Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA.

BACKGROUND: Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma. METHODS: For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET-CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on ClinicalTrials.gov (NCT03267888); it is completed and closed to accrual. FINDINGS: 32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths. INTERPRETATION: Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed. FUNDING: Merck Sharp & Dohme.

Full-dose whole-body PET synthesis from low-dose PET using high-efficiency denoising diffusion probabilistic model: PET consistency model.

PURPOSE: Positron Emission Tomography (PET) has been a commonly used imaging modality in broad clinical applications. One of the most important tradeoffs in PET imaging is between image quality and radiation dose: high image quality comes with high radiation exposure. Improving image quality is desirable for all clinical applications while minimizing radiation exposure is needed to reduce risk to patients. METHODS: We introduce PET Consistency Model (PET-CM), an efficient diffusion-based method for generating high-quality full-dose PET images from low-dose PET images. It employs a two-step process, adding Gaussian noise to full-dose PET images in the forward diffusion, and then denoising them using a PET Shifted-window Vision Transformer (PET-VIT) network in the reverse diffusion. The PET-VIT network learns a consistency function that enables direct denoising of Gaussian noise into clean full-dose PET images. PET-CM achieves state-of-the-art image quality while requiring significantly less computation time than other methods. Evaluation with normalized mean absolute error (NMAE), peak signal-to-noise ratio (PSNR), multi-scale structure similarity index (SSIM), normalized cross-correlation (NCC), and clinical evaluation including Human Ranking Score (HRS) and Standardized Uptake Value (SUV) Error analysis shows its superiority in synthesizing full-dose PET images from low-dose inputs. RESULTS: In experiments comparing eighth-dose to full-dose images, PET-CM demonstrated impressive performance with NMAE of 1.278 ± 0.122%, PSNR of 33.783 ± 0.824 dB, SSIM of 0.964 ± 0.009, NCC of 0.968 ± 0.011, HRS of 4.543, and SUV Error of 0.255 ± 0.318%, with an average generation time of 62 s per patient. This is a significant improvement compared to the state-of-the-art diffusion-based model with PET-CM reaching this result 12× faster. Similarly, in the quarter-dose to full-dose image experiments, PET-CM delivered competitive outcomes, achieving an NMAE of 0.973 ± 0.066%, PSNR of 36.172 ± 0.801 dB, SSIM of 0.984 ± 0.004, NCC of 0.990 ± 0.005, HRS of 4.428, and SUV Error of 0.151 ± 0.192% using the same generation process, which underlining its high quantitative and clinical precision in both denoising scenario. CONCLUSIONS: We propose PET-CM, the first efficient diffusion-model-based method, for estimating full-dose PET images from low-dose images. PET-CM provides comparable quality to the state-of-the-art diffusion model with higher efficiency. By utilizing this approach, it becomes possible to maintain high-quality PET images suitable for clinical use while mitigating the risks associated with radiation. The code is availble at https://github.com/shaoyanpan/Full-dose-Whole-body-PET-Synthesis-from-Low-dose-PET-Using-Consistency-Model.

Advancing medical imaging with language models: featuring a spotlight on ChatGPT.

This review paper aims to serve as a comprehensive guide and instructional resource for researchers seeking to effectively implement language models in medical imaging research. First, we presented the fundamental principles and evolution of language models, dedicating particular attention to large language models. We then reviewed the current literature on how language models are being used to improve medical imaging, emphasizing a range of applications such as image captioning, report generation, report classification, findings extraction, visual question response systems, interpretable diagnosis and so on. Notably, the capabilities of ChatGPT were spotlighted for researchers to explore its further applications. Furthermore, we covered the advantageous impacts of accurate and efficient language models in medical imaging analysis, such as the enhancement of clinical workflow efficiency, reduction of diagnostic errors, and assistance of clinicians in providing timely and accurate diagnoses. Overall, our goal is to have better integration of language models with medical imaging, thereby inspiring new ideas and innovations. It is our aspiration that this review can serve as a useful resource for researchers in this field, stimulating continued investigative and innovative pursuits of the application of language models in medical imaging.

Impact of Antegrade Pulmonary Blood Flow as Patients Progress Through Single-Ventricle Palliations.

BACKGROUND: The impact of antegrade pulmonary blood flow (APBF) during single-ventricle (SV) palliation continues to be debated. We sought to assess its impact on the hemodynamic profile and the short- and long-term outcomes of patients progressing through stages of SV palliation. METHODS: A retrospective single-center study was conducted of SV patients who underwent surgery between January 2010 and December 2020. Patients with APBF were matched to those with no APBF by a propensity score based on body surface area, sex, and type of systemic ventricle. Analysis was performed using appropriate statistics with a significance level of P = .05. RESULTS: Sixty-three patients with APBF were matched with 95 patients with no APBF. At the pre-stage 2 catheterization, APBF patients had a larger left pulmonary artery diameter (z score, 0.1 vs -0.8; P < .042). Patients with APBF had shorter cardiopulmonary bypass time (57.0 vs 79.0 minutes), shorter duration of mechanical ventilation (14.1 vs 17.4 hours), and shorter hospital length of stay (5.0 vs 7.0 days) at stage 2 palliation (P < .05). In the multivariable Cox regression analysis, patients with hypoplastic pulmonary arteries (z scores < -2; adjusted hazard ratio, 9.17) and patients with chromosomal abnormalities/genetic syndrome (adjusted hazard ratio, 4.03) were at increased risk for poor outcomes (P < .05). During the follow-up period, there was no significant difference in risk of the composite poor outcome and long-term survival between groups. CONCLUSIONS: SV patients with APBF had shorter cardiopulmonary bypass time, duration of mechanical ventilation, and hospital length of stay after stage 2 palliation. Patients with hypoplastic pulmonary arteries or chromosomal abnormalities/genetic syndromes had increased risk for poor outcomes. Maintaining APBF has better short-term outcomes, but there are no long-term hemodynamic or survival benefits.

Thrombogenicity of biomaterials depends on hemodynamic shear rate.

BACKGROUND: While it is well recognized that different biomaterials induce thrombosis at low shear rates, the effect of high shear rates may be quite different. We hypothesize that the amount of thrombus formation on a given material can be greatly influenced by the local shear rate. METHODS: We tested this hypothesis with two different whole blood perfusion loop assays to quantify biomaterial thrombogenicity as a function of shear stress. One assay uses obstructive posts (pins) of material positioned centrally in a tube perfused at high shear rate of >5000/s for 24 h. A second assay uses a parallel plate chamber to perfuse low (<150/s), medium (~500/s), and high shear rates over 96 h. We evaluated the thrombogenicity of seven different biomaterials including stainless steel, acrylic, ceramic, Dacron, polytetrafluoroethylene (PTFE), silicone, and polyvinyl chloride (PVC). RESULTS: For the pin assay, thrombus mass was significantly greater for stainless steel than either zirconia ceramic or acrylic (p < 0.001). Similarly, the parallel plate chamber at high shear showed that steel and PTFE (p < 0.02) occluded the chamber faster than acrylic. In contrast, a low shear parallel plate chamber revealed that stainless steel and PTFE were least thrombogenic, while silicone, Dacron, and other plastics such as acrylic were most thrombogenic. Histology revealed that high shear thrombi had a large proportion of platelets not seen in the low shear fibrin-rich thrombi. CONCLUSION: This differential thrombogenicity based on shear rate conditions may be important in the selection of biomaterials for blood-contacting devices.