In-beam PET monitoring of proton therapy: a method for filtering prompt radiation events.

Objective. In-beam positron emission tomography (PET) is a promising technology for real-time monitoring of proton therapy. Random coincidences between prompt radiation events and positron annihilation photon pairs can deteriorate imaging quality during beam-on operation. This study aimed to improve the PET image quality by filtering out the prompt radiation events.Approach. We investigated a prompt radiation event filtering method based on the accelerator radio frequency phase and assessed its performance using various prompt gamma energy thresholds. An in-beam PET prototype was used to acquire the data when the 70 MeV proton beam irradiated a water phantom and a mouse. The signal-to-background ratio (SBR) indicator was utilized to evaluate the quality of the PET reconstruction image.Main results. The selection of the prompt gamma energy threshold will affect the quality of the reconstructed image. Using the optimal energy threshold of 580 keV can obtain a SBR of 1.6 times for the water phantom radiation experiment and 2.0 times for the mouse radiation experiment compared to those without background removal, respectively.Significance. Our results show that using this optimal threshold can reduce the prompt radiation events, enhancing the SBR of the reconstructed image. This advancement contributes to more accurate real-time range verification in subsequent steps.

A back propagation neural network based respiratory motion modelling method.

BACKGROUND: This study presents the development of a backpropagation neural network-based respiratory motion modelling method (BP-RMM) for precisely tracking arbitrary points within lung tissue throughout free respiration, encompassing deep inspiration and expiration phases. METHODS: Internal and external respiratory data from four-dimensional computed tomography (4DCT) are processed using various artificial intelligence algorithms. Data augmentation through polynomial interpolation is employed to enhance dataset robustness. A BP neural network is then constructed to comprehensively track lung tissue movement. RESULTS: The BP-RMM demonstrates promising accuracy. In cases from the public 4DCT dataset, the average target registration error (TRE) between authentic deep respiration phases and those forecasted by BP-RMM for 75 marked points is 1.819 mm. Notably, TRE for normal respiration phases is significantly lower, with a minimum error of 0.511 mm. CONCLUSIONS: The proposed method is validated for its high accuracy and robustness, establishing it as a promising tool for surgical navigation within the lung.

Evaluation of an automated clinical decision system with deep learning dose prediction and NTCP model for prostate cancer proton therapy.

Objective.To evaluate the feasibility of using a deep learning dose prediction approach to identify patients who could benefit most from proton therapy based on the normal tissue complication probability (NTCP) model.Approach.Two 3D UNets were established to predict photon and proton doses. A dataset of 95 patients with localized prostate cancer was randomly partitioned into 55, 10, and 30 for training, validation, and testing, respectively. We selected NTCP models for late rectum bleeding and acute urinary urgency of grade 2 or higher to quantify the benefit of proton therapy. Propagated uncertainties of predicted ΔNTCPs resulting from the dose prediction errors were calculated. Patient selection accuracies for a single endpoint and a composite evaluation were assessed under different ΔNTCP thresholds.Main results.Our deep learning-based dose prediction technique can reduce the time spent on plan comparison from approximately 2 days to as little as 5 seconds. The expanded uncertainty of predicted ΔNTCPs for rectum and bladder endpoints propagated from the dose prediction error were 0.0042 and 0.0016, respectively, which is less than one-third of the acceptable tolerance. The averaged selection accuracies for rectum bleeding, urinary urgency, and composite evaluation were 90%, 93.5%, and 93.5%, respectively.Significance.Our study demonstrates that deep learning dose prediction and NTCP evaluation scheme could distinguish the NTCP differences between photon and proton treatment modalities. In addition, the dose prediction uncertainty does not significantly influence the decision accuracy of NTCP-based patient selection for proton therapy. Therefore, automated deep learning dose prediction and NTCP evaluation schemes can potentially be used to screen large patient populations and to avoid unnecessary delays in the start of prostate cancer radiotherapy in the future.

In vivo EPID-based daily treatment error identification for volumetric-modulated arc therapy in head and neck cancers with a hierarchical convolutional neural network: a feasibility study.

We proposed a deep learning approach to classify various error types in daily VMAT treatment of head and neck cancer patients based on EPID dosimetry, which could provide additional information to support clinical decisions for adaptive planning. 146 arcs from 42 head and neck patients were analyzed. Anatomical changes and setup errors were simulated in 17,820 EPID images of 99 arcs obtained from 30 patients using in-house software for model training, validation, and testing. Subsequently, 141 clinical EPID images from 47 arcs belonging to the remaining 12 patients were utilized for clinical testing. The hierarchical convolutional neural network (HCNN) model was trained to classify error types and magnitudes using EPID dose difference maps. Gamma analysis with 3%/2 mm (dose difference/distance to agreement) criteria was also performed. The F1 score, a combination of precision and recall, was utilized to evaluate the performance of the HCNN model and gamma analysis. The adaptive fractioned doses were calculated to verify the HCNN classification results. For error type identification, the overall F1 score of the HCNN model was 0.99 and 0.91 for primary type and subtype identification, respectively. For error magnitude identification, the overall F1 score in the simulation dataset was 0.96 and 0.70 for the HCNN model and gamma analysis, respectively; while the overall F1 score in the clinical dataset was 0.79 and 0.20 for the HCNN model and gamma analysis, respectively. The HCNN model-based EPID dosimetry can identify changes in patient transmission doses and distinguish the treatment error category, which could potentially provide information for head and neck cancer treatment adaption.

Mixed-size spot scanning with a compact large momentum acceptance superconducting (LMA-SC) gantry beamline for proton therapy.

Objective. Lowering treatment costs and improving treatment quality are two primary goals for next-generation proton therapy (PT) facilities. This work will design a compact large momentum acceptance superconducting (LMA-SC) gantry beamline to reduce the footprint and expense of the PT facilities, with a novel mixed-size spot scanning method to improve the sparing of organs at risk (OAR).Approach. For the LMA-SC gantry beamline, the movable energy slit is placed in the middle of the last achromatic bending section, and the beam momentum spread of delivered spots can be easily changed during the treatment. Simultaneously, changing the collimator size can provide spots with various lateral spot sizes. Based on the provided large-size and small-size spot models, the treatment planning with mixed spot scanning is optimized: the interior of the target is irradiated with large-size spots (to cover the uniform-dose interior efficiently), while the peripheral of the target is irradiated with small-size spots (to shape the sharp dose falloff at the peripheral accurately).Main results. The treatment plan with mixed-size spot scanning was evaluated and compared with small and large-size spot scanning for thirteen clinical prostate cases. The mixed-size spot plan had superior target dose homogeneities, better protection of OAR, and better plan robustness than the large-size spot plan. Compared to the small-size spot plan, the mixed-size spot plan had comparable plan quality, better plan robustness, and reduced plan delivery time from 65.9 to 40.0 s.Significance. The compact LMA-SC gantry beamline is proposed with mixed-size spot scanning, with demonstrated footprint reduction and improved plan quality compared to the conventional spot scanning method.

Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT.

The impact of neo/adjuvant treatment choices on prognosis for surgically treated small-cell neuroendocrine carcinoma of the cervix.

Small-cell neuroendocrine carcinoma of the cervix (SCNCC) is a rare and aggressive tumor with a poor prognosis. Surgical resection followed by adjuvant therapy is the standard treatment for early-stage disease but the influence of different neo/adjuvant treatment approaches remains unclear. Retrospectively, we collected patients' characteristics and treatments in two medical centers. Disease status and survival outcomes were renewed through follow-up. Statistics analysis mainly included Kaplan-Meier methods for survival curve estimation, log-rank test for survival curve comparison, and Cox proportional hazards models for independent prognostic factors prediction. Finally, 51 patients treated by radical surgery between January 2010 and April 2020 were enrolled with a median age of 50 years (range: 32-68). 12 (23.5%) patients were at stage IIIC1 according to the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging systems and the rest were at the early stage. The mean tumor size was 3.6±1.3 cm. Pathological examination found 24 cases with pure SCNCC and 27 cases with admixed SCCC. 29 (56.9%) patients had deep stromal infiltration and 19 (37.3%) patients had lymphovascular space invasion. 34 (66.7%) patients received neo/adjuvant chemotherapy and pelvic radiation was conducted in 41 (80.39%) patients with a median dose of 46 Gy (range: 40-50.4 Gy). The median follow-up time was 25.0 months. The median disease-free survival (DFS) time was 23.0 months. 27 (52.9%) patients developed distant metastasis and 14 (27.5%) experienced local failure. The median overall survival (OS) was 32.0 months. Univariate and multivariate analysis showed neoadjuvant chemotherapy as negative (HR=2.081, 95% CI 1.030-4.203, p=0.041) and adjuvant chemotherapy (HR=0.409, 95% CI 0.213-0.784, p=0.020) as positive independent prognostic factor for DFS. For OS, only lymph node metastasis was confirmed as an independent prognostic factor in both univariate analysis (HR=1.528, 95% CI 1.011-2.308, p=0.044) and multivariate analysis (HR=1.697, 95% CI 1.041-2.768, p=0.034). In conclusion, for surgically treated SCNCC, adjuvant chemotherapy showed a positive influence on DFS while neoadjuvant chemotherapy harmed DFS. OS was unaffected by either treatment choice.

Feasibility study of multiple-energy Bragg peak proton FLASH on a superconducting gantry with large momentum acceptance.

BACKGROUND: While the Bragg peak proton beam (BP) is capable of superior target conformity and organs-at-risk sparing than the transmission proton beam (TB), its efficacy in FLASH-RT is hindered by both a slow energy switching process and the beam current. A universal range shifter (URS) can pull back the high-energy proton beam while preserving the beam current. Meanwhile, a superconducting gantry with large momentum acceptance (LMA-SC gantry) enables fast energy switching. PURPOSE: This study explores the feasibility of multiple-energy BP FLASH-RT on the LMA-SC gantry. METHOD AND MATERIALS: A simultaneous dose and spot map optimization algorithm was developed for BP FLASH-RT treatment planning to improve the dose delivery efficiency. The URS was designed to be 0-27 cm thick, with 1 cm per step. BP plans using the URS were optimized using single-field optimization (SFO) and multiple-field optimization (MFO) for ten prostate cancer patients and ten lung cancer patients. The plan delivery parameters, dose, and dose rate metrics of BP plans were compared to those of TB plans using the parameters of the LMA-SC gantry. RESULTS: Compared to TB plans, BP plans significantly reduced MUs by 42.7% (P < 0.001) with SFO and 33.3% (P < 0.001) with MFO for prostate cases. For lung cases, the reduction in MUs was 56.8% (P < 0.001) with SFO and 36.4% (P < 0.001) with MFO. BP plans also outperformed TB plans by reducing mean normal tissue doses. BP-SFO plans achieved a reduction of 56.7% (P < 0.001) for prostate cases and 57.7% (P < 0.001) for lung cases, while BP-MFO plans achieved a reduction of 54.2% (P < 0.001) for the prostate case and 40.0% (P < 0.001) for lung cases. For both TB and BP plans, normal tissues in prostate and lung cases received 100.0% FLASH dose rate coverage (>40 Gy/s). CONCLUSIONS: By utilizing the URS and the LMA-SC gantry, it is possible to perform multiple-energy BP FLASH-RT, resulting in better normal tissue sparing, as compared to TB plans.

Unlocking the potential of N-acetylcysteine: Improving hepatopancreas inflammation, antioxidant capacity and health in common carp (Cyprinus carpio) via the MAPK/NF-κB/Nrf2 signalling pathway.

N-acetylcysteine (NAC) positively contributes to enhancing animal health, regulating inflammation and reducing stress by participating in the synthesis of cysteine, glutathione, and taurine in the body. The present study aims to investigate the effects of dietary different levels of NAC on the morphology, function and physiological state of hepatopancreas in juvenile common carp (Cyprinus carpio). 450 common carps were randomly divided into 5 groups: N1 (basal diet), N2 (1.5 g/kg NAC diet), N3 (3.0 g/kg NAC diet), N4 (4.5 g/kg NAC diet) and N5 (6.0 g/kg NAC diet), and fed for 8 weeks. The results indicated that dietary 3.0-6.0 g/kg NAC reduced hepatopancreas lipid vacuoles and nuclear translocation, and inhibited apoptosis in common carp. Simultaneously, the activities of hepatopancreas alanine aminotransferase and aspartate aminotransferase progressively increased with rising dietary NAC levels. Dietary NAC enhanced the non-specific immune function of common carp, and exerted anti-inflammatory effects by inhibiting the MAPK/NF-κB signaling pathway. Additionally, dietary 3.0-6.0 g/kg NAC significantly improved the antioxidant capacity of common carp, which was associated with enhanced glutathione metabolism, clearance of ROS and the activation of Nrf2 signaling pathway. In summary, NAC has the potential to alleviate inflammation, mitigate oxidative stress and inhibit apoptosis via the MAPK/NF-κB/Nrf2 signaling pathway, thereby improving hepatopancreas function and health of common carp. The current findings provide a theoretical basis for promoting the application of NAC in aquaculture and ecological cultivation of aquatic animals.

A spatial registration method based on 2D-3D registration for an augmented reality spinal surgery navigation system.

BACKGROUND: In order to provide accurate and reliable image guidance for augmented reality (AR) spinal surgery navigation, a spatial registration method has been proposed. METHODS: In the AR spinal surgery navigation system, grayscale-based 2D/3D registration technology has been used to register preoperative computed tomography images with intraoperative X-ray images to complete the spatial registration, and then the fusion of virtual image and real spine has been realised. RESULTS: In the image registration experiment, the success rate of spine model registration was 90%. In the spinal model verification experiment, the surface registration error of the spinal model ranged from 0.361 to 0.612 mm, and the total average surface registration error was 0.501 mm. CONCLUSION: The spatial registration method based on 2D/3D registration technology can be used in AR spinal surgery navigation systems and is highly accurate and minimally invasive.

Extrahepatic Angiogenesis: A Potential Common Pathophysiological Basis of Multiple Organ Dysfunction in Rats with Cholestasis Cirrhosis.

BACKGROUND: In addition to intrahepatic angiogenesis, patients with cholestasis cirrhosis develop extrahepatic vasculature disorders and functional disturbances of multiple organ systems. Without effective intervention, these vascular disorders will eventually turn into multiple organs vascular syndromes, including the brain, lung and other organ systems. However, studies on the pathogenesis of vascular alterations among extrahepatic organ disturbances are still carried out separately, which hampered the successful translation of preclinical studies to the human setting and required further mechanistic insight into these complications. This study aims to investigate the relationship between extrahepatic angiogenesis and multiple organ impairment, and whether the vascular endothelial growth factor (VEGF) family members and their receptors are involved in this process. METHODS: Pathological changes of the multiple organs were determined by histopathological and immunohistochemical staining in the established common bile duct ligation (CBDL) rats, and angiogenesis was estimated by microvessel density (MVD). Levels of the VEGF family members and their receptors in the serum and organ tissues were also measured by using enzyme-linked immunosorbent assays. RESULTS: The MVD and VEGF family members and their receptors were significantly increased in CBDL rats with multiple organ injury, especially in the liver, lung and cerebral cortex. Meanwhile, we noticed moderate elevation of soluble receptor of the vascular endothelial growth factor-1 (sFlt-1) in the liver, lung, and cerebral cortex, whereas the levels of placental growth factor (PLGF) increased significantly. CONCLUSIONS: Extrahepatic angiogenesis may represent a common pathophysiological basis for multiple organ dysfunction and the sFlt-1/PLGF ratio could offer an avenue for further studies to target extrahepatic angiogenesis in cholestatic cirrhosis.

Comparison and evaluation of different deep learning models of synthetic CT generation from CBCT for nasopharynx cancer adaptive proton therapy.

BACKGROUND: Cone-beam computed tomography (CBCT) scanning is used for patient setup in image-guided radiotherapy. However, its inaccurate CT numbers limit its applicability in dose calculation and treatment planning. PURPOSE: This study compares four deep learning methods for generating synthetic CT (sCT) to determine which method is more appropriate and offers potential for further clinical exploration in adaptive proton therapy for nasopharynx cancer. METHODS: CBCTs and deformed planning CT (dCT) from 75 patients (60/5/10 for training, validation and testing) were used to compare cycle-consistent Generative Adversarial Network (cycleGAN), Unet, Unet+cycleGAN and conditionalGenerative Adversarial Network (cGAN) for sCT generation. The sCT images generated by each method were evaluated against dCT images using mean absolute error (MAE), structural similarity (SSIM), peak signal-to-noise ratio (PSNR), spatial non-uniformity (SNU) and radial averaging in the frequency domain. In addition, dosimetric accuracy was assessed through gamma analysis, differences in water equivalent thickness (WET), and dose-volume histogram metrics. RESULTS: The cGAN model has demonstrated optimal performance in the four models across various indicators. In terms of image quality under global condition, the average MAE has been reduced to 16.39HU, SSIM has increased to 95.24%, and PSNR has increased to 28.98. Regarding dosimetric accuracy, the gamma passing rate (2%/2 mm) has reached 99.02%, and the WET difference is only 1.28 mm. The D95 value of CTVs coverage and Dmax value of spinal cord, brainstem show no significant differences between dCT and sCT generated by cGAN model. CONCLUSIONS: The cGAN model has been shown to be a more suitable approach for generating sCT using CBCT, considering its characteristics and concepts. The resulting sCT has the potential for application in adaptive proton therapy.

Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk.

Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05-1.16, P = 4.02 × 10-5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.

Association of nickel exposure with body mass index, waist circumference and incidence of obesity in US adults.

This study aimed to detect the relationship between nickel exposure and body mass index (BMI), waist circumference and incidence of obesity in the general population of the United States. The National Health and Nutrition Examination Survey (NHANES) 2017-2018 database was utilized, and the sample comprised 1702 participants aged 18 years and above with complete urinary nickel, body mass index, and waist circumference data. Obesity was determined using BMI and waist circumference data. The multivariate linear regression and logistic regression models were utilized to detect the association between urinary nickel concentration and BMI, waist circumference, and incidence of obesity. After multivariable adjustment, the log-transformed urinary nickel concentration was inversely associated with BMI [ß = -0.87; 95% confidence interval (CI): (-1.36, -0.38)] and waist circumference [ß = -1.51; 95% CI: (-2.93, -0.08)]. Compared with the lowest tertile of urinary nickel, the ß value and 95% CI of BMI and waist circumference for the highest tertile were ß = -1.65.95% CI: (-2.85, -0.45) and ß = -2.78, 95% CI: (-6.17, 0.62), respectively. The log-transformed urinary nickel concentration was also negatively associated with obesity status [adjusted odds ratio (OR) = 0.81, 95% CI: (0.64, 1.01)]. Compared with the lowest tertile of urinary nickel, the adjusted OR and 95% CI of obesity status for the highest tertile were OR = 0.64 and 95% CI: (0.37, 1.12). Smooth curve fitting and the generalized additive model indicated that elevated urinary nickel concentration was associated with decreased BMI, waist circumference, and incidence of obesity. The negative association was consistent and robust in different subgroups, according to stratified analysis. This study found that nickel exposure may be negatively associated with BMI, waist circumference and incidence of obesity in US Adults.

Cross-organ single-cell transcriptome profiling reveals macrophage and dendritic cell heterogeneity in zebrafish.

Tissue-resident macrophages (TRMs) and dendritic cells (DCs) are highly heterogeneous and essential for immunity, tissue regeneration, and homeostasis maintenance. Here, we comprehensively profile the heterogeneity of TRMs and DCs across adult zebrafish organs via single-cell RNA sequencing. We identify two macrophage subsets: pro-inflammatory macrophages with potent phagocytosis signatures and pro-remodeling macrophages with tissue regeneration signatures in barrier tissues, liver, and heart. In parallel, one conventional dendritic cell (cDC) population with prominent antigen presentation capacity and plasmacytoid dendritic cells (pDCs) featured by anti-virus properties are also observed in these organs. Remarkably, in addition to a single macrophage/microglia population with potent phagocytosis capacity, a pDC population and two distinct cDC populations are identified in the brain. Finally, we generate specific reporter lines for in vivo tracking of macrophage and DC subsets. Our study depicts the landscape of TRMs and DCs and creates valuable tools for in-depth study of these cells in zebrafish.

Selenium-Containing Type-I Organic Photosensitizers with Dual Reactive Oxygen Species of Superoxide and Hydroxyl Radicals as Switch-Hitter for Photodynamic Therapy.

Organic type-I photosensitizers (PSs) which produce aggressive reactive oxygen species (ROS) with less oxygen-dependent exhibit attractive curative effect for photodynamic therapy (PDT), as they adapt better to hypoxia microenvironment in tumors. However, the reported type-I PSs are limited and its exacted mechanism of oxygen dependence is still unclear. Herein, new selenium-containing type-I PSs of Se6 and Se5 with benzoselenadiazole acceptor has been designed and possessed aggregation-induced emission characteristic. Benefited from double heavy-atom-effect of selenium and bromine, Se6 shows a smaller energy gap (ΔEST ) of 0.03 eV and improves ROS efficiency. Interestingly, type-I radicals of both long-lived superoxide anion (O2 •‾ ) and short-lived hydroxyl (• OH) are generated from them upon irradiation. This may provide a switch-hitter of dual-radical with complementary lifetimes for PDT. More importantly, simultaneous processes to produce • OH are revealed, including disproportionation of O2 •‾ and reaction between excited PS and water. Actually, Se6 displays superior in-vitro PDT performance to commercial chlorin e6 (Ce6), under normoxia or hypoxia. After intravenous injection, a significantly in-vivo PDT performance is demonstrated on Se6, where tumor growth inhibition rates of 99% is higher than Ce6. These findings offer new insights about both molecular design and mechanism study of type-I PSs.

Clinical efficacy of PD-1 inhibitor combined with radiotherapy in a multi-drug resistant patient with liver metastasis from gastric cancer.

A 54-year-old male was diagnosed with extensive liver metastasis and small nodule metastasis in the lungs from gastric adenocarcinoma [Her-2 (-)]. The patient achieved significant partial response (PR) after chemotherapy combined with anti-angiogenesis therapy but developed progressive disease (PD) after 5 months. Then, the chemotherapeutic and anti-angiogenic drugs were replaced. Meanwhile, the delivery route of some chemotherapeutic drugs was changed, and some chemotherapeutic drugs were given via transcatheter arterial chemoembolization (TACE) to achieve PR, and PD developed after 3 months of remission maintenance. During chemotherapy combined with anti-angiogenesis, the application of programmed cell death-1 (PD-1) inhibitor achieved PR again and maintained for 5 months before disease progression. The progression of the lesions in the left lobe of the liver and the hepatic hilar lymph nodes was significant. Hence, chemotherapy was terminated and gamma stereotactic body radiation therapy (SBRT) was performed on left lobe lesions and hilar lymph nodes. The lesions both inside and outside the radiation field regressed significantly, reaching PR and abscopal effects. The immune-related adverse events (irAEs) occurred, including erythema and black and luster hair. The abscopal effects of lesion reduction in the radiation field and the enhancement of the immune function stimulated by radiation are a highlight of the combination of radiation and immunotherapy. In the end, the patient died of gastrointestinal failure, with overall survival of 18 months.

m6A methyltransferase METTL3 facilitates multiple myeloma cell growth through the m6A modification of BZW2.

N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) has been confirmed to be involved in multiple myeloma (MM) progression, and basic leucine zipper and W2 domains 2 (BZW2) is considered to be a regulator for MM development. However, whether METTL3 mediates MM progression by regulating BZW2 remains unclear. The messenger RNA (mRNA) and protein levels of METTL3 and BZW2 in MM specimens and cells were determined using quantitative real-time PCR and western blot analysis. Cell proliferation and apoptosis were assessed by cell counting kit 8 assay, 5-ethynyl-2'-deoxyuridine assay, colony formation assay, and flow cytometry. Methylated RNA immunoprecipitation-qPCR was used to detect the m6A modification level of BZW2. Xenograft tumor models were constructed to confirm the effect of METTL3 knockdown on MM tumor growth in vivo. Our results showed that BZW2 was upregulated in MM bone marrow specimens and cells. BZW2 downregulation reduced MM cell proliferation and promoted apoptosis, while its overexpression enhanced MM cell proliferation and inhibited apoptosis. METTL3 was highly expressed in MM bone marrow specimens, and its expression was positively correlated with BZW2 expression. BZW2 expression was positively regulated by METTL3. Mechanistically, METTL3 could upregulate BZW2 expression by modulating its m6A modification. Additionally, METTL3 accelerated MM cell proliferation and restrained apoptosis via increasing BZW2 expression. In vivo experiments showed that METTL3 knockdown reduced MM tumor growth by decreasing BZW2 expression. In conclusion, these data indicated that METTL3-mediated the m6A methylation of BZW2 to promote MM progression, suggesting a novel therapeutic target for MM.