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PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

e12562 Background: Previous research has suggested that breast cancer (BC) diagnosed during pregnancy or the postpartum period exhibits more aggressive clinical features, possibly due to pregnancy-related hormonal changes, immune modulation, and alterations in the mammary microenvironment compared to nulligravid or women many years out from pregnancy. Emerging data have demonstrated potential worse outcomes for patients (pts) diagnosed in post-partum. This study evaluated the influence of timing of diagnosis in relation to pregnancy history and recency of childbirth on long-term outcomes in a modern cohort of young pts with early-stage BC. Methods: Pts with stage I–III BC age < 40y in the prospective Young Women’s Breast Cancer Study (YWBCS) were categorized at diagnosis as Nulligravid (no prior pregnancy), Nulliparous (prior pregnancy without live birth), Currently Pregnant, or Parous (subdivided by time since last childbirth: within 5 years [≤ 5y PP], and 5–10 years postpartum [5–10y PP]). Baseline characteristics and outcomes were compared across BC subtypes (estrogen receptor+/HER2- [ER+/HER2-], HER2+, and triple-negative BC [TNBC]). Prognostic analyses for distant recurrence-free survival (DRFS) used Cox models. Results: 859 pts were included, 257 (30%) nulligravid, 50 (6%) nulliparous, 37 (4%) pregnant, and 515 (60%) parous (348 [68%] were ≤5y PP, and 167 [32%] were 5–10y PP). Median follow-up was 133 (6–209) months. Median age at diagnosis was lower in nulligravid pts (33 vs. 35–38 years); T1 tumors were most common in pts >5y PP (62%), and N0 status was highest in nulligravid pts (64%) (all p < 0.0001). Pregnant pts had higher rates of TNBC (27%), and T3 tumors (14%), N1 status, N1 (41%), and Grade 3 (81%) tumors compared to other groups (all p < 0.0001). Overall, only tumor size (T2-T4 vs T1, HR 2.03; 95% CI 1.37–3.03) and nodal status (N1 vs N0, HR 2.22; 1.48–3.34; N2/3 vs N0, HR 3.23; 1.96-5.33) were independently associated with worse DRFS; pregnancy history was not: nulligravid + nulliparous pts had no significant differences in DRFS compared to Pregnant (HR 1.46; 0.75–2.86), Parous <5y PP (HR 0.86; 0.58–1.26), and Parous 5–10y PP (HR 0.89; 0.54–1.48). Subgroup analyses by BC subtype (Table) and sensitivity analyses (excluding currently pregnant pts or separating nulligravid and nulliparous pts) demonstrated no significant associations between pregnancy history and DRFS. Conclusions: In this cohort study of very young patients with early breast cancer with contemporary treatment including management of breast cancer during pregnancy, pregnancy history and recency of pregnancy were not independent predictors of long-term disease outcomes. DRFS results by subgroup. Pregnancy Group N (%) HR (95% CI) ER+/HER2- Nulligravid + Nulliparous 173 (38.1) Ref Pregnant 16 (3.5) 0.93 (0.32–2.70) Parous ≤5y PP 177 (39.0) 0.77 (0.45–1.29) Parous 5–10y PP 88 (19.4) 0.78 (0.39–1.53) HER2+ Nulligravid + Nulliparous 77 (30.8) Ref Pregnant 11 (4.4) 3.27 (0.80–13.38) Parous ≤5y PP 113 (45.2) 1.50 (0.60–3.75) Parous 5–10y PP 49 (19.6) 1.45 (0.45–4.66) TNBC Nulligravid + Nulliparous 56 (36.8) Ref Pregnant 10 (6.6) 1.92 (0.61–6.09) Parous ≤5y PP 57 (37.5) 0.68 (0.28–1.63) Parous 5–10y PP 29 (19.1) 1.16 (0.43–3.14)

9002 Background: The field of AI is rapidly evolving. With recent development of more user-friendly AI software, its integration into healthcare across different medical specialties, including HemOnc has emerged. Data detailing the perception and concerns of the HemOnc workforce about AI’s roles is lacking and is needed if AI is to be integrated in HemOnc CliPr and MedEd. Methods: Questionnaires about the perception and concerns regarding AI in CliPr and MedEd were created on REDCap and approved by IRB. We surveyed the entire HemOnc workforce at the 3 Mayo Clinic major sites between 11/07/24 and 01/20/25, including physicians, both faculty (FAC) and fellows (FEL), advanced practice providers (APP), and nurses (RN). Participation was voluntary. Simple statistical analyses were employed for the results. Results: 344 participants (PTP) responded to the survey, 118 physicians (41 FEL and 77 FAC), 49 APP, and 177 RN. 64% of PTP report having used AI but only 31% used it in HemOnc MedEd, and 28% in HemOnc CliPr, with 67% considering themselves to have little to no knowledge about AI. 94% of PTP believe AI will be integrated in HemOnc MedEd, with such integration being seen as beneficial by 90%. Among physicians, 85% of FEL and 92% of FAC report that fellowship programs should incorporate AI training into curricula. 95% of PTP believe AI will be incorporated into HemOnc CliPr. Meanwhile, 62% of PTP (50.8% of physicians, and 68% of APP and RN) are concerned about risks it may pose to CliPr. Nevertheless, 90% of PTP would embrace AI’s use in HemOnc. Table 1 details the perceptions and concerns about AI in HemOnc MedEd and CliPr. The main perceived risks are decreased time spent with patients (pts), and inaccuracies or worse pt care. Meanwhile, 33% believe AI would increase efficiency and quality of care, while 30% believe it would increase time spent with pts. 14% of PTP worry their role could be replaced by AI. Conclusions: To the best of our knowledge, this is the largest assessment of HemOnc workforce’s perception and concerns about AI. Based on our survey, the HemOnc workforce, in general, endorses AI use, but with some concerns raised. While incorporation in MedEd is perceived with excitement, many envision the use in CliPr involves risks and challenges. Proper systematic education of the workforce about AI, with well-designed CliPr integration methods are needed to mitigate the legitimate existing concerns. Perceptions & concerns about AI in HemOnc MedEd & CliPr. FEL % APP % RN % FAC % AI will assist documentation in CliPr 98 82 79 92 AI will be used in pt communication 73 80 78 87 AI will screen pts for clinical trial enrollment 85 86 76 96 AI will increase the efficiency and quality of CliPr 43 37 24 46 AI will increase time spent with pts 39 27 25 38 AI will decrease time spent with pts 29 41 48 23 AI will lead to inaccuracies or worse CliPr 12 20 25 20 AI may replace the HemOnc workforce 11 16 19 5

4119 Background: TP53 mutations are frequent genetic alterations in cancers and also prevalent in biliary tract cancer (BTC). In non-small cell lung cancer, TP53 mutations have been reported to enhance immune checkpoint inhibitor (ICI) efficacy and improve outcomes. However, their impact on BTC remains unclear. This study investigated the clinico-molecular characteristics, prognosis, and ICI efficacy in TP53 -mutated BTC. Methods: Patient data were collected from the SCRUM-Japan GOZILA and MONSTAR-SCREEN-1/2 databases (Japan) and the Duke university and Mayo clinic databases (U.S.), which included patients receiving first-line ICI therapy. Comparisons between TP53 wild-type (WT) and mutation groups were performed in the Japanese cohort. Subsequently, analyses were expanded to include U.S. patients, focusing on comparisons between non-ICI and ICI groups. Tumor Immune Dysfunction and Exclusion (TIDE) scores were calculated using MONSTAR-SCREEN-2 whole transcriptome sequencing (WTS) data to evaluate ICI responsiveness, and gene set enrichment analysis (GSEA) explored pathways associated with TP53 mutations. Results: In the Japanese cohort (n=594), TP53 mutations were identified in 311 patients (52.4%). KRAS , ERBB2 , CDKN2A , and SMAD4 alterations were more frequent in the TP53 mutation group, while IDH1, BAP1 , and FGFR2 fusions were more common in the WT group. Multivariable analysis showed TP53 mutations were independent prognostic factors for poor outcomes (progression-free survival [PFS]: HR 1.37, 95% CI: 1.11–1.69, P=0.003; overall survival [OS]: HR 1.36, 95% CI: 1.06–1.75, P=0.017). Incorporating the U.S. cohort (n=625; non-ICI: 548; ICI: 77), no significant differences in overall response rate (ORR) or disease control rate (DCR) were observed in the non-ICI group between the groups. However, in the ICI group, TP53 mutations tended to show higher ORR (21.1% vs. 38.5%, P=0.16) and DCR (47.4% vs. 66.7%, P=0.14). In the non-ICI group, TP53 mutations were associated with worse PFS (HR 1.46, median PFS: 7.4 vs. 5.3 months, P<0.001), whereas, in the ICI group, no significant difference was observed; however, a trend toward better PFS was seen in the TP53 mutation group (median PFS: 5.0 vs. 6.4 months, P=0.163). TIDE scores were significantly lower in the TP53 mutation group, indicating higher ICI responsiveness. GSEA revealed enrichment of oxidative phosphorylation and hypoxia pathways. Conclusions: TP53 mutations are independent prognostic factors for poor outcomes in BTC. However, patients with TP53 mutations may derive greater benefits from ICIs, underscoring the importance of tailored therapeutic strategies in TP53- mutated BTC.

Abstract The availability of knowledge about the effects of buprenorphine on pain perception in healthy adults could help investigators select experimental tests with evidence of responsiveness to buprenorphine in nondiseased states. The purpose of this meta-narrative systematic review is to summarize the effects of buprenorphine on pain perception in healthy adults. Comprehensive database searches were conducted from inception dates through July 16, 2024. Inclusion criteria included all study designs involving healthy adults receiving buprenorphine and tests of pain perception. Risk of bias was assessed using a tool developed for randomized controlled trials (RCTs). A meta-narrative approach was used due to high levels of clinical heterogeneity. A total of 10 RCTs were included, and healthy adults comprised the comparator groups in all trials. Three RCTs had a low risk of bias, 6 had some concerns, and 1 had a high risk of bias. Six RCTs used intravenous buprenorphine, 3 used transdermal, and 1 study used intravenous and sublingual buprenorphine. The effects of buprenorphine on pain perception are influenced by the route of administration, dose, and pain stimulus modality. Considerable differences exist in the effects of intravenous and transdermal buprenorphine, but only 1 study used sublingual buprenorphine, which limited comparison with the other drug formulations. Based on these findings, recommendations for clinical trials are proposed. These recommendations should be cautiously interpreted due to the clinical heterogeneity, but they provide a framework for advancing the use of experimental pain tests in trials of buprenorphine involving comparator groups of healthy adults.

Abstract The establishment of guidelines and curriculum standards for medical physics residency training is a critical component of setting expectations and competencies for the profession. Since the last publication of these standards, residency training has become integrated into the eligibility criteria for most medical physics certification bodies. The rapid growth of medical physics requires periodic review of the curriculum to remove outdated approaches, update established knowledge, and add emerging technologies. The goal of this document is to provide a reference standard for residency training program directors, training mentors, and residents to guide creation and/or optimization of their program's curriculum. The document is intentionally forward‐looking to capture emerging technological advances including hybrid diagnostic and therapeutic delivery systems and applications of image processing. This document is an update of the current residency training curriculum. Version history of residency training guidelines Publication Title Date 2013 Essentials and Guidelines for Clinical Medical Physics Residency Training Programs—AAPM Report No. 249 2006 Essentials and Guidelines for Hospital‐Based Medical Physics Residency Training Programs—Report No. 90 1992 Essentials and Guidelines for Hospital‐Based Medical Physics Residency Training Programs—Report No. 36 The Work Group on Periodic Review of Medical Physics Residency Training (WGMPRT) would like to acknowledge the authors of past versions of this document as they form the basis for this update. It is the sincere hope of the WGMPRT that this report will continue to be used by the medical physics community to guide training in the profession.

Abstract Molecular mechanisms underlying disruptions in brain glucose uptake and metabolism, linked with cognitive decline in Alzheimer’s disease (AD) patients, are only partially understood. This study investigated how soluble amyloid beta (sAβ) peptides affect glucose transport at the blood-brain barrier (BBB), the primary portal for glucose entry into the brain. We demonstrated that [ 18 F]-fluorodeoxyglucose ( 18 FDG) uptake is reduced in sAβ overproducing APP,PS1 transgenic mice compared to wild-type mice. Moreover, the influx rate of 18 FDG decreased in sAβ40 or sAβ42 pre-infused mice, highlighting the inhibitory effect of sAβ peptides on glucose transport at the BBB. Consistently, the expression of GLUT1, the primary glucose transporter at the BBB, is reduced in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers upon exposure to sAβ peptides and in Aβ-laden cerebral vasculature in vivo. The study further examined the influence of sAβ on the insulin-AKT pathway, known to regulate glucose uptake through modulation of thioredoxin-interacting protein (TXNIP) expression. Results showed that sAβ peptides suppress AKT phosphorylation and reduce GLUT1 expression by upregulating TXNIP levels in hCMEC/D3 monolayers. Co-incubation of resveratrol with sAβ peptides reduced TXNIP expression and rectified reductions in GLUT1 expression. In summary, toxic sAβ impairs BBB glucose transport by disrupting the insulin/AKT/TXNIP axis.

AbstractThe sliding filament theory explains skeletal muscle fibre force change as a function of length based on the overlap of actin and myosin filaments. Although this length‐tension (LT) relationship has been well investigated in animal models, it is not known whether this microscopic sarcomere LT property can be scaled up five orders of magnitude to explain the LT behaviour of a long human muscle such as the gracilis. The goal of this study is to validate the sarcomere LT curve in humans based on human filament length combined with in vivo experimental data. Intraoperative measurements of maximal tetanic force and muscle‐tendon unit length at four different joint configurations (JC) were obtained from 19 patients undergoing free functioning muscle transfer surgery. With physiologically measured fibre length and estimated sarcomere shortening resulting from tendon compliance, we show that 79.7% variance in isometric force data is explained by a simple human sarcomere LT model. This study demonstrates that the human whole muscle LT relationship can be modelled by the sliding filament theory given patient‐specific fibre length, filament length, tendon compliance and sarcomere shortening. imageKey points Whole human gracilis muscle isometric length‐tension relationships were measured in the operating room. Grouped whole muscle raw length‐tension curves showed no obvious form. The width of each experimental length‐tension curve was highly variable across subjects and used to predict fibre length (serial sarcomere number). After whole muscle length‐tension curves were normalized to each patient's serial sarcomere number, the whole human muscle length‐tension curve was well predicted by the sliding filament theory.

Abstract Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of aggressive inflammation and immune system activation. Its diagnosis is often hindered by its clinical overlap with sepsis, multiorgan failure, and other severe diseases common in the intensive care unit. We present a case of HLH diagnosed in the setting of multiple confounding conditions. Case Presentation: 24-year-old Caucasian male with common variable immunodeficiency presented to local hospital after a week of diffuse swelling and shortness of breath, initially found to be hypoxemic, hypoglycemic, hypovolemic, and febrile to 105°F. He was treated for septic shock, requiring norepinephrine, vasopressin, angiotensin, and stress dose hydrocortisone to maintain perfusion pressures. For work of breathing, he failed noninvasive ventilation and was intubated. Initial labs showed shock liver, acute kidney injury with severe metabolic acidosis, and MSSA bacteremia without endocarditis on transesophageal echocardiogram. He met HLH diagnostic criteria with high fever and ferritin 44,838 ng/mL; other inflammatory markers were not tested. Over two weeks the patient developed significant left lower extremity soft tissue infection concerning for Staphylococcus toxic shock syndrome, cholecystitis with cholecystostomy tube placement, hemorrhagic bullae on all limbs, left thigh hematoma, and new liver lesion that underwent biopsy complicated by significant bleeding requiring interventional radiology embolization. After transfer to our institution, he remained on fluctuating doses of norepinephrine with recurring fevers despite broad spectrum antibiotic and antifungal coverage. Repeat blood cultures were negative, MRI negative for osteomyelitis, pan-CT negative for other occult sources of infection, broad laboratory workup negative for atypical infections or antibodies related to rheumatologic diseases. At this point, he fulfilled HLH criteria given high fever, anemia and thrombocytopenia, splenomegaly, triglyceride 417 mg/dL, ferritin 1,953 ng/mL, and soluble IL-2 receptor &gt;4,000 pg/mL. A multidisciplinary decision was made to start methylprednisone. Patient's fever and hemodynamic instability quickly resolved. He was then transitioned to anakinra with downtrend in his inflammatory markers. Discussion: HLH syndrome is often a delayed diagnosis as clinical manifestations mimic infections, can be triggered by such infections, or mimic other diseases in which a robust inflammatory response occurs. HLH laboratory findings are nonspecific or can have long turnaround time. Even its namesake of “hemophagocytosis” is not pathognomic for the disease. It is only in the case of excessive pathologic immune system activation, i.e. HLH syndrome, that immunosuppression is beneficial. Diagnosing HLH requires a curious clinical mind while treating concomitant urgent conditions, to avoid the “tunnel vision” of the often-cited occam's razor.

Artificial intelligence (AI)-based object detection in radiology can assist in clinical diagnosis and treatment planning. This article examines the AI-based object detection models currently used in many imaging modalities, including X-ray Magnetic Resonance Imaging (MRI), Computed Tomography (CT), and Ultrasound (US). The key models from the convolutional neural network (CNN) as well as the contemporary transformer and hybrid models are analyzed based on their ability to detect pathological features, such as tumors, lesions, and tissue abnormalities. In addition, this review offers a closer look at the strengths and weaknesses of these models in terms of accuracy, robustness, and speed in real clinical settings. The common issues related to these models, including limited data, annotation quality, and interpretability of AI decisions, are discussed in detail. Moreover, the need for strong applicable models across different populations and imaging modalities are addressed. The importance of privacy and ethics in general data use as well as safety and regulations for healthcare data are emphasized. The future potential of these models lies in their accessibility in low resource settings, usability in shared learning spaces while maintaining privacy, and improvement in diagnostic accuracy through multimodal learning. This review also highlights the importance of interdisciplinary collaboration among artificial intelligence researchers, radiologists, and policymakers. Such cooperation is essential to address current challenges and to fully realize the potential of AI-based object detection in radiology.