Citations

Abstract In radiotherapy, 2D orthogonally projected kV images are used for patient alignment when 3D-on-board imaging(OBI) unavailable. But tumor visibility is constrained due to the projection of patient’s anatomy onto a 2D plane, potentially leading to substantial setup errors. In treatment room with 3D-OBI such as cone beam CT(CBCT), the field of view(FOV) of CBCT is limited with unnecessarily high imaging dose, thus unfavorable for pediatric patients. A solution to this dilemma is to reconstruct 3D CT from kV images obtained at the treatment position. Here, we propose a dual-models framework built with hierarchical ViT blocks. Unlike a proof-of-concept approach, our framework considers kV images as the solo input and can synthesize accurate, full-size 3D CT in real time(within milliseconds). We demonstrate the feasibility of the proposed approach on 10 patients with head and neck(H\&N) cancer using image quality(MAE:<45HU), dosimetric accuracy(Gamma passing rate(2%/2mm/10%):>97%) and patient position uncertainty(shift error:<0.4mm). The proposed framework can generate accurate 3D CT faithfully mirroring real-time patient position, thus significantly improving patient setup accuracy, keeping imaging dose minimum, and maintaining treatment veracity.

AbstractBackgroundEmbryonal sarcoma of the liver (ESL) is a rare mesenchymal tumor most common in childhood; the optimal treatment approach is uncertain. The clinical features and outcomes of patients with ESL enrolled in a Children’s Oncology Group (COG) clinical trial that evaluated a risk‐based strategy for treating soft tissue sarcomas in patients aged <30 years were evaluated.MethodsThis subset analysis included patients with ESL enrolled in COG study ARST0332. Central review of records, pathology, and imaging confirmed the diagnosis, presenting features, and surgery extent and complications. All patients received dose‐intensive ifosfamide/doxorubicin chemotherapy, with cycle timing dependent on surgery and radiotherapy. Tumor resection occurred before study entry or after four cycles of chemotherapy; radiotherapy for residual tumor was optional.ResultsThirty‐nine eligible/evaluable patients with ESL were analyzed. All tumors were >10 cm in diameter; four were metastatic. Tumor resection was performed upfront in 23 and delayed in 16. Positive surgical margins (n = 6) and intraoperative tumor rupture (n = 6) occurred only in upfront resections. Eight patients received radiotherapy. Estimated 5‐year event‐free and overall survival were 79% (95% confidence interval [CI], 65%–93%) and 95% (95% CI, 87%–100%), respectively. Positive margins increased the local recurrence risk. One of 13 patients with documented hemorrhagic ascites and/or tumor rupture developed extrahepatic intra‐abdominal tumor recurrence.ConclusionsThe treatment strategy used in ARST0332 achieved favorable outcomes for patients with ESL despite a substantial proportion having high‐risk disease features. Deferring tumor resection until after neoadjuvant chemotherapy may decrease the risk of intraoperative tumor rupture and improve the likelihood of adequate surgical margins.

Optical imaging is an ancient branch of imaging dating back to thousands of years. Radiographic imaging and tomography (RadIT), including the first use of X-rays by Wilhelm Röntgen, and then, γ -rays, energetic charged particles, neutrons, etc. are about 130 years young. The synergies between optical and radiographic imaging can be cast in the framework of these building blocks: Physics, Sources, Detectors, Methods , and Data Science , as described in Appl. Opt. 61 , RDS1 ( 2022 ) APOPAI 0003-6935 10.1364/AO.455628 . Optical imaging has expanded to include three-dimensional (3D) tomography (including holography), due in to part the invention of optical (including infrared) lasers. RadIT are intrinsically 3D because of the penetrating power of ionizing radiation. Both optical imaging and tomography (OIT) and RadIT are evolving into even higher dimensional regimes, such as time-resolved tomography (4D) and temporarily and spectroscopically resolved tomography (4D + ). Further advances in OIT and RadIT will continue to be driven by desires for higher information yield, higher resolutions, and higher probability models with reduced uncertainties. Synergies in quantum physics, laser-driven sources, low-cost detectors, data-driven methods, automated processing of data, and artificially intelligent data acquisition protocols will be beneficial to both branches of imaging in many applications. These topics, along with an overview of the Radiography, Applied Optics, and Data Science virtual feature issue, are discussed here.

Abstract Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and 52%/38%, respectively. The median progression-free and overall survival estimates for the same treatment groups were 4.9/14.3 months, 14.9 months/not reached, and 3.3/9 months, respectively. CLL with del(17p) was associated with a lower complete response rate in the total cohort (odds ratio [OR] 0.15; 95% confidence interval [CI] 0.04-0.6; p=0.01) and venetoclax-naïve subgroup (OR 0.13; 95%CI 0.02-0.66; p=0.01). TP53 mutated CLL was associated with a lower complete response rate (OR 0.15; 95%CI 0.03-0.74; p=0.02) and shorter progression-free survival (hazard ratio 3.1; 95%CI 1.21-7.95; p=0.02) only in venetoclax-naïve subgroup. No other clinical or baseline characteristics, including prior venetoclax treatment for CLL, showed statistically significant association with outcomes. Grade 3-4 neutropenia and thrombocytopenia events were most frequent with intensive chemoimmunotherapy + venetoclax; grade 3-4 infection rates were similar across treatment groups. In this difficult-to-treat RT patient population, venetoclax-based combination regimens achieved high response rates, with durable remission and survival observed in a subset of patients.

Abstract Radiation therapy (RT) is a cornerstone of oncologic therapy for the majority of solid malignancies, and unrepaired DNA double-strand breaks are responsible for radiation-induced cytotoxicity. RT-induced DNA lesions can be repaired by multiple mechanisms including homologous recombination (HR) and non-homologous end joining (NHEJ), and disruption of either of these pathways can enhance cytotoxicity. A key component of the NHEJ pathway is the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), and loss of kinase activity can significantly increase radiosensitivity. Herein we describe the results of our medicinal chemistry campaign to develop a potent and selective DNA-PKcs inhibitor, WNC0901. WNC0901 inhibits DNA-PKcs kinase activity in a cell free system with an IC50 of 0.071 nM and demonstrated at least 30-fold higher sensitivity than other family members (ATM, ATR, mTOR, PI3K). WNC0901 has limited aldehyde oxidase (AO) liability with a T1/2 &gt;2000 min in liver cytosol and is stable for over 120 minutes in the presence and absence of an AO inhibitor. A preliminary pharmacokinetic analysis in wista han rat (IV=2mg/kg, PO=20mg/kg) demonstrated 116% apparent absolute oral bioavailability, 2.6 hour terminal half-life, 33.0 mL/min/kg clearance, and a 2.6% unbound brain-to-plasma partition coefficient (Kpuu). WNC0901 also had favorable pharmacokinetic properties in beagle dog (IV=2mg/kg, PO=20mg/kg) with moderate clearance (8.5 mL/min/kg), high apparent absolute oral bioavailability (131%) with good exposure (AUC=36092 h*ng/mL), moderate half-life (4.28 h), and low protein binding (74.3% fraction unbound). The volume of distribution was moderate in both species (Vss = 1.32 L/kg in wistar han rat and 1.87 L/kg in beagle dog). In cell culture, WNC0901 inhibited autophosphorylation of DNA-PKcs in HT29 cells irradiated with 10 Gy with an IC50 of 32.7 nM and robustly inhibited autophosphorylation in both U251 glioma and A549 lung cancer cell lines at 300 nM in combination with 5Gy. In a clonogenic assay, 5Gy irradiation (10% survival) combined with 100nM WNC0901 demonstrated modestly enhanced cell killing (1.5% survival), and maximal effects were seen at 300nM (0.04% survival, p&lt;0.01). Similar radiosensitizing effects with 300 nM WNC0901 were seen in the A549 cell line (0.2% survival with combination compared to 19% with 5Gy alone, p&lt;0.01). In summary, WNC0901 inhibits DNA-PK kinase activity and provides potent radiosensitization in a GBM and lung cancer cell line. Future studies will assess the combination of WNC0901 and RT in GBM patient-derived xenograft models in vivo. Citation Format: Ann C. Mladek, Danielle L. Burgenske, William F. Elmquist, Wei Zhong, Jann N. Sarkaria. Preclinical data of a novel DNA-PK inhibitor in combination with radiation therapy shows promise in the treatment of established GBM and lung carcinoma cell lines [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 701.

Abstract Background: Assessing treatment response in gliomas with high fidelity remains challenging. Cell-free DNA (cfDNA) is increasingly recognized as a liquid biomarker in plasma and cerebrospinal fluid (CSF), showing promise in optimizing therapeutic regimens for various cancers. While CSF has been explored as a source of cfDNA for gliomas, understanding the dynamics of cfDNA abundance and sequencing changes during treatment and recurrence is essential. Leveraging our biobank of longitudinal CSF specimens obtained through CSF access devices, we aimed to determine the potential utility of CSF cfDNA as a monitoring tool for treatment response in glioma patients. Materials and methods: Longitudinal CSF specimens were collected through Ommaya reservoirs (NCT04692337) or ventriculoperitoneal shunts (NCT04692324) from patients with brain tumors, including gliomas. cfDNA was extracted from 1-5 mL of CSF based on available sample volumes and quantified using Qubit. Next-Generation sequencing using PredicineCARE or PredicineSCORE low-pass whole genome sequencing (LPWGS) was performed based on the available cfDNA. Results: CSF collected before versus after resection showed an increase in quantified cfDNA (2.97x, range: 1.58-5.26x), indicating the impact of increased parenchymal disruption and closer contact with CSF. Subsequently, CSF cfDNA decreased during chemoradiation and adjuvant treatment and increased at recurrence, even in patients co-enrolled in immunotherapy trials for IL-7 agonists and pembrolizumab. Notably, copy number burden (CNB) increased at recurrence in three patients with known disease progression and decreased throughout immunotherapy treatment in one patient despite concerns of pseudoprogression. In a patient with a hypermutated glioblastoma, CSF cfDNA revealed over 59 genomic alterations, including MAP2K1, KIT, and PDGFRA. Another patient with a progressing EGFR-amplified GBM showed over 200 new variants in the final sample, with EGFR copy number increasing from 2 to over 30. Conclusion: Analysis of cfDNA throughout a patient’s disease course, encompassing resection and treatment with standard-of-care and experimental therapies, may aid in disease monitoring and treatment response. Further evaluation in a larger patient cohort is needed to determine the sensitivity of changes in mutations, CNB, and cfDNA quantity for glioma disease burden. Citation Format: Riviere-Cazaux Cecile, Xiaoxi Dong, Chao Dai, Wei Mo, Pan Du, Shidong Jia, Terence Burns. Monitoring glioma treatment response through longitudinal analysis of cell-free DNA in cerebrospinal fluid: Insights from a comprehensive study using next-generation sequencing [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 2294.

Clarkson disease, or monoclonal gammopathy–associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N (γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.

Abstract Context Tumor-induced osteomalacia (TIO) is a rare condition with evidence mostly derived from case reports and case series. Objective We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with TIO, with a focus on patients with nonlocalizing and malignant TIO. Methods This is a retrospective cohort of patients with TIO in an academic medical center, diagnosed between January 1998 and May 2023. We describe their demographics, biochemistries, tumor features, localization, treatment, and complications. Results Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. Twenty (40%) had persistent disease due to the wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus, or baseline fibroblast growth factor-23 (FGF23) levels between localizing vs nonlocalizing groups, and malignant vs nonmalignant groups. The lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. Sixty percent of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R = 0.566, P &lt; .001) but was not associated with malignancy risk (P = .479). A cut-off FGF23 of &gt;20 times upper limit of normal in the presence of normal renal function (P = .025) and recurrence after initial cure (P = .013) were factors significantly associated with malignancy. The nonlocalizing group had lower survival than the localizing group (P = .0097). Conclusion TIO is a condition with significant morbidity. Very high FGF23 levels and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in nonlocalizing TIO should be further explored.

AbstractBackgroundDiffusion‐weighted magnetic resonance imaging (dMRI) examines tissue microstructure integrity in vivo. Prior dementia with Lewy bodies (DLB) diffusion tensor imaging studies yielded mixed results.ObjectiveWe employed free‐water (FW) imaging to assess DLB progression and correlate with clinical decline in DLB.MethodsBaseline and follow‐up MRIs were obtained at 12 and/or 24 months for 27 individuals with DLB or mild cognitive impairment with Lewy bodies (MCI‐LB). FW was analyzed using the Mayo Clinic Adult Lifespan Template. Primary outcomes were FW differences between baseline and 12 or 24 months. To compare FW change longitudinally, we included 20 cognitively unimpaired individuals from the Alzheimer's Disease Neuroimaging Initiative.ResultsWe followed 23 participants to 12 months and 16 participants to 24 months. Both groups had worsening in Montreal Cognitive Assessment (MoCA) and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) scores. We found significant FW increases at both time points compared to baseline in the insula, amygdala, posterior cingulum, parahippocampal, entorhinal, supramarginal, fusiform, retrosplenial, and Rolandic operculum regions. At 24 months, we found more widespread microstructural changes in regions implicated in visuospatial processing, motor, and cholinergic functions. Between‐group analyses (DLB vs. controls) confirmed significant FW changes over 24 months in most of these regions. FW changes were associated with longitudinal worsening of MDS‐UPDRS and MoCA scores.ConclusionsFW increased in gray and white matter regions in DLB, likely due to neurodegenerative pathology associated with disease progression. FW change was associated with clinical decline. The findings support dMRI as a promising tool to track disease progression in DLB. © 2024 International Parkinson and Movement Disorder Society.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.