AFM) in a small cohort to investigate the impact of LD-RT and CAR-T cell therapy on tumor stiffness and plasticity. Results: The synergistic effect of combining low-dose radiotherapy (LD-RT) with T-cell therapy resulted in enhanced tumor control and prolonged survival in mice with tumors, surpassing the outcomes observed with either monotherapy alone. This combined treatment holds promise for improving responses in patients with solid tumors by leveraging LD-RT to enhance the intratumoral infiltration of effector T cells. Our findings suggest that the nanomechanical signature may be a potential biomarker for LD-RT combined CAR T cell therapy in solid tumors. Conclusions: Our findings substantially contribute to treating solid tumors using cell therapies, highlighting the potential for improved infiltration of adoptively transferred T cells following radiotherapy (RT), which can transform existing therapeutic strategies for solid tumors while minimizing toxicity. Citation Format: Nahum Puebla, Gitika Srivastava, Sara Nizzero, Natalie Wall Fowlkes, Hampartsoum Barsoumian, Yun Hu, Carola Leuschner, Thomas Riad, Marko Loparic, Marija Plodinec, James Welsh. Enhanced tumor control and survival in solid tumor models following combined low dose radiotherapy and T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 697.

Abstract 6298: The value of routine trastuzumab-related cardiac toxicity monitoring in gastrointestinal cancers

Abstract Background: It is a common practice to monitor trastuzumab-related cardiac toxicity (TRCT) using left ventricular ejection fraction (LVEF) in patients who receive trastuzumab-containing therapy for human epidermal growth factor receptor 2 (HER2)-positive cancers. However, this monitoring approach does not appear cost effective in patients with HER2-positive gastrointestinal (GI) cancers given poor overall survival (OS). Here, we aim to examine the incidence of clinically significant TRCT in this target population. Methods: This is a retrospective cohort study of patients with advanced HER2-positive GI cancers who received trastuzumab-containing therapies (trastuzumab +/- pertuzumab, chemotherapy +/- immunotherapy + trastuzumab, trastuzumab deruxtecan) between 2011 and 2023. HER2 status was determined by immunohistochemistry, fluorescent in situ hybridization, and/or next generation sequencing. LVEF was estimated by serial transthoracic echocardiograms (TTE). Continuous variables were summarized as median and interquartile range (IQR). Paired Wilcoxon signed rank test was used to compare serial LVEF. OS was estimated using Kaplan-Meier method. Results: A total of 243 patients were included in this study with a median age of 64 (IQR: 55-70) years. 139 (57%) patients had esophageal or GEJ adenocarcinoma; 45 (19%) patients had gastric cancer; 37 (15%) patients had colorectal cancer; and the rest had other GI cancers. Median follow-up time was 18.6 (IQR: 9.2-36) months. Median OS from cancer diagnosis and the first dose of trastuzumab-containing therapy were 24.1 (95%CI: 20.2-30.2) and 11.7 (95%CI: 10.4-15.6) months, respectively. Patients received a median of 13 cycles of trastuzumab-containing therapy for a median duration of 4.1 (IQR: 1.4-10.1) months. The median number of TTE each patient had throughout therapy was 2 (IQR: 1-4). Median baseline LVEF was 61% (IQR: 56-65%) which was significantly higher (p<0.001) than the median lowest LVEF of 58% (IQR: 53-62%) during therapy, but not different (p=0.14) from the most recent median LVEF of 60% (IQR: 56-64%) after discontinuation of trastuzumab. Among 176 patients with serial LVEF data, 16 (9%) had > 10% LVEF drop; 7 (44%) of these 16 patients had LVEF recovery. None of the cardiovascular risk factors prior to trastuzumab treatment including hypertension, diabetes, hyperlipidemia, peripheral arterial disease, coronary artery disease, and stroke were significantly associated with the development of TRCT. Conclusion: The incidence of clinically significant LVEF drop appears low in patients with advanced GI cancers as post-treatment LVEF recovery to baseline was observed at the population level. The value of using TTE to monitor TRCT in these patients with short OS should be further assessed in the perspective of cost effectiveness. Citation Format: Samual R. Kosydar, Matteo Castrichini, Mojun Zhu, Hao Xie. The value of routine trastuzumab-related cardiac toxicity monitoring in gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6298.

A New Dosing Frontier: Retrospective Assessment of Effluent Flow Rates and Residual Renal Function Among Critically Ill Patients Receiving Continuous Renal Replacement Therapy.

In 2020, cefiderocol became the first Food and Drug Administration-approved medication with continuous renal replacement therapy (CRRT) dosing recommendations based on effluent flow rates (QE). We aimed to evaluate the magnitude and frequency of factors that may influence these recommendations, that is, QE intrapatient variability and residual renal function. Retrospective observational cohort study. ICUs within Hartford Hospital (890-bed, acute-care hospital) in Connecticut from 2017 to 2023. Adult ICU patients receiving CRRT for greater than 72 hours. CRRT settings including QE and urine output (UOP) were extracted from the time of CRRT initiation (0 hr) and trends were assessed. To assess the impact on antibiotic dosing, cefiderocol doses were assigned to 0 hour, 24 hours, 48 hours, and 72 hours QE values per product label, and the proportion of antibiotic dose changes required as a result of changes in inpatient's QE was evaluated. Among the 380 ICU patients receiving CRRT for greater than 72 hours, the median (interquartile range) 0 hour QE was 2.96 (2.35-3.29) L/hr. Approximately 9 QE values were documented per patient per 24-hour window. QE changes of greater than 0.75 L/hr were observed in 21.6% of patients over the first 24 hours and in 7.9% (24-48 hr) and 5.8% (48-72 hr) of patients. Approximately 40% of patients had UOP greater than 500 mL at 24 hours post-CRRT initiation. Due to QE changes within 24 hours of CRRT initiation, a potential cefiderocol dose adjustment would have been warranted in 38% of patients (increase of 21.3%; decrease of 16.6%). QE changes were less common after 24 hours, warranting cefiderocol dose adjustments in less than 15% of patients. Results highlight the temporal and variable dynamics of QE and prevalence of residual renal function. Data also demonstrate a risk of antibiotic under-dosing in the first 24 hours of CRRT initiation due to increases in QE. For antibiotics with QE-based dosing recommendations, empiric dose escalation may be warranted in the first 24 hours of CRRT initiation.

Different dose aspirin plus immunoglobulin (DAPI) for prevention of coronary artery abnormalities in Kawasaki disease: Study protocol for a multi-center, prospective, randomized, open-label, blinded end-point, non-inferiority trial

BackgroundKawasaki disease is a pediatric acute systemic vasculitis that specifically involves the coronary arteries. Timely initiation of immunoglobulin plus aspirin is necessary for diminishing the incidence of coronary artery abnormalities (CAAs). The optimal dose of aspirin, however, remains controversial. The trial aims to evaluate if low-dose aspirin is noninferior to moderate-dose in reducing the risk of CAAs during the initial treatment of Kawasaki disease. MethodsThis is a multi-center, prospective, randomized, open-label, blinded endpoint, noninferiority trial to be conducted in China. The planned study duration is from 2023 to 2026. Data will be analyzed according to intention-to-treat principles. Participants are children and adolescents under the age of 18 with Kawasaki disease, recruited from the inpatient units. A sample size of 1,346 participants will provide 80% power with a one-sided significance level of 0.025. Qualifying children will be randomized (1:1) to receive either intravenous immunoglobulin (2 g/kg) plus oral moderate-dose aspirin (30-50 mg·kg−1·d−1) until the patient is afebrile for at least 48 hours, or immunoglobulin plus low-dose aspirin (3-5 mg·kg−1·d−1) as initial treatment. The primary outcome will be the occurrence of CAAs at 8 weeks after immunoglobulin infusion. Independent blinded pediatric cardiologists will assess the primary endpoint using echocardiography. ConclusionsThere is a shortage of consensus on the dose of aspirin therapy for Kawasaki disease due to the lack of evidence. The results of our randomized trial will provide more concrete evidence for the efficacy and adverse events of low- or moderate-dose aspirin in the acute phase of Kawasaki disease. Trial Registrationwww.chictr.org.cn: ChiCTR2300072686.

First evidence of a biomarker-based dose-response relationship in chronic pain using physiological closed-loop spinal cord stimulation

Background and objectivesIn spinal cord stimulation (SCS) therapy, electricity is the medication delivered to the spinal cord for pain relief. In contrast to conventional medication where dose is determined by...

Imaging and characterization of optical emission from ex vivo tissue during conventional and UHDR PBS proton therapy

Objective. Imaging of optical photons emitted from tissue during radiotherapy is a promising technique for real-time visualization of treatment delivery, offering applications in dose verification, treatment monitoring, and retrospective treatment plan comparison. This research aims to explore the feasibility of intensified imaging of tissue luminescence during proton therapy (PT), under both conventional and ultra-high dose rate (UHDR) conditions. Approach. Conventional and UHDR pencil beam scanning (PBS) PT irradiation of fresh ex vivo porcine tissue and tissue-mimicking plastic phantom was imaged using intensified complementary metal-oxide-semiconductor(CMOS) cameras. The optical emission from tissue was characterized during conventional irradiation using both blue and red-sensitive intensifiers to ensure adequate spectral coverage. Spectral characterization was performed using bandpass filters between the lens and sensor. Imaging of conventional proton fields (240 MeV, 10 nA) was performed at 100 Hz frame rate, while UHDR PBS proton delivery (250 MeV, 99 nA) was recorded at 1 kHz frame rate. Dependence of optical emission yield on proton energy was studied using an optical tissue-mimicking plastic phantom and a range shifter. Finally, we demonstrated fast beam tracking capability of fast camera towards in vivo monitoring of FLASH PT. Main results. Under conventional treatment dose rates optical emission was imaged with single spot resolution. Spot profiles were found to agree with the treatment planning system calculation within >90% for all spectral bands and spot intensity was found to vary with spectral filtration. The resultant polychromatic emission presented a maximum intensity at 650 nm and decreasing signal at lower wavelengths, which is consistent with expected attenuation patterns of high fat and muscle tissue. For UHDR beam imaging, optical yield increased with higher proton energy. Imaging at 1 kHz allowed continuous monitoring of delivery during porcine tissue irradiation, with clear identification of individual dwell positions. The number of dwell positions matched the treatment plan in total and per row showing adequate temporal capability of iCMOS imaging. Significance. For the first time, this study characterizes optical emission from tissue during PT and demonstrates our capability of fast optical tracking of pencil proton beam on the tissue anatomy in both conventional and UHDR setting. Similar to the Cherenkov imaging in radiotherapy, this imaging modality could enable a seamless, independent validation of PT treatments.

Mathematical modelling of clonal reduction therapeutic strategies in acute myeloid leukemia

Over the years, the overall survival of older patients diagnosed with acute myeloid leukemia (AML) has not significantly increased. Although standard cytotoxic therapies that rapidly eliminate dividing myeloblasts are used to induce remission, relapse can occur due to surviving therapy-resistant leukemic stem cells (LSCs). Hence, anti-LSC strategies have become a key target to cure AML. We have recently shown that previously approved cardiac glycosides and glucocorticoids target LSC-enriched CD34+ cells in the primary human AML 8227 model with more efficacy than normal hematopoietic stem cells (HSCs). To translate these in vitro findings into humans, we developed a mathematical model of stem cell dynamics that describes the stochastic evolution of LSCs in AML post-standard-of-care. To this, we integrated population pharmacokinetic-pharmacodynamic (PKPD) models to investigate the clonal reduction potential of several promising candidate drugs in comparison to cytarabine, which is commonly used in high doses for consolidation therapy in AML patients. Our results suggest that cardiac glycosides (proscillaridin A, digoxin and ouabain) and glucocorticoids (budesonide and mometasone) reduce the expansion of LSCs through a decrease in their viability. While our model predicts that effective doses of cardiac glycosides are potentially too toxic to use in patients, simulations show the possibility of mometasone to prevent relapse through the glucocorticoid’s ability to drastically reduce LSC population size. This work therefore highlights the prospect of these treatments for anti-LSC strategies and underlines the use of quantitative approaches to preclinical drug translation in AML.

Determination of HPA axis suppression in patients on systemic steroids in dermatology

Steroids are mainstay of treatment in most of the non-infectious dermatological conditions. The study was conducted to determine how various doses and duration of systemic steroid therapy affects HPA axis. To determine HPA axis status in patients on systemic steroids in dermatology. To study how various doses and duration of steroid treatment affects HPA axis. This longitudinal study was conducted on 77 patients who were on systemic steroids for dermatological conditions. Patients were categorized into 6 groups depending on the dosage and duration of steroid treatment. Serum 8 a.m. Cortisol and ACTH levels were tested. About 54 patients were on long term steroids and 23 were on short term steroids. 44 patients (81.5%) on long term steroids had suppressed levels of cortisol and 39 patients (72.2%) had suppressed levels of ACTH. Suppression was maximum in patients on high dose and taken for long duration (p<0.001). There was significant lowering in mean 8AM cortisol and ACTH levels after short term steroid therapy; however, no suppression was seen. Duration of steroid therapy and suppression of 8AM cortisol and ACTH values were associated significantly. Patients on short term steroids showed no suppression of both serum 8 a.m. cortisol and ACTH levels but there was statistically significant lowering of levels. The study found that longer the duration and higher the dose of steroid therapy, the greater is the suppression of both serum 8 a.m. cortisol and ACTH levels.

Analysis of appropriateness and safety when discharging patients on triple-antithrombotic therapies.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. To analyze the appropriateness of triple-antithrombotic therapy based on the 2020 American College of Cardiology (ACC) consensus statement while evaluating safety outcomes for patients with respect to adverse events. A single-center, retrospective chart review was conducted using electronic medical records from December 18, 2020, to August 31, 2022. The primary endpoint was the rate of appropriateness for triple-antithrombotic therapy in patients discharged from Ochsner LSU Health Shreveport. Appropriateness was a composite endpoint extrapolated from the 2020 ACC consensus statement. For therapy to be defined as appropriate, patients had to have had the correct therapy indication, medications, dosing, and 30-day duration. Secondary safety endpoints included the percentage of patients rehospitalized at 14 and 30 days, the rate of major bleeding events, and the percentage of patients on gastrointestinal prophylaxis while on triple-antithrombotic therapy. A total of 93 patients were included in the study, of whom 31 (33%) received appropriate triple-antithrombotic therapy. Prolonged duration of triple-antithrombotic therapy was the most common reason that therapy did not meet the primary endpoint. The readmission rate due to bleeding was 2.2% at 14 days and 6.5% at 30 days. Within 30 days of initiation of triple therapy, 4.3% of patients endured major bleeding as defined by the International Society on Thrombosis and Hemostasis and 2 patients died. In this single-center study, triple-antithrombotic therapy appropriately adhered to the 2020 ACC consensus statement for one-third of patients discharged on this therapy.

Biomarker-Driven Radiation Therapy Dose Reduction after Transoral Robotic Surgery for the Treatment of HPV-Positive Oropharyngeal Cancer

Biomarker-Driven Radiation Therapy Dose Reduction after Transoral Robotic Surgery for the Treatment of HPV-Positive Oropharyngeal Cancer

Functional Outcomes from a Phase II Trial of Adaptive Deescalation of Radiation Therapy Dose in p16+ Oropharyngeal Cancer Patients Demonstrating Favorable Mid-treatment Nodal Response

Functional Outcomes from a Phase II Trial of Adaptive Deescalation of Radiation Therapy Dose in p16+ Oropharyngeal Cancer Patients Demonstrating Favorable Mid-treatment Nodal Response

Evaluation of serum pro/anti-angiogenic biomarkers in hyperglycemic rats treated with Securigera securidaca seeds, alone and in combination with Glibenclamide.

Herbal medicines are commonly used by many people with diabetes in addition to standard treatment. Plants contain numerous known and unknown compounds that may exacerbate or ameliorate diabetes complications. Therefore, it is crucial to be aware of the side effects of these herbs before prescribing them. This study aimed to investigate the effects of hydroalcoholic extracts of Securigera securidaca (HESS) seeds alone and in combination with glibenclamide on the angiogenic/anti-angiogenic balance in streptozotocin (STZ)-induced diabetic rats. Groups involved in this animal study included diabetic and healthy controls, three doses of HESS, glibenclamide, and combination therapy. Serum samples were collected and analyzed for a vascular endothelial growth factor (VEGF), fibroblast growth factor 21 (FGF21), fetal liver kinase 1 (FLK-1), soluble fms-like tyrosine kinase 1 (sFLT-1), and transforming growth factor -beta (TGF-β). Induction of diabetes increased VEGF, FGF21, and TGF-β serum levels and decreased circulating FLK-1 and sFLT-1 factors. Herbal extract, except TGF-β, had little effect on the above blood levels even at the highest doses. Glibenclamide was more effective than the highest dose of HESS in improving the vascular complications of diabetes. Combination therapy with the highest dose of HESS partly enhanced the glibenclamide effects. Compared with glibenclamide as a standard chemical drug, HESS had no significant effects on the blood levels of the pro/anti-angiogenesis factor in diabetic rats. Glibenclamide attenuated the levels of the biomarkers and its effects were somewhat enhanced in combination with the highest dose of HESS.

Evaluation of an enhanced depression and anxiety screening with targeted pharmacist intervention

BackgroundDepression is a major source of morbidity but often goes undiagnosed. Broader screening is recommended, and pharmacists could contribute. ObjectivesThis study aimed to assess the feasibility of community pharmacy depression and anxiety screening and describe the medication-related problems (MRPs) identified, pharmacist interventions, and provider responses for high-risk patients. MethodsThis pilot was conducted between October 2022 and January 2023 at an independently owned community pharmacy in the Midwest United States. Patients aged 18-45 years with ready prescriptions were identified through weekly reports, and tags were placed on prescription bags. A convenience sample of patients fluent in English were offered the Patient Health Questionnaire (PHQ2) and Generalized Anxiety Disorder (GAD2), with follow-up PHQ9 and GAD7 for at-risk individuals. High-risk individuals met with the pharmacist for consultation and recommendations were discussed. Descriptive statistics were calculated for participant demographics, questionnaire responses, MRPs, and provider responses. Patient profiles were examined 2 months after the workup to identify medication changes. ResultsA total of 29 patients volunteered to be screened for anxiety and depression; of these, 41% scored in the high-risk category for depression or anxiety and met with the pharmacist for the consultation. The pharmacist identified multiple MRPs. The most common was the need for additional therapy and inadequate dosages. Patients were reluctant for the pharmacist to follow up with their prescriber and were unreachable for telephone follow-up. Profiles reviewed 2 months after assessment showed half of the at-risk patients had one or more mental health medication changes. ConclusionCommunity pharmacists may have a role in the screening and management of patient mental health, although there were challenges with screening uptake and follow-up. The pharmacist identified multiple MRPs for this high-risk group for which greater routine monitoring and follow-up may be beneficial. More work seems needed to engage both patients and prescribers.

Assessing push-out bond strength in re-irradiated teeth: Universal resin cement performance in self-etch and self-adhesive modes.

To investigate the effect of cumulative doses of radiation on the pushout bond strength (BS) of a universal resin cement used in the self-etch (SE) and self-adhesive (SA) modes to the intraradicular dentin. Forty-eight human teeth were distributed into three groups (n = 16) according to the radiation therapy dose (RT): NoRT (no-radiotherapy), 70RT (70 Gy), and 70 + 70RT (70 Gy + 70 Gy). The teeth were redistributed into two subgroups (n = 8), according to the adhesive mode: SE (NoRT-SE, 70RT-SE, and 70 + 70RT-SE) and SA (NoRT-SA, 70RT-SA, and 70 + 70RT-SA). Data were statistically compared after BS test (ANOVA, Tukey's post hoc test, and Fisher's exact test). In the SA mode, BS was significantly higher in nonirradiated teeth compared with 70RT and 70 + 70RT (p < 0.0001). There were no significant differences between SE and SA modes in nonirradiated teeth (p = 0.14). In the 70RT group, SE mode increased BS compared with SA mode (p < 0.0001). Most specimens had adhesive and mixed failures in SA and SE modes, respectively. The universal resin cement in the SE mode had greater BS to the irradiated dentin. When teeth were re-irradiated, the universal resin cement had similar performance in terms of BS, regardless of the adhesive approach. There is no research establishing a correlation between radiotherapy and its impact on the BS of a universal resin cement used in SE and SA modes to intraradicular dentin.

Aerosol Therapy With Inhalers During Mechanical Ventilation

What Is the Issue?&#x0D; &#x0D; Mechanical ventilation helps individuals breathe when they cannot do so on their own. During mechanical ventilation, aerosol therapy is used to deliver medication to the lungs of the person who is using the ventilator.&#x0D; High doses of aerosol therapy administered via metered dose inhaler for adults and older adults who are mechanically ventilated is common clinical practice. However, the reasoning behind this practice, and whether it has clinical benefits compared to no doses and standard doses, is unclear.&#x0D; &#x0D; What Did We Do?&#x0D; &#x0D; To inform decisions about high doses of aerosol therapy delivered with metered dose inhalers in adults and older adults receiving mechanical ventilation, we sought to identify and summarize literature comparing the clinical effectiveness of inhaled high doses of aerosol therapy versus no aerosol therapy. We also sought to identify and summarize literature comparing the clinical effectiveness of inhaled high doses of aerosol therapy versus standard doses.&#x0D; A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2004, and January 25, 2024. The search was limited to English-language documents. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included study, and narratively summarized the findings.&#x0D; &#x0D; What Did We Find?&#x0D; &#x0D; We found 1 retrospective chart review that compared the clinical effectiveness of 2 different doses of inhaled high doses of aerosol therapy. The findings from this study suggest that, compared to lower doses, higher doses of salbutamol are associated with more days alive and free of acute lung injury and more days alive and free of indicators of acute respiratory distress and respiratory failure.&#x0D; We did not find any studies that compared the clinical effectiveness of inhaled high doses of aerosol therapy to no aerosol therapy for adults and older adults receiving mechanical ventilation that met inclusion criteria for our review.&#x0D; &#x0D; What Does It Mean?&#x0D; &#x0D; The available evidence with methodological limitations suggests that high doses of aerosol therapy with salbutamol may be associated with better clinical respiratory outcomes when compared to low doses in patients with acute lung injury who are mechanically ventilated. To inform future clinical practice, decision-makers may want to consider the potential risks and benefits and environmental implications of aerosol therapy, as well as implementation factors (e.g., resource needs, risk of contamination).&#x0D; Additional clinical studies would help provide a better understanding of the optimal dosage and clinical effectiveness of aerosol therapy for patients who are mechanically ventilated.&#x0D;

(043) Gender-Affirming Bilateral Orchiectomy Prior to Vaginoplasty versus with Vaginoplasty: A Comparison of Preoperative Goals and Postoperative Satisfaction

Abstract Introduction Gender-affirming bilateral orchiectomy (GA-BO), defined here as either a standalone procedure and/or precursor to vaginoplasty, is associated with a decrease in gender-affirming hormone therapy (GAHT) dosages. In comparison to bilateral orchiectomy at time of gender-affirming vaginoplasty (GA-V), GA-BO is associated with shorter waitlist times, procedure duration, and outpatient recovery. While objective benefits of GA-BO have been described, there is limited qualitative data that assesses the preoperative goals and postoperative satisfaction of patients who elect GA-BO. We aim to assess the decision-guiding factors that led patients to select GA-BO, and to compare measures of patient satisfaction between GA-BO and GA-V patients. Objective To assess the decision-guiding factors that led patients to select gender-affirming bilateral orchiectomy before vaginoplasty versus with vaginoplasty, and to compare measures of patient satisfaction between groups. Methods A retrospective chart review identified 170 patients who underwent GA-BO (n=106; 64%) or GA-V (n=64; 36%) between 4/2017 and 12/2020 at our institution. Patients were emailed a link to an anonymous, online questionnaire (QualtricsTM). Results 136/170 (80%) patients completed the questionnaire: 86/136 (63%) respondents were GA-BO patients and 50/136 GA-V (37%). 78/86 (91%) of GA-BO respondents had either subsequently undergone vaginoplasty, or, planned to do so in the future. For patients who later underwent vaginoplasty, the mean reported time interval between GA-BO and vaginoplasty was 15 months [Range: 1–34 months]. Respondents prioritized the following expectations in their decision to undergo GA-BO: potential to decrease GAHT medications and dosages (reported as important by 67%), low rates of complications (56.5%), short recovery time (51.6%), and low postoperative pain (46.2%). GA-BO and GA-V patients reported high postoperative improvement in various indices of gender dysphoria and body image, with only 1/4 indices of gender dysphoria differing significantly between the two groups (Figure 1). Unsurprisingly, GA-V patients reported a significantly greater improvement in 3/3 body image indices. Conclusions GA-BO is a low-risk procedure that provides a more immediate option to decrease gender dysphoria and improve QOL. All patients who were assigned male at birth and are interested in genital gender-affirming surgery should be made aware of the advantages of GA-BO and offered GA-BO alongside GA-V. Disclosure No.

Visual outcome of various dose of glucocorticoids treatment in nonarteritic anterior ischemic optic neuropathy– a retrospective analysis

Background and purposeThe objective of this investigation was to assess the therapeutic efficacy of distinct glucocorticoid therapy dosages in the management of acute nonarteritic anterior ischemic optic neuropathy (NAION).Materials and methodsThis retrospective, unmasked, and non-randomized study included a total of 85 patients. The patients were categorized into four groups: Group 1 (control) consisted of 15 patients who did not receive glucocorticoids, Group 2 included 16 patients administered with oral prednisone at a dosage of 1 mg/kg/d for 14 days, Group 3 comprised 30 patients who received 250 units of methylprednisolone once daily for 3 days, followed by oral prednisone at a dosage of 1 mg/kg/d for 11 days, and Group 4 encompassed 24 patients who received 500 units of methylprednisolone once daily for 3 days, followed by oral prednisone at a dosage of 1 mg/kg/d for 11 days. The best-corrected visual acuity (BCVA) was assessed at baseline and the final follow-up (> 7 days post-treatment). The changes in visual acuity between baseline and the 7–14 day follow-up, as well as between baseline and the concluding appraisal, were employed as metrics for assessing the extent of visual enhancement.ResultsNo significant differences were noted in the final visual outcomes or in the changes between final visual acuity and baseline across the four groups. In Group 1 (control), the best-corrected visual acuity (BCVA) remained unchanged during final follow-ups compared to baseline. Conversely, the intervention groups exhibited statistically significant enhancements in BCVA during final follow-up (p = 0.012, p = 0.03, and p = 0.009 for Group 2, Group 3, and Group 4, respectively) when compared to baseline. During the 7–14 day follow-up, there was a significant difference in the changes between baseline BCVA and follow-up BCVA across the groups (p = 0.035). Go a step further by Bonferroni correction for multiple comparisons, group 4 showed a greater change in vision compared with group1 (p = 0.045).ConclusionOur study on acute nonarteritic anterior ischemic optic neuropathy (NAION) showed no significant final visual outcome differences. Nevertheless, Groups 2, 3, and 4 demonstrated improved best-corrected visual acuity (BCVA) during the final follow-up. Notably, a 500-unit dose of methylprednisolone resulted in short-term BCVA enhancement. This suggests potential consideration of 500 units of methylprednisolone for short-term NAION vision improvement, despite its limited long-term impact.

Radiation therapy of renal cell carcinoma skeletal metastases – Does histologic subtype predict progression?: Renal cell histology and radiotherapy response

IntroductionThis investigation assessed whether the following factors were associated with radiographic local progression in bone metastases from renal cell carcinoma (RCC): (1) high-risk histologic features (2) lesional surgery (3) biologically effective dose (BED) of radiation therapy. Methods and materialsA single-institution database identified all patients who underwent surgery and radiation therapy for bone metastases from RCC to the appendicular skeleton and pelvis from 2006 to 2016. Thirty-six patients underwent radiotherapy for 80 metastases. While all patients had surgical stabilization, 17/36 also had lesional surgery to address the metastatic lesion. Progression of each individual lesion was determined using the application of RECIST criteria to imaging at last follow-up. ResultsThe rate of progressive disease was 8/25 (32%) in the high-risk group versus 5/55 (9%) in the standard-risk group (p ​= ​0.019). The rate of progression among high-risk metastases undergoing lesional surgery was 0/9 versus 8/16 (50%) having non-lesional surgery (p ​= ​0.0218). The rate of progression among standard-risk metastases undergoing lesional surgery was 1/16 (6%) versus 4/39 (10%) with non-lesional surgery (p ​= ​1.00). High-risk histologic features (OR: 10.592, 95% confidence interval: 1.347–83.271, p ​= ​0.025) and as well as a reduction in risk with every additional Gray of BED (OR: 0.902, 95% confidence interval: 0.827–0.984, p ​= ​0.021) were found to predict progressive disease. ConclusionsBone metastases from renal cell carcinoma with high-risk histologic features are associated with less favorable response to radiotherapy than those with standard-risk histology. Delivery of a higher BED was associated with lower odds of progression.

Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial

Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial. We report post-hoc 24-month efficacy and safety data from this trial to evaluate the longer-term effects of etranacogene dezaparvovec in individuals with haemophilia B. The phase 3 HOPE-B trial enrolled males aged 18 years or older with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis. Participants were treated with a single infusion of etranacogene dezaparvovec (2 × 1013 genome copies per kg of bodyweight). The primary endpoint, reported previously, was non-inferiority of the annualised bleeding rate (ABR) during the 52 weeks following stable factor IX expression (defined as months 7-18 after treatment) versus an at least 6-month lead-in period in which participants received their usual continuous factor IX prophylaxis, and is updated here up to month 24. Additional, post-hoc efficacy analyses, including adjusted ABR, factor IX activity, participants within factor IX ranges, and factor IX use, and safety analyses were performed at 24 months after gene therapy. Data were analysed in the full analysis set, which comprised the 54 patients who received at least a partial dose of gene therapy. The trial is ongoing and is registered with ClinicalTrials.gov, number NCT03569891. The study began on June 27, 2018, and participants were treated between January, 2019, and March, 2020; the date of data cutoff was April 21, 2022. 54 adult males (40 White, two Asian, one Black or African American, 11 other or missing) received a single intravenous infusion of etranacogene dezaparvovec and were followed for a median of 26·51 months (IQR 24·54-27·99), after a lead-in period of 7·13 months (6·51-7·82). In the updated analysis comparing months 7-24 after gene therapy to the lead-in period, mean adjusted ABR significantly reduced from 4·18 to 1·51 (p=0·0002) for all bleeds and from 3·65 to 0·99 (p=0·0001) for factor IX-treated bleeds. During each 6-month period after gene therapy, at least 67% of participants experienced no bleeding (36 of 54 during months 0-6 and stable thereafter), compared with 14 (26%) of 54 during the lead-in period. 24 months after gene therapy, 1 (2%) participant had one-stage factor IX activity less than 5%, whereas 18 (33%) had factor IX activity more than 40% (non-haemophilia range), with mean factor IX activity stable and sustained at 36·7% (SD 19·0%). 52 (96%) of 54 participants expressed endogenous factor IX, remaining free of factor IX prophylaxis at month 24. No new safety concerns were identified and no treatment-related serious adverse events or treatment-related deaths occurred. The most common treatment-related adverse events were an increase in alanine aminotransferase (nine [17%] of 54 patients), headache (eight [15%]), influenza-like illness (seven [13%]), and an increase in aspartate aminotransferase (five [9%]). By providing durable disease correction throughout the 24 months after gene therapy, etranacogene dezaparvovec provides a safe and effective therapeutic option for patients with severe or moderately severe haemophilia B. uniQure and CSL Behring.