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PURPOSE: To demonstrate the possibility of using a lower imaging rate while maintaining acceptable accuracy by applying motion prediction to minimize the imaging dose in real-time image-guided radiation therapy. METHODS: Time-series of three-dimensional internal marker positions obtained from 98 patients in liver stereotactic body radiation therapy were used to train and test the long-short-term memory (LSTM) network. For real-time imaging, the root mean squared error (RMSE) of the prediction on three-dimensional marker position made by LSTM, the residual motion of the target under respiratory-gated irradiation, and irradiation efficiency were evaluated. In the evaluation of the residual motion, the system-specific latency was assumed to be 100 ms. RESULTS: Except for outliers in the superior-inferior (SI) direction, the median/maximum values of the RMSE for imaging rates of 7.5, 5.0, and 2.5 frames per second (fps) were 0.8/1.3, 0.9/1.6, and 1.2/2.4 mm, respectively. The median/maximum residual motion in the SI direction at an imaging rate of 15.0 fps without prediction of the marker position, which is a typical clinical setting, was 2.3/3.6 mm. For rates of 7.5, 5.0, and 2.5 fps with prediction, the corresponding values were 2.0/2.6, 2.2/3.3, and 2.4/3.9 mm, respectively. There was no significant difference between the irradiation efficiency with and that without prediction of the marker position. The geometrical accuracy at lower frame rates with prediction applied was superior or comparable to that at 15 fps without prediction. In comparison with the current clinical setting for real-time image-guided radiation therapy, which uses an imaging rate of 15.0 fps without prediction, it may be possible to reduce the imaging dose by half or more. CONCLUSIONS: Motion prediction can effectively lower the frame rate and minimize the imaging dose in real-time image-guided radiation therapy.

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RATIONALE: Radiation-induced liver disease (RILD) is an established complication of hepatic irradiation that is typically reported in patients receiving high-dose radiotherapy for hepatocellular carcinoma or liver metastases. However, RILD can also occur after unintentional low-dose liver exposure during radiotherapy for other gastrointestinal malignancies when careful precautions are not taken. PATIENT CONCERNS: We report the case of a 44-year-old woman with gastric mucosa-associated lymphoid tissue lymphoma who underwent salvage radiotherapy administered to the entire stomach. One month after completing this radiotherapy, computed tomography and magnetic resonance imaging of the patient's abdomen revealed a 4 cm lesion in the left lateral liver segment, suggestive of metastasis. DIAGNOSES: An ultrasound-guided biopsy was performed, and the histopathological findings were consistent with those of RILD. INTERVENTIONS: Conservative management was pursued with close monitoring of liver function tests. OUTCOMES: The patient's imaging findings and liver enzyme levels normalized approximately 3 months after the initial diagnosis. LESSONS: This case highlights the importance of considering RILD in the differential diagnosis of new hepatic lesions detected after radiotherapy, even in patients with low-dose liver exposure within generally acceptable limits. Careful correlation with the radiotherapy plan is crucial to avoid misdiagnosing RILD as metastatic disease and to guide appropriate management.

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PURPOSE: Proton therapy is highly effective for liver malignancies, and to increase its accuracy, placement of fiducial markers in the liver is preferred. We retrospectively evaluated the safety and feasibility of CT-guided fiducial marker implantation using ultra-fine 25-gauge needles before proton therapy for liver malignancies. MATERIALS AND METHODS: Between May 2016 and April 2021, 334 cases were investigated. All of procedures were performed without anesthesia. Technical success was defined as the completion of implantation at the intended site. Tumor-marker distance and possibility of synchronization between tumors and markers were evaluated and compared with Mann-Whitney U test. Complications were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Technical success rate was 97.3%. Tumor-marker distance was 19.1 mm (median, range 0-96) in the group in which the implanted marker was synchronized with tumor (n = 315), while it was 34.5 mm (median, range 6-94) in the group in which the implanted marker was not synchronized (n = 13) (p value = 0.011 < 0.05). The complication rate was 2.4%, 2 were classified as grade 4 and 5 as grade 1, and 1 as grade 2. There were no grade 3 or higher complications that seemed to be related to the procedure. CONCLUSION: CT-guided marker implantation using a 25-gauge needle achieved a satisfactory success rate with few complications and was useful for the image-guided and respiratory-synchronized proton therapy. LEVEL OF EVIDENCE 3: Local non-random sample.

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INTRODUCTION: No study has yet investigated the minimum amount of data required for deep learning-based liver contouring. Therefore, this study aimed to investigate the feasibility of automated liver contouring using limited data. METHODS: Radiotherapy planning Computed tomography (CT) images were subjected to various preprocessing methods, such as denoising and windowing. Segmentation was conducted using the modified Attention U-Net and Residual U-Net networks. Two different modified networks were trained separately for different training sizes. For each architecture, the model trained with the training set size that achieved the highest dice similarity coefficient (DSC) score was selected for further evaluation. Two unseen external datasets with different distributions from the training set were also used to examine the generalizability of the proposed method. RESULTS: The modified Residual U-Net and Attention U-Net networks achieved average DSCs of 97.62% and 96.48%, respectively, on the test set, using 62 training cases. The average Hausdorff distances (AHDs) for the modified Residual U-Net and Attention U-Net networks were 0.57 mm and 0.71 mm, respectively. Also, the modified Residual U-Net and Attention U-Net networks were tested on two unseen external datasets, achieving DSCs of 95.35% and 95.82% for data from another center and 95.16% and 94.93% for the AbdomenCT-1K dataset, respectively. CONCLUSION: This study demonstrates that deep learning models can accurately segment livers using a small training set. The method, utilizing simple preprocessing and modified network architectures, shows strong performance on unseen datasets, indicating its generalizability. IMPLICATIONS FOR PRACTICE: This promising result suggests its potential for automated liver contouring in radiotherapy planning.

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BACKGROUND/AIMS:  Hepatocellular carcinoma is a major cause of mortality and morbidity in both cirrhotic and non-cirrhotic patients, and most patients are suitable for locoregional and/or systemic therapy at the time of diagnosis. In this study, we aimed to determine the efficacy and safety of transarterial radioembolization in elderly patients. MATERIALS AND METHODS:  Patients diagnosed with hepatocellular carcinoma between 2013 and 2022 were screened retrospectively. The patients were divided into 2 groups: the elderly (age >70 years) and the young (age <70 years). Transarterial radioembolization response was evaluated according to the Response Evaluation Criteria in Solid Tumors. RESULTS:  Ninety patients were included in the young group, and 56 patients were in the elderly group. It was observed that male dominance was less in the elderly group (P > .05). Hepatitis B was the most common cause in both groups. There were no significant differences between groups with regard to morphological features of tumors [tumor focality (single; 62.2% and 60.7%, respectively) and maximal tumor diameter (6.9 and 6.55 cm, respectively)], transarterial radioembolization responses (51.1% and 39.3%, respectively), survival (9 and 8.5 months), and both early and late side effects (P > .05). Age was not found to be an effective factor in transarterial radioembolization response (P > .05). CONCLUSION:  No differences in the safety and efficacy of transarterial radioembolization were observed between the groups. In addition, it was observed that age was not a predictive factor for adverse events. In elderly patients in the frail group, it should be considered that age alone should not be seen as a limitation in the transarterial radioembolization decision.

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AIMS: This study aimed to retrospectively assess the safety and efficacy of radioactive iodine-125 (I-125) seed implantation for liver malignancies in challenging locations. MATERIALS AND METHODS: Between December 2015 and December 2021, 49 patients with 60 liver malignancies in challenging locations who underwent computed tomography (CT)-guided I-125 seed implantation were retrospectively analyzed. The primary endpoints included technical success rate and overall survival (OS), whereas the secondary endpoints included progression-free survival (PFS), disease control rate (DCR), objective response rate (ORR), and liver recurrence. Potential factors associated with liver recurrence were also evaluated. RESULTS: The technical success rate was 100%. The median follow-up duration was 12 months (range, 2-68 months). The mean OS and PFS were 17.58 months (95% CI: 13.64-21.52 months) and 13.14 months (95% CI: 10.36-15.92 months), respectively. The 2-month, 6-month, and 1-year DCR and ORR were 97.96% and 93.88%, 93.75% and 77.08%, and 93.48% and 60.87%, respectively. The 6- and 12-month tumor recurrence rates were 20.41% and 28.26%, respectively. The Kaplan-Meier method was used to estimate the time of liver recurrence, with our results showing that patients with primary intrahepatic cholangiocarcinoma had an increased likelihood of having earlier liver recurrence. No major complications developed during follow-up. CONCLUSION: CT-guided radioactive I-125 implantation could be a safe and effective alternative with promising survival benefits and high local control rates for liver malignancies in challenging locations.

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ABSTRACT: We report a case of a 48-year-old man with recurrent hepatocellular carcinoma, who underwent FDG PET for restaging and demonstrated mildly tracer-avid arterial enhancing lesion in segment III (SUV max , 5.7). Owing to low FDG uptake, patient was planned for 68 Ga-SA.FAPi PET, which demonstrated higher tracer avidity in the lesion (SUV max , 24.4). Subsequently, patient underwent 177 Lu-microsphere SIRT (2.2 GBq) in segment III. The 3- and 6-month posttherapy SA.FAPi PET demonstrated an interval decrease in tracer uptake and size of treated lesion. This case highlighted the promising role of SA.FAPi PET in patient selection for 177 Lu-SIRT and subsequent response assessment.

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PURPOSE: Transarterial radioembolization (TARE) for hepatocellular carcinoma (HCC) is performed after a mapping angiogram involving infusion of radiolabeled macroaggregated albumin to assess for non-target embolization and pulmonary shunting. The purpose of this case series was to evaluate the safety and feasibility of single-session TARE without the initial procedure. MATERIALS AND METHODS: A single-institution case series of 16 consecutive procedures on 15 patients with 18 tumors who underwent an attempted single-session TARE procedures with glass microspheres are presented. A lung shunt fraction (LSF) of 5% was assumed for planning purposes. RESULTS: Sixty-seven percent (10/15) of patients were male with a median age of 72 years. Median tumor size was 2.5 cm (IQR 2.0-3.2 cm). Sixteen of the 18 targeted tumors were untreated prior to the single-session TARE. Rate of technical success was 88% (14/16). Two patients did not ultimately receive a single-session TARE due to intraprocedural findings. The mean administered activity was 2.0 GBq, and the mean MIRD dose was 464 Gy based on pre-treatment anatomic imaging and 800 Gy based on cone-beam CT. There were no cases of radiation pneumonitis. Mean post-procedural calculated lung dose was 4.9 Gy (range 3.1-9.3) based on SPECT. CONCLUSIONS: An initial experience with single-session TARE using Y-90 glass microspheres without pre-procedural mapping angiography and lung shunt estimation demonstrates that it is a feasible and safe treatment option for select patients with small (< 5 cm) HCC. LEVEL OF EVIDENCE IV: Level 4 case series.

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Yttrium-90 (90Y) transarterial radioembolization can safely and effectively treat hepatocellular carcinoma (HCC). Clinical trials combining 90Y with immunotherapy are aimed at improving treatment response rates. The impact of transient 90Y-induced lymphopenia on T-cell homeostasis and functional dynamics is unknown. Paired blood specimens were collected prior to first-cycle 90Y and at imaging follow-up in patients with HCC Barcelona Clinic Liver Cancer stages A-B. Flow cytometry and T-cell receptor (TCR) sequencing were used to monitor changes in T-cell subsets and TCR repertoire following 90Y. Objective response (OR) rates were determined using modified RECIST and defined as either OR or nonobjective response. Time-to-progression (TTP) was defined as progression to Barcelona Clinic Liver Cancer stage C within 6 months following 90Y. 90Y induced shifts in both CD4+ (P = 0.049) and CD8+ (P < 0.001) toward an effector memory T-cell response independent of treatment response rate. Nonresponders to 90Y were characterized by a sustained elevation in both naïve CD4+ cells (P = 0.019) and programmed cell death protein 1 expression in CD8+ cells (P = 0.003). Paired analysis of the TCR repertoire revealed a variable induction of neoantigen clonotypes and expansion of existing clonotypes independent of 90Y response. In patients with an OR, changes in TCR clonality did not influence TTP. However, polyclonal profiles in patients without an OR were associated with shorter TTP (P = 0.005; HR, 10.8) and 75% disease progression rates 6 months following treatment. 90Y induces a population shift from central to effector memory accompanied by neoantigen T-cell responses independent of treatment response rate. Monoclonal shifts in the post-90Y T-cell repertoire had superior overall TTP and improved TTP in patients with a first-cycle nonobjective response. SIGNIFICANCE: 90Y can safely treat HCC; however, it causes transient lymphopenia. In this article, 90Y stimulates a peripheral effector memory response independent of initial treatment response. TCR sequencing revealed that polyclonal profiles in patients without an OR to treatment were associated with rapid progression rates 6 months after 90Y.

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BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

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ABSTRACT: Metastatic insulinomas can cause recurrent hypoglycemia requiring continuous IV glucose infusion. Various medical and chemotherapeutic treatment options are used to reduce the patient's risk of death due to hypoglycemia. Treatment-resistant hepatic metastatic insulinomas may benefit clinically from 90Y transarterial radioembolization therapy. In this case, we present a case of liver metastatic insulinoma that achieved clinical improvement after 2 cycles of 90Y microspheres transarterial radioembolization, and the presence of active metastases was demonstrated with 68Ga-NODAGA-exendin-4 PET/CT imaging.

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Because of the challenges posed by anatomical uncertainties and the low resolution of plain computed tomography (CT) scans, implementing adaptive radiotherapy (ART) for small hepatocellular carcinoma (sHCC) using artificial intelligence (AI) faces obstacles in tumor identification-alignment and automatic segmentation. The current study aims to improve sHCC imaging for ART using a gold nanoparticle (Au NP)-based CT contrast agent to enhance AI-driven automated image processing. The synthesized charged Au NPs demonstrated notable in vitro aggregation, low cytotoxicity, and minimal organ toxicity. Over time, an in situ sHCC mouse model was established for in vivo CT imaging at multiple time points. The enhanced CT images processed using 3D U-Net and 3D Trans U-Net AI models demonstrated high geometric and dosimetric accuracy. Therefore, charged Au NPs enable accurate and automatic sHCC segmentation in CT images using classical AI models, potentially addressing the technical challenges related to tumor identification, alignment, and automatic segmentation in CT-guided online ART.

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Doxorubicin (DOX) has been an effective antitumor agent for human liver cancer cells; however, an overdose might lead to major side effects appearing in clinical applications. In this work, we present a strategy of combining DOX and blue light (BL) irradiation for the antitumor treatment of HepG2 cells (one typical human liver cancer cell line). It is demonstrated that synergetic DOX and BL can significantly reduce cell proliferation and increase the apoptotic rate of HepG2 cells in comparison to individual DOX treatment. The additional BL irradiation is further helpful for enhancing the inhibition of cell migration and invasion. Analyses of reactive oxygen species (ROS) level and Western blotting reveal that the strategy results in more ROS accumulation, mitochondrial damage, and the upregulation of proapoptotic protein (Bcl-2) and downregulation of antiapoptotic protein (Bax). In addition to the improved therapeutic effect, the non-contact BL irradiation is greatly helpful for reducing the dosage of DOX, and subsequently reduces the side effects caused by the DOX drug. These findings offer a novel perspective for the therapeutic approach toward liver cancer with high efficiency and reduced side effects.

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Objective.Contrast-enhanced computed tomography (CECT) is commonly used in the pre-treatment evaluation of liver Y-90 radioembolization feasibility. CECT provides detailed imaging of the liver and surrounding structures, allowing healthcare providers to assess the size, location, and characteristics of liver tumors prior to the treatment. Here we propose a method for translating CECT images to an expected dose distribution for tumor(s) and normal liver tissue.Approach.A pre-procedure CECT is used to obtain an iodine arterial-phase distribution by subtracting the non-contrast CT from the late arterial phase. The liver segments surrounding the targeted tumor are selected using Couinaud's method. The resolution of the resulting images is then degraded to match the resolution of the positron emission tomography (PET) images, which can image the Y-90 activity distribution post-treatment. The resulting images are then used in the same way as PET images to compute doses using the local deposition method. CECT images from three patients were used to test this method retrospectively and were compared with Y-90 PET-based dose distributions through dose volume histograms.Main results.Results show a concordance between predicted and delivered Y-90 dose distributions with less than 10% difference in terms of mean dose, for doses greater than 10% of the 98th percentile (D2%).Significance.CECT-derived predictions of Y-90 radioembolization dose distributions seem promising as a supplementary tool for physicians when assessing treatment feasibility. This dosimetry prediction method could provide a more comprehensive pre-treatment evaluation-offering greater insights than a basic assessment of tumor opacification on CT images.

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Metal artifacts notoriously pose significant challenge in computed tomography (CT), leading to inaccuracies in image formation and interpretation. Artifact reduction tools have been designed to improve cone beam computed tomography (CBCT) image quality by reducing artifacts caused by certain high-density materials. Metal artifact reduction (MAR) tools are specific algorithms that are applied during image reconstruction to minimize or eliminate artifacts degrading CBCT images. The purpose of the study is to evaluate the effect of a MAR algorithm on image quality in CBCT performed for evaluating patients before transarterial radioembolization (TARE). We retrospectively included 40 consecutive patients (aged 65 ± 13 years; 23 males) who underwent 45 CBCT examinations (Allura FD 20, XperCT Roll protocol, Philips Healthcare, Best, The Netherlands) in the setting of evaluation for TARE between January 2017 and December 2018. Artifacts caused by coils, catheters, and surgical clips were scored subjectively by four readers on a 5-point scale (1 = artifacts affecting diagnostic information to 5 = no artifacts) using a side-by-side display of uncorrected and MAR-corrected images. In addition, readers scored tumor visibility and vessel discrimination. MAR-corrected images were assigned higher scores, indicating better image quality. The differences between the measurements with and without MAR were most impressive for coils with a mean improvement of 1.6 points (95%CI [1.5 1.8]) on the 5-point likert scale, followed by catheters 1.4 points (95%CI [1.3 1.5]) and clips 0.7 points (95%CI [0.3 1.1]). Improvements for other artifact sources were consistent but relatively small (below 0.25 points on average). Interrater agreement was good to perfect (Kendall's W coefficient = 0.68-0.95) and was higher for MAR-corrected images, indicating that MAR improves diagnostic accuracy. A metal artifact reduction algorithm can improve diagnostic and interventional accuracy of cone beam CT in patients undergoing radioembolization by reducing artifacts caused by diagnostic catheters and coils, lowering interference of metal artifacts with adjacent major structures, and improving tumor visibility.

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Objective.To develop and validate a dose-of-the-day (DOTD) treatment plan verification procedure for liver and pancreas cancer patients treated with an magnetic resonance (MR)-Linac system.Approach.DOTD was implemented as an automated process that uses 3D datasets collected during treatment delivery. Particularly, the DOTD pipeline's input included the adapt-to-shape (ATS) plan-i.e. 3D-MR dataset acquired at beginning of online session, anatomical contours, dose distribution-and 3D-MR dataset acquired during beam-on (BON). The DOTD automated analysis included (a) ATS-to-BON image intensity-based deformable image registration (DIR), (b) ATS-to-BON contours mapping via DIR, (c) BON-to-ATS contours copying through rigid registration, (d) determining ATS-to-BON dosimetric differences, and (e) PDF report generation. The DIR process was validated by two expert reviewers. ATS-plans were recomputed on BON datasets to assess dose differences. DOTD analysis was performed retrospectively for 75 treatment fractions (12-liver and 5-pancreas patients).Main results.The accuracy of DOTD process relied on DIR and mapped contours quality. Most DIR-generated contours (99.6%) were clinically acceptable. DICE correlated with depreciation of DIR-based region of interest mapping process. The ATS-BON plan difference was found negligible (<1%). The duodenum and large bowel exhibited highest variations, 24% and 39% from fractional values, for 5-fraction liver and pancreas. For liver 1-fraction, a 62% variation was observed for duodenum.Significance.The DOTD methodology provides an automated approach to quantify 3D dosimetric differences between online plans and their delivery. This analysis offers promise as a valuable tool for plan quality assessment and decision-making in the verification stage of the online workflow.

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