Citations

Abstract Disclosure: B. Clarke: Advisory Board Member; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. Consulting Fee; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. Grant Recipient; Self; Ascendis Pharma, Takeda. Research Investigator; Self; Ascendis Pharma, Takeda. Other; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. A.A. Khan: Advisory Board Member; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, Takeda, Ultragenyx. Consulting Fee; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Amolyt, Ascendis Pharma, Ultragenyx. Grant Recipient; Self; Amolyt. Research Investigator; Self; Radius Health, Inc, Takeda, Ultragenyx, Amolyt, Ascendis Pharma, Chugai. Speaker; Self; Amgen Inc. Other; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, Takeda, Ultragenyx. M.R. Rubin: Research Investigator; Self; Chugai Pharma. P.E. Schwarz: Stock Owner; Self; Novo Nordisk, Genmab. T.J. Vokes: Consulting Fee; Self; Takeda, Ascendis Pharma. Research Investigator; Self; Ascendis Pharma, Radius Health, Inc. D.M. Shoback: Research Investigator; Self; Bone Health Tech. C. Gagnon: Advisory Board Member; Self; Novo Nordisk. Grant Recipient; Self; Shire, Takeda, Ascendis Pharma. Research Investigator; Self; Novo Nordisk. Other; Self; Amgen Inc. A. Palermo: Consulting Fee; Self; Theramex, Bruno, Farmaceutici, Amgen Inc. Grant Recipient; Self; Amgen Inc. Research Investigator; Self; Amgen Inc, Shire, Ascendis Pharma. Speaker; Self; UCB, Amgen Inc. L.G. Abbott: Advisory Board Member; Self; Ascendis. Research Investigator; Self; Takeda, Shire, Ascendis Pharma. Speaker; Self; Abbott Laboratories, Clarus. Other; Self; Ascendis. L.C. Hofbauer: Advisory Board Member; Self; Amgen Inc, UCB. Other; Self; Amgen Inc, UCB. L. Kohlmeier: Advisory Board Member; Self; Alexion Pharmaceuticals, Inc., Ascendis Pharma. Research Investigator; Self; Ascendis Pharma. Speaker; Self; Amgen Inc, Radius Health, Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma. Other; Self; Amgen Inc, Radius Health, Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, MediMaps. F. Cetani: None. S. Phil: Employee; Self; Ascendis Pharma. X. An: Employee; Self; Ascendis Pharma. A.R. Smith: Employee; Self; Ascendis Pharma. B. Lai: Employee; Self; Ascendis Pharma. J. Le: Employee; Self; Ascendis Pharma. J. Ukena: Employee; Self; Ascendis Pharma. C. Sibley: Employee; Self; Ascendis Pharma. A. Shu: Employee; Self; Ascendis Pharma. L. Rejnmark: Advisory Board Member; Self; Takeda, Amolyt. Research Investigator; Self; Takeda, Kyowa Kirin International, Ascendis Pharma, Calcilytix Therapeutics. Other; Self; Calcilytix Therapeutics. Objective: Evaluate the long-term efficacy and safety of TransCon PTH as a potential hormone replacement therapy for hypoparathyroidism. Methods: PaTHway is a phase 3 trial of TransCon PTH with a placebo (PBO)-controlled 26-week blinded period and a 156-week open-label extension (OLE) period. Results through Week 52 (26 weeks blinded + 26 weeks OLE) are reported. Three-component efficacy endpoint: normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other endpoints: Hypoparathyroidism Patient Experience Scale (HPES); 36-Item Short Form Survey (SF-36); bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA); bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTx). Safety was assessed by 24-hour urine calcium and reported treatment-emergent adverse events (TEAEs). Results: Of the 82 participants given study drug, 79 completed blinded treatment and entered the OLE, and 78 (59 TransCon PTH/TransCon PTH, 19 PBO/TransCon PTH) completed Week 52. Overall at Week 52, 81% (63/78) met the efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. Mean albumin-adjusted serum calcium was within the normal range at all time points in the OLE (8.9 mg/dL at Week 52). Mean Week 52 HPES scores showed sustained improvement from baseline in disease-related symptoms and the impact of hypoparathyroidism on physical functioning and daily life. Mean Week 52 SF-36 physical functioning scores also remained above baseline. In the TransCon PTH/TransCon PTH group, mean BMD corrected Z-scores trended toward norms from baseline to Weeks 26 and 52:1.5, 0.7, 0.7 at the lumbar spine (L1-L4); 0.8, 0.3, 0.3 at femoral neck; 0.9, 0.5, 0.4 at total hip; and 0.3, 0.3, 0.3 at distal 1/3 radius; P1NP peaked at Week 26 and CTx at Week 12. Smaller incremental changes were seen in BMD and BTM from Weeks 26 to 52 than baseline to Week 26. In the PBO/TransCon PTH group, changes in BMD and BTM from Week 26 to 52 resembled those in the TransCon PTH/TransCon PTH group from baseline to Week 26. Mean 24-hour urine calcium excretion decreased from 376 mg/day at baseline to 195 mg/day at Week 52. Most TEAEs were mild or moderate and none led to discontinuation of the study drug or trial. Conclusions: At Week 52 of the PaTHway trial, TransCon PTH showed a similar sustained efficacy, safety, and tolerability profile to that of Week 26, demonstrating its potential as a hormone replacement therapy for adults with hypoparathyroidism. Indices of skeletal dynamics trended toward age- and sex-matched norms in the TransCon/TransCon PTH group. TransCon PTH treatment in the PBO/TransCon PTH group showed rapid improvement in all outcomes in the first 26 weeks of the OLE consistent with the pattern in the TransCon PTH group during the blinded period. Presentation: Saturday, June 17, 2023

ABSTRACTObjectivesWe aimed to investigate the gender-based differences in idiopathic inflammatory myopathies (IIMs), with a particular focus on patient-reported outcomes, utilizing the data obtained through the international COVID-19 vaccination in autoimmune disease e-survey.MethodsPatient-reported outcomes including fatigue, pain, and physical function were extracted from the COVID-19 vaccination in autoimmune disease database and compared between genders, adjusting for demographics and IIM subgroups by multivariable analysis. Inclusion body myositis (IBM) was analysed separately because of the substantial differences in outcomes.ResultsA total of 1197 complete responses from patients with IIMs as of 31 August 2021 were analysed. Seventy percent were women. Women were younger (58 [48–68] vs. 69 [58–75] years old, median [interquartile range], P < .001) and were more likely to suffer from autoimmune multimorbidity, defined as three or more autoimmune diseases in an individual patient (11.4% vs. 2.8%, P < .001). In non-IBM IIMs, fatigue visual analogue scale scores were higher in women (5 [3–7] vs. 4 [2–6], median [interquartile range], P = .004), whereas no significant gender-based differences were noted in IBM. Multivariable analysis in non-IBM IIMs revealed that women, residence in high-income countries, overlap myositis, and autoimmune multimorbidity were independently associated with increased fatigue.ConclusionsWomen with IIMs suffer from autoimmune multimorbidity and experience increased fatigue compared to men.

ABSTRACT We have previously reported on the susceptibility and epidemiology of Clostridioides difficile isolates from six geographically dispersed medical centers in the United States. This current survey was conducted with isolates collected in 2020–2021 from six geographically dispersed medical centers in the United States, with specific attention to susceptibility to ridinilazole as well as nine comparators. C. difficile isolates or stools from patients with C. difficile antibiotic-associated diarrhea were collected and referred to a central laboratory. After species confirmation of 300 isolates at the central laboratory, antibiotic susceptibilities were determined by the agar dilution method [M11-A9, Clinical and Laboratory Standards Institute (CLSI)] against the 10 agents. Ribotyping was performed by PCR capillary gel electrophoresis on all isolates. Ridinilazole had a minimum inhibitory concentration (MIC) 90 of 0.25 mcg/mL, and no isolate had an MIC greater than 0.5 mcg/mL. In comparison, fidaxomicin had an MIC 90 of 0.5 mcg/mL. The vancomycin MIC 90 was 2 mcg/mL with a 0.7% resistance rate [both CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria]. The metronidazole MIC 90 was 1 mcg/mL, with none resistant by CLSI criteria, and a 0.3% resistance rate by EUCAST criteria. Among the 50 different ribotypes isolated in the survey, the most common ribotype was 014–020 (14.0%) followed by 106 (10.3%), 027 (10%), 002 (8%), and 078–126 (4.3%). Ridinilazole maintained activity against all ribotypes and all strains resistant to any other agent tested. Ridinilazole showed excellent in vitro activity against C. difficile isolates collected between 2020 and 2021 in the United States, independent of ribotype.

Abstract AIMS High-grade glioma continues to have dismal survival with current standard-of-care treatment, owing in part to its intra- and inter-patient heterogeneity. Typical diagnostic biopsies are taken from the dense tumor core to determine the presence of abnormal cells and the status of a few key genes (e.g. IDH1, MGMT). However, the tumor core is typically resected, leaving behind possibly genetically, transcriptomically and/or phenotypically distinct invasive margins that repopulate the disease. As these remaining populations are the ones ultimately being treated, it is important to know their compositional differences from the tumor core. We aim to identify the phenotypic niches defined by the relative composition of key cellular populations and understand their variation amongst patients. METHOD We have established an image-localized research biopsy study, that samples from both the invasive margin and tumor core. From this protocol, we currently have 202 samples from 58 patients with available bulk RNA-Seq, collected between Mayo Clinic and Barrow Neurological Institute. Using a single-cell reference dataset from our collaborators at Columbia University, we used CIBERSORTx, a deconvolution method, to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell states for each sample. RESULTS We find that these cell state abundances connect to patient survival and show regional differences. For example, proneural glioma states were higher in invasive regions, whereas proliferative and mesenchymal states were higher in the tumor core. CONCLUSIONS Our analysis demonstrates a need to characterize the residual tissue following glioma resection to better understand the recurrent disease.

Abstract Objective . To investigate the impact of scan path optimization on the dose accuracy and beam delivery time (BDT) of proton pencil beam scanning in the dose-driven continuous scanning (DDCS). Approach . A diverse set of six clinical plans, representing various spot patterns and treatment sites, was used to evaluate the effectiveness of scan time optimization and scan length optimization. The DDCS dose discrepancy and BDT with optimized scan paths was compared to the default serpentine scan path. Main results . Both scan time optimization and scan path optimization were able to reduce the DDCS dose discrepancy compared to the default serpentine scan path. All plans, except for the layer repainting lung plan, achieved a 2%/2 mm gamma pass rate of over 99% and less than 1% PTV DVH root mean square error (RMSE) through scan path optimization. In the case of the layer repainting lung plan, when compared to the default serpentine scan path, the 2%/2 mm gamma pass rate showed improvements from 91.3% to 93.1% and 95.8%, while the PTV DVH RMSE decreased from 2.1% to 1.7% and 1.1% for scan time optimization and scan length optimization, respectively. Although scan time optimization resulted in shorter total scan times for all plans compared to the default scan path and scan length optimization tended to have longer total scan times. However, due to the short total scan times and their minimal contribution to the total BDT, the impact of scan path optimization on the total BDT was practically negligible. Significance . Both scan time optimization and scan length optimization proved to be effective in minimizing DDCS dose discrepancy. No definitive winner can be determined between these two optimization approaches. Both scan time and scan length optimization had minimal effect on the total BDT.

AbstractBackgroundKilo‐voltage cone‐beam computed tomography (CBCT) is a prevalent modality used for adaptive radiotherapy (ART) due to its compatibility with linear accelerators and ability to provide online imaging. However, the widely‐used Feldkamp‐Davis‐Kress (FDK) reconstruction algorithm has several limitations, including potential streak aliasing artifacts and elevated noise levels. Iterative reconstruction (IR) techniques, such as total variation (TV) minimization, dictionary‐based methods, and prior information‐based methods, have emerged as viable solutions to address these limitations and improve the quality and applicability of CBCT in ART.PurposeOne of the primary challenges in IR‐based techniques is finding the right balance between minimizing image noise and preserving image resolution. To overcome this challenge, we have developed a new reconstruction technique called high‐resolution CBCT (HRCBCT) that specifically focuses on improving image resolution while reducing noise levels.MethodsThe HRCBCT reconstruction technique builds upon the conventional IR approach, incorporating three components: the data fidelity term, the resolution preservation term, and the regularization term. The data fidelity term ensures alignment between reconstructed values and measured projection data, while the resolution preservation term exploits the high resolution of the initial Feldkamp‐Davis‐Kress (FDK) algorithm. The regularization term mitigates noise during the IR process. To enhance convergence and resolution at each iterative stage, we applied Iterative Filtered Backprojection (IFBP) to the data fidelity minimization process.ResultsWe evaluated the performance of the proposed HRCBCT algorithm using data from two physical phantoms and one head and neck patient. The HRCBCT algorithm outperformed all four different algorithms; FDK, Iterative Filtered Back Projection (IFBP), Compressed Sensing based Iterative Reconstruction (CSIR), and Prior Image Constrained Compressed Sensing (PICCS) methods in terms of resolution and noise reduction for all data sets. Line profiles across three line pairs of resolution revealed that the HRCBCT algorithm delivered the highest distinguishable line pairs compared to the other algorithms. Similarly, the Modulation Transfer Function (MTF) measurements, obtained from the tungsten wire insert on the CatPhan 600 physical phantom, showed a significant improvement with HRCBCT over traditional algorithms.ConclusionThe proposed HRCBCT algorithm offers a promising solution for enhancing CBCT image quality in adaptive radiotherapy settings. By addressing the challenges inherent in traditional IR methods, the algorithm delivers high‐definition CBCT images with improved resolution and reduced noise throughout each iterative step. Implementing the HR CBCT algorithm could significantly impact the accuracy of treatment planning during online adaptive therapy.

Abstract Purpose A human cadaveric model combining standard lung protective mechanical ventilation and modified cardiac bypass techniques was developed to allow investigation into automated modes of detection of venous air emboli (VAE) prior to in vivo human or animal investigations. Methods In this study, in order to create an artificial cardiopulmonary circuit in a cadaver that could mimic VAE physiology, the direction of flow was reversed from conventional cardiac bypass. Saline was circulated in isolation through the heart and lungs as opposed to the peripheral organs by placing the venous cannula into the aorta and the arterial cannula into the inferior vena cava with selective ligation of other vessels. Results Mechanical ventilation and this reversed cardiac bypass scheme allowed preliminary detection of VAE independently but not in concert in our current simulation scheme due to pulmonary edema in the cadaver. A limited dissection approach was used initially followed by a radical exposure of the great vessels, and both proved feasible in terms of air signal detection. We used electrical impendence as a preliminary tool to validate detection in this cadaveric model however we theorize that it would work for echocardiographic, intravenous ultrasound or other novel modalities as well. Conclusion A cadaveric model allows monitoring technology development with reduced use of animal and conventional human testing.