Citations

PURPOSE To investigate the clinical behavior of breast cancer in young BRCA carriers according to the specific BRCA gene ( BRCA1 v BRCA2 ) and the association of the timing of genetic testing (before v at diagnosis) with prognosis. METHODS This was an international, multicenter, hospital-based, retrospective cohort study that included 4,752 patients harboring germline pathogenic/likely pathogenic variants (PVs) in BRCA1 or BRCA2 , who were diagnosed with stage I-III invasive breast cancer at 40 years or younger between January 2000 and December 2020 in 78 centers worldwide (ClinicalTrials.gov identifier: NCT03673306 ). RESULTS Compared with BRCA2 carriers (n = 1,683), BRCA1 carriers (n = 3,069) had more frequently hormone receptor–negative (74.4% v 15.5%) and high-grade (77.5% v 49.1%) tumors. Similar outcomes were observed in BRCA1 and BRCA2 carriers but with a different pattern and risk of disease-free survival events over time. Compared with patients tested for BRCA at diagnosis (ie, between 2 months before and up to 6 months after diagnosis; n = 1,671), those tested before diagnosis (ie, any time up to 2 months before diagnosis; n = 411) had smaller tumors (T1: 61.3% v 32.4%), less nodal involvement (N0: 65.9% v 50.8%), less frequently received chemotherapy (84.4% v 92.9%), and axillary dissection (37.5% v 47.4%). Patients tested before diagnosis had better overall survival (OS; unadjusted hazard ratio [HR], 0.61 [95% CI, 0.40 to 0.92]); however, this result lost statistical significance after adjustment for potential confounders including tumor stage (adjusted HR, 0.74 [95% CI, 0.47 to 1.15]). CONCLUSION This global study provides evidence on the different clinical behavior of breast cancer in young BRCA1 and BRCA2 carriers. Identifying a BRCA PV in healthy individuals was associated with earlier-stage breast cancer diagnosis and lower treatment burden, as well as better unadjusted OS.

Abstract Background Accurate low‐dose CT simulation is required to efficiently assess reconstruction and dose reduction techniques. Projection domain noise insertion requires proprietary information from manufacturers. Analytic image domain noise insertion methods are successful for linear reconstruction algorithms, however extending them to non‐linear algorithms remains challenging. Emerging, deep‐learning‐based image domain noise insertion methods have potential, but few approaches have explicitly incorporated physics information and a texture‐synthesis model to guide the generation of locally and globally correlated noise texture. Purpose We proposed a p hysics‐informed model‐based gener a tive neura l network for simulating scann e r‐ and algori t hm‐specific low‐dose C T e xams (PALETTE). It is expected to provide an alternative to projection domain noise insertion methods in the absence of manufacturers’ proprietary information and tools. Methods PALETTE integrated a physics‐based noise prior generation process, a Noise2Noisier sub‐network, and a noise texture synthesis sub‐network. The Noise2Noisier sub‐network provided a bias prior, which, combined with the noise prior, served as the inputs to noise texture synthesis sub‐network. Explicit regularizations in spatial and frequency domains were developed to account for noise spatial correlation and frequency characteristics. For proof‐of‐concept, PALETTE was trained and validated for a commercial iterative reconstruction algorithm (SAFIRE, Siemens Healthineers), using the paired routine and 25% dose images from CT phantoms (lateral size 30–40 cm; three training and four testing phantoms) and open‐access patient cases (10 training and 20 testing cases). In phantom validation, noise power spectra (NPS) were compared in water background and tissue‐mimicking inserts, using peak frequency and mean‐absolute‐error (MAE). In patient case evaluation, visual inspection and quantitative assessment were conducted on axial, coronal, and sagittal planes. Local and global noise texture were visually inspected in low‐dose CT images and the difference images between routine and low dose. Noise levels in liver and fat were measured. Local and global 2D Fourier magnitude spectra of the difference images and the corresponding radial mean profiles were used to assess similarity in noise frequency components within tissues and entire field‐of‐view, using spectral correlation mapper (SCM) and spectral angle mapper (SAM). Several baseline neural network models (e.g., GAN) were included in the evaluation. Statistical significance was tested using a t ‐test for related samples. Results PALETTE‐derived NPS showed accurate noise peak frequency (PALETTE/reference: water 1.40/1.40 lp/cm; inserts 1.7/1.7lp/cm) and small MAE (≤0.65 HU 2 cm 2 ). PALETTE created anatomy‐dependent noise texture, showing realistic local and global granularity and streaks. No statistically significant difference was observed in noise levels ( p > 0.05). Noise range was comparable across 3D image volume (PALETTE / reference):liver – [18.0, 53.4] / [19.3, 50.0] HU; fat – [11.7, 42.4] / [12.1, 41.3] HU. Percent absolute difference of local noise was small (mean ± standard deviation): liver 4.1%±3.1%, fat 4.6%±3.1%. Noise frequency distribution was close to the reference (mean per case): SCM ≥ 0.92, SAM ≤ 0.22. Additionally, PALETTE outperformed all baseline models in visual inspection and quantitative comparison. Conclusion PALETTE can provide high‐quality image domain noise insertion for simulating accurate low‐dose CT images created with a commercial non‐linear reconstruction algorithm.

Context.— A monthly pathology journal club has met for 24 years. It was established to help members stay apprised of the literature relevant to diagnostic pulmonary pathology. Objective.— To assess whether the journal club met its goal and to report on opportunities identified for improvement. Design.— To determine whether articles chosen for discussion as opposed to notation were more significant, Scopus citation indices for article types reviewed from January 2007 to November 2023 were compared. A survey of current faculty was undertaken to determine if the club was meeting expectations and to identify improvement opportunities. Results.— Articles from January 2007 to November 2023 included 858 discussed and 3385 noted. Mean (SD) citation count was 103.0 (409.80) for discussion and 64.9 (259.77) for notation articles ( P < .001). The citation count was noticeably right skewed, as articles with high citation counts inflated the mean. Members were mostly satisfied with the way the journal club was structured and managed. Members most valued the summary of the articles, followed by the live discussion. Opportunities for improvement included decreasing the number of journals scanned, decreasing detail in summaries, and using generative artificial intelligence (AI) to facilitate summary generation. A pilot using AI anecdotally reduced preparatory time, but the human-edited summary included more specific context, critical commentary, and enhanced take-home messages, providing a more nuanced analysis. Conclusions.— The journal club met its initial goal. Opportunities for improvement have been identified including the use of generative AI to facilitate article summarization.

Abstract The Physician-Scientist Trainee Diversity Summit, hosted by the American Physician Scientists Association and the Burroughs Wellcome Fund, was conceived in 2019 with the mission of developing strategic plans to diversify the physician-scientist community using human-centered design thinking. In June 2024, the second iteration of this conference was held in Raleigh, North Carolina, and brought together a network of scientific and medical organizations to discuss issues of justice, equity, diversity, and inclusion facing physician-scientist trainees. This article summarizes the progress made from the first meeting, the proceedings of the 2024 Summit, and a thematic analysis of the recent meeting, offering tangible solutions to the physician-scientist community for supporting diversity and accessibility.

Abstract Background Multi‐energy CT (MECT) enables quantification of material concentrations by measuring linear attenuation coefficient line integrals with multiple x‐ray spectra. Photon counting detector (PCD)‐CT utilizes a detector‐based approach for MECT that can suffer from substantial spectral overlap, resulting in amplified material quantification noise. Dual‐source dual‐kV approaches for MECT are currently utilized in some energy‐integrating detector (EID)‐CT systems and can potentially be utilized with PCD‐CT for improved spectral separation. Purpose To evaluate the iodine quantification performance of a novel dual‐source (DS)‐PCD‐CT scan mode and compare to single‐source (SS)‐PCD‐CT and DS‐EID‐CT. Materials and Methods A 30 cm × 40 cm solid water phantom with four iodine inserts (2, 5, 10, and 15 mg/mL) was scanned with the three spectral modalities: SS‐PCD‐CT with two energy thresholds, DS‐PCD‐CT (90/Sn150 kV), and DS‐EID‐CT (90/Sn150 kV). For each modality, full‐dose (12 mGy) and half‐dose scans were acquired, and images were reconstructed with filtered back‐projection using a quantitative (Qr40) kernel. When scanning in a DS configuration, the total radiation dose budget is split between two detectors, increasing the strength of a signal‐dependent filter compared to a SS acquisition. To account for this effect, the modulation transfer function (MTF) for each modality was measured from a 0.05 mm tungsten wire. A linear spatial filter was applied to the SS images to match their MTF to that of the DS images. The resulting high‐ and low‐energy images were input into an image‐domain least squares material decomposition algorithm with iodine and water as the two basis materials. Iodine quantification accuracy and noise measured from the iodine basis images were used as figures of merit, and t‐tests used to compare between modalities. Results The 10% MTF cutoffs were 0.56, 0.57, 0.60, and 0.57 lp/mm for DS‐EID‐CT, DS‐PCD‐CT, SS‐PCD‐CT, and SS‐PCD‐CT after MTF‐matching, respectively, with the SS‐PCD‐CT MTF cutoff dropping to 0.58 lp/mm at half‐dose. Without accounting for the signal‐dependent filter by matching the MTFs, the noise in iodine material basis images from SS‐PCD‐CT was 10% higher than that of DS‐EID‐CT. After matching the MTFs, the noise in the SS‐PCD‐CT iodine image was 9%–22% lower than that of the DS‐EID‐CT. The lowest iodine image noise was from the DS‐PCD‐CT, which was 39%–41% lower than the DS‐EID‐CT. The DS‐PCD‐CT noise magnitude was significantly different from the other modalities. Mean iodine quantification accuracy across all measured concentrations was within 5% for all modalities at full dose, but was only below 5% for the DS‐PCD‐CT at half‐dose. Conclusions SS‐PCD‐CT with two energy thresholds outperformed DS‐EID‐CT in terms of image noise in iodine basis images when spatial resolution was matched. DS‐PCD‐CT gave the lowest noise due to the combination of PCD technology and improved spectral separation from the different x‐ray spectra.

Background/Objectives: Adolescents with autonomic disorders who attend Intensive Interdisciplinary Pain Treatment (IIPT) programs report improvements in functioning. However, it is unclear whether they experience corresponding improvements in physiological measures. As such, the aim of this pilot study was to examine changes in physiological measures in youth attending an IIPT program who demonstrated excessive postural tachycardia on an active stand test. The secondary goal was to examine associations between physiological measurements and self-reported measures of chronic orthostatic intolerance (cOI) and functioning. Methods: At admission and discharge, eighteen adolescents and young adults (AYAs) attending IIPT (M age = 17.39 years; SD = 2.15 years) completed an active stand test, measures of breathing rate and muscle tension, as well as self-reported measures of cOI symptoms and functioning. Results: AYAs showed significant reduction in active stand test heart rate increase (p < 0.001; d = 1.07) and maximum heart rate (p = 0.002, d = 0.76) from admission to discharge. Improvements were also observed in resting respiration rate (p = 0.001, d = 89) and resting trapezoid tension (p = 0.03, d = 0.49). Although patients showed significant improvements on self-report measures of functioning (p < 0.001, d = 1.78), changes on subjective report of cOI symptoms did not reach significance. Exploratory analyses that only included patients with a POTS diagnosis were consistent with the overall results. Conclusions: Youth who demonstrated excessive postural tachycardia on active stand test at admission to an IIPT showed significant improvements from admission to discharge in their active stand maximum heart rate and heart rate increase, as well as respiration rate, muscle tension, and reports of their functioning. Future research is necessary to examine the mechanisms of change that contribute to symptom improvement.

Abstract Background Characterization of transplant transmitted infections associated with drowned organ donors and the recipients is not well delineated, posing challenges for optimal management and prophylaxis strategies. Broader organ sharing may pose additional considerations due to pathogen variation. Methods We reviewed 22 potential donor disease transmission events (PDDTEs) from drowned donors reported to the Organ Procurement and Transplantation Network (OPTN) ad hoc Disease Transmission Advisory Committee (DTAC) from 2017-2022 to estimate the incidence of PDDTEs among all US drowned organ donors and identify the most common pathogens in this setting. We also characterized donor/recipient epidemiology, infection timing and risk factors, and recipient survival. Results From 2017-2022, drowning was the mechanism of death in 777/74,232 (1.0%) of all US organ donors, from whom 2500 organs were transplanted. Among the 22 PDDTEs, there were 70 organ recipients. The median donor age was 17.5 years (range 1-70 years) and lung recipients accounted for 5/70 organ recipients. All PDDTE reports were submitted due to recipient disease, and index cases occurred 2-19 days post-transplant. 7/22 (7/777 drowned donors, 0.9%) PDDTEs were associated with pathogens consistent with plausible waterborne transmission, of which 4 were due to invasive molds (Zygomycetes and Scedosporium) and 3 were due to bacteria (Pseudomonas and Legionella). Of the 21 organ recipients from these 7 donors, 8 had proven or probable infections. 6/8 recipients had severe infection with 3 deaths, all from invasive mold infections. There were no identifiable infection risk factors related to drowning water source, donor immersion time, or geographic region. However, donor/recipient regional discordance occurred in 5/21 recipients, demonstrating the trend in broader organ sharing. Conclusion Though rare, organ recipients are at risk for transplant transmitted infection from drowned donors, particularly invasive mold infections. All infections occurred within the first month after transplant with high associated mortality. Though optimal management and prophylaxis strategies in these scenarios remain uncertain, post-transplant vigilance for early infection is paramount. Disclosures Helen S. Te, MD, CVS Caremark: Advisor/Consultant Lara A. Danziger-Isakov, MD, MPH, Aicuris: clinical research contract, paid to institutio|Ansun BioPharma: clinical research contract, paid to institution|Astellas: Advisor/Consultant|Astellas: clinical research contract, paid to institutio|Merck: clinical research contract, paid to institutio|Pfizer: Grant/Research Support|Takeda: clinical research contract, paid to institutio Anil J. Trindade, MD, CareDx, Inc.: Advisor/Consultant|CareDx, Inc.: Grant/Research Support|TFF Pharmaceuticals: Advisor/Consultant|Veloxis Pharmaceuticals, Inc.: Grant/Research Support

142 Background: Fruquintinib (F) is a highly selective, oral tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors (VEGFRs -1, -2, -3) that is approved by the US FDA and in the EU, UK, and Japan for previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. FRESCO-2 (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival (OS) with F + best supportive care (BSC) vs placebo (P) + BSC. This subgroup analysis assessed landmark survival of all FRESCO-2 patients (pts), and baseline (BL) characteristics and safety data of pts treated with F who had OS ≥10 months (mos) compared with the intent-to-treat (ITT) population (pop). Methods: Pts were randomized 2:1 to receive F 5 mg or matching P, by mouth, once daily, 3 weeks on, 1 week off, + BSC. Pts had received prior chemotherapy, anti-VEGF therapy and, if RAS wild type, anti-EGFR therapy; and had prior exposure to trifluridine/tipiracil (TAS-102) and/or regorafenib. The hazard ratio (HR) between the two treatment arms was calculated from a stratified Cox proportional hazard model with treatment group as the only covariate in the model. Results: In the ITT pop, OS was improved with F vs P (HR 0.66); OS rates (95% confidence intervals [CIs]) at 6 and 9 mos were 60.4% (55.9–64.9) vs 41.5% (35.0–48.0) and 41.1% (36.4–45.8) vs 28.2% (22.1–34.3), respectively. Progression-free survival (PFS) rates (95% CIs) at 6 and 9 mos were 23.8% (19.7–28.0) vs 1.1% (0–2.6) and 11.3% (8.1–14.6) vs 0.5% (0–1.6), respectively. Of 461 pts who received F, 113 (24.5%) had OS ≥10 mos (range 10.0–18.9) with a median duration of F treatment of 6.3 mos (range 0.7–19.1). Among pts receiving F, a higher proportion (≥10% difference) of pts with OS ≥10 mos had no liver metastases (mets) and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 at BL compared with the ITT pop (Table). In pts with OS ≥10 mos, 61.9% experienced a grade ≥3 treatment-emergent adverse event compared with 62.7% in the ITT pop. Conclusions: Longer-term OS and PFS rates at 6 and 9 mos were higher with F vs P in the FRESCO-2 ITT pop. The data show a higher proportion of pts with OS ≥10 mos had an absence of liver mets and ECOG PS 0 at BL than the ITT pop. The safety profile of F in pts with OS ≥10 mos was consistent with the ITT pop. Clinical trial information: NCT04322539 . BL characteristics of pts treated with F with OS ≥10 mos vs ITT pop. BL characteristic Pts with OS ≥10 mos (n=113) ITT pop(n=461) ECOG PS (0 / 1), % 54.0 / 46.0 42.5 / 57.5 Median time since 1 st CRC diagnosis, mos 52.0 47.2 Primary tumor location at 1 st diagnosis (colon / rectum / both), % 51.3 / 35.4 / 13.3 60.5 / 31.0 / 8.5 Primary site at 1 st diagnosis (colon left / colon right), % 42.5 / 15.9 41.6 / 21.0 Liver mets, % 58.4 73.5 Median duration of mCRC, mos 42.7 37.9 Prior lines of therapy for mCRC (≤3 / >3), % 26.5 / 73.5 27.1 / 72.9 Prior TAS-102, % 46.9 52.1 Prior regorafenib, % 12.4 8.7

ABSTRACT Background Existing risk scores assessing geriatric vulnerability in the emergency department (ED) have shown limited predictive power, especially in diverse populations. We investigated the relationship of a quick and easy‐to‐administer geriatric vulnerability scoring system with functional decline and mortality in older patients admitted to multiple hospitals through the ED in the United States (US) and Brazil (BR). Method Federated, international, multicenter observational study of hospitalized ED patients aged ≥ 65 from US and BR. The six criteria from the PRO‐AGE score (Physical impairment, Recent hospitalization, Older age [≥ 90], Acute mental alteration, Getting thinner, and Exhaustion; 0–8; higher scores = greater vulnerability) were assessed on admission. We used proportional hazards models to investigate the relationships between PRO‐AGE score groups and 90‐day mortality and functional decline, defined as new dependence in activities of daily living (ADL) and instrumental ADL (IADL), after adjusting for age, sex, race and ethnicity, education, Charlson comorbidity score, and study site. Death was considered a competing event for the functional decline outcome. Results A total of 1390 patients were included (US = 560; Brazil = 830). The 90‐day risk of death was higher for the upper compared with the lower (reference) PRO‐AGE group in both cohorts (US: HR = 11.76; 95% confidence interval [CI] = 2.56–54.04; BR: HR = 12.29; 95% CI = 3.54–42.59), whereas the risk of new 90‐day ADL disability was higher for upper (HR = 2.08; 95% CI = 1.21–3.56) and middle groups (HR = 2.10; 95% CI = 1.35–3.27) in the US but only the upper group in BR (HR = 1.70; 95% CI = 1.02–2.85). Conclusion A higher PRO‐AGE score was associated with mortality and functional decline in older ED patients admitted to hospitals in the US and BR, demonstrating its generalizability as a geriatric vulnerability risk score.