Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A novel evaluation model of image registration for cone-beam computed tomography guided lung cancer radiotherapy.

BACKGROUND: The aim of the study was to establish a weighted comprehensive evaluation model (WCEM) of image registration for cone-beam computed tomography (CBCT) guided lung cancer radiotherapy that considers the geometric accuracy of gross target volume (GTV) and organs at risk (OARs), and assess the registration accuracy of different image registration methods to provide clinical references. METHODS: The planning CT and CBCT images of 20 lung cancer patients were registered using diverse algorithms (bony and grayscale) and regions of interest (target, ipsilateral, and body). We compared the coverage ratio (CR) of the planning target volume (PTVCT) to GTVCBCT, as well as the dice similarity coefficient (DSC) of the GTV and OARs, considering the treatment position across various registration methods. Furthermore, we developed a mathematical model to assess registration results comprehensively. This model was evaluated and validated using CRFs across four automatic registration methods. RESULTS: The grayscale registration method, coupled with the registration of the ipsilateral structure, exhibited the highest level of automatic registration accuracy, the DSC were 0.87 ± 0.09 (GTV), 0.71 ± 0.09 (esophagus), 0.74 ± 0.09 (spinal cord), and 0.91 ± 0.05 (heart), respectively. Our proposed WCEM proved to be both practical and effective. The results clearly indicated that the grayscale registration method, when applied to the ipsilateral structure, achieved the highest CRF score. The average CRF scores, excellent rates, good rate and qualification rates were 58 ± 26, 40%, 75%, and 85%, respectively. CONCLUSIONS: This study successfully developed a clinically relevant weighted evaluation model for CBCT-guided lung cancer radiotherapy. Validation confirmed the grayscale method's optimal performance in ipsilateral structure registration.

Flavonoids from mulberry leaves inhibit fat production and improve fatty acid distribution in adipose tissue in finishing pigs.

This study evaluated the effects of flavonoids from mulberry leaves (FML) on plasma biochemical indices, serum activities of lipid metabolism-related enzymes, fat morphology, fatty acid composition, and lipid metabolism in different adipose tissues of finishing pigs. We used 120 Chinese hybrid barrows of Berkshire and Bama mini-pigs with an average initial body weight of 45.11 ± 4.23 kg. The pigs were randomly assigned to five treatment groups and fed a control diet based on corn, soybean meal, and wheat bran or a control diet supplemented with 0.02%, 0.04%, 0.08%, or 0.16% FML. Each experimental group had six replicates (pens), with four pigs per pen. After a 7-d adaptation period, the feeding trial was conducted for 58 d. Blood and adipose tissue samples were collected from 30 pigs (one pig per pen) at the end of the test. The results showed that FML supplementation significantly decreased the feed intake to body gain ratio, the plasma concentrations of total cholesterol and free fatty acids, and the serum activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (linear or quadratic effects, P < 0.05), and decreased the plasma triglyceride concentration (quadratic, P = 0.07). Increasing FML supplementation increased the average daily gain and serum activities of lipoprotein lipase (linear and quadratic effects, P < 0.05) and adipose triglyceride lipase (linear, P < 0.05). Dietary FML supplementation decreased the adipocyte area in the dorsal subcutaneous adipose (DSA) tissue of finishing pigs (linear, P = 0.05) and increased the adipocyte area in the visceral adipose tissue (quadratic, P < 0.01). Increasing FML supplementation decreased the C20:1 content in DSA, abdominal subcutaneous adipose, and visceral adipose tissues of finishing pigs (P < 0.05) and increased the C18:3n3 and n-3 PUFA contents (P < 0.05). The lipid metabolism genes were regulated by the PPARγ-LXRα-ABCA1 signaling pathway, and their expressions differed in different adipose tissues. These findings suggest that FML improved growth performance, regulated lipid metabolism, inhibited fat production, and improved fatty acid distribution in the adipose tissue of finishing pigs, thereby improving pig fat's nutritional quality and health value.

Integrated analysis strategy of genome-wide functional gene mining reveals DKK2 gene underlying meat quality in Shaziling synthesized pigs.

BACKGROUND: Shaziling pig is a well-known indigenous breed in China who has superior meat quality traits. However, the genetic mechanism and genomic evidence underlying meat quality characteristics of Shaziling pigs are still unclear. To explore and investigate the germplasm characteristics of Shaziling pigs, we totally analyzed 67 individual's whole genome sequencing data for the first time (20 Shaziling pigs [S], 20 Dabasha pigs [DBS], 11 Yorkshire pigs [Y], 10 Berkshire pigs [BKX], 5 Basha pigs [BS] and 1 Warthog). RESULTS: A total of 2,538,577 SNPs with high quality were detected and 9 candidate genes which was specifically selected in S and shared in S to DBS were precisely mined and screened using an integrated analysis strategy of identity-by-descent (IBD) and selective sweep. Of them, dickkopf WNT signaling pathway inhibitor 2 (DKK2), the antagonist of Wnt signaling pathway, was the most promising candidate gene which was not only identified an association of palmitic acid and palmitoleic acid quantitative trait locus in PigQTLdb, but also specifically selected in S compared to other 48 Chinese local pigs of 12 populations and 39 foreign pigs of 4 populations. Subsequently, a mutation at 12,726-bp of DKK2 intron 1 (g.114874954 A > C) was identified associated with intramuscular fat content using method of PCR-RFLP in 21 different pig populations. We observed DKK2 specifically expressed in adipose tissues. Overexpression of DKK2 decreased the content of triglyceride, fatty acid synthase and expression of relevant genes of adipogenic and Wnt signaling pathway, while interference of DKK2 got contrary effect during adipogenesis differentiation of porcine preadipocytes and 3T3-L1 cells. CONCLUSIONS: Our findings provide an analysis strategy for mining functional genes of important economic traits and provide fundamental data and molecular evidence for improving pig meat quality traits and molecular breeding.

Commissioning and clinical evaluation of a novel high-resolution quality assurance digital detector array for SRS and SBRT.

PURPOSE: We aimed to perform the commissioning and clinical evaluation of myQA SRS detector array for patient-specific quality assurance (PSQA) of stereotactic radiosurgery (SRS)/ stereotactic body radiotherapy (SBRT) plans. METHODS: To perform the commissioning of myQA SRS, its dose linearity, dose-rate dependence, angular dependence, and field-size dependence were investigated. Ten SBRT plans were selected for clinical evaluation: 1) Common clinical deviations based on the original SBRT plan (Plan0), including multileaf collimator (MLC) positioning deviation and treatment positioning deviation were introduced. 2) Compared the performance of the myQA SRS and a high-resolution EPID dosimetry system in PSQA measurement for the SBRT plans. Evaluation parameters include gamma passing rate (GPR) and distance-to-agreement (DTA) pass rate (DPR). RESULTS: The dose linearity, angle dependence, and field-size dependence of myQA SRS system exhibit excellent performance. The myQA SRS is highly sensitive in the detection of MLC deviations. The GPR of (3%/1 mm) decreases from 90.4% of the original plan to 72.7%/62.9% with an MLC outward/inward deviation of 3 mm. Additionally, when the setup error deviates by 1 mm in the X, Y, and Z directions with the GPR of (3%/1 mm) decreasing by an average of -20.9%, -25.7%, and -24.7%, respectively, and DPR (1 mm) decreasing by an average of -33.7%, -32.9%, and -29.8%. Additionally, the myQA SRS has a slightly higher GPR than EPID for PSQA, However, the difference is not statistically significant with the GPR of (3%/1 mm) of (average 90.4%% vs. 90.1%, p = 0.414). CONCLUSION: Dosimetry characteristics of the myQA SRS device meets the accuracy and sensitivity requirement of PSQA for SRS/SBRT treatment. The dose rate dependence should be adequately calibrated before its application and a more stringent GPR (3%/1 mm) evaluation criterion is suggested when it is used for SRS/SBRT QA.

Genome-Wide Association Study and Identification of Candidate Genes for Intramuscular Fat Fatty Acid Composition in Ningxiang Pigs.

Ningxiang pigs exhibit a diverse array of fatty acids, making them an intriguing model for exploring the genetic underpinnings of fatty acid metabolism. We conducted a genome-wide association study using a dataset comprising 50,697 single-nucleotide polymorphisms (SNPs) and samples from over 600 Ningxiang pigs. Our investigation yielded novel candidate genes linked to five saturated fatty acids (SFAs), four monounsaturated fatty acids (MUFAs), and five polyunsaturated fatty acids (PUFAs). Significant associations with SFAs, MUFAs, and PUFAs were found for 37, 21, and 16 SNPs, respectively. Notably, some SNPs have significant PVE, such as ALGA0047587, which can explain 89.85% variation in Arachidic acid (C20:0); H3GA0046208 and DRGA0016063 can explain a total of 76.76% variation in Elaidic Acid (C18:1n-9(t)), and the significant SNP ALGA0031262 of Arachidonic acid (C20:4n-6) can explain 31.76% of the variation. Several significant SNPs were positioned proximally to previously reported genes. In total, we identified 11 candidate genes (hnRNPU, CEPT1, ATP1B1, DPT, DKK1, PRKG1, EXT2, MEF2C, IL17RA, ITGA1 and ALOX5), six candidate genes (ALOX5AP, MEDAG, ISL1, RXRB, CRY1, and CDKAL1), and five candidate genes (NDUFA4L2, SLC16A7, OTUB1, EIF4E and ROBO2) associated with SFAs, MUFAs, and PUFAs, respectively. These findings hold great promise for advancing breeding strategies aimed at optimizing meat quality and enhancing lipid metabolism within the intramuscular fat (IMF) of Ningxiang pigs.

Identification of crucial modules and genes associated with backfat tissue development by WGCNA in Ningxiang pigs.

Fat deposition is an economically important trait in pigs. Ningxiang pig, one of the four famous indigenous breeds in China, is characterized by high fat content. The underlying gene expression pattern in different developmental periods of backfat tissue remains unclear, and the purpose of this investigation is to explore the potential molecular regulators of backfat tissue development in Ningxiang pigs. Backfat tissue (three samples for each stage) was initially collected from different developmental stages (60, 120, 180, 240, 300, and 360 days after birth), and histological analysis and RNA sequencing (RNA-seq) were then conducted. Fragments per kilobase of transcript per million (FPKM) method was used to qualify gene expressions, and differentially expressed genes (DEGs) were identified. Furthermore, strongly co-expressed genes in modules, which were named by color, were clustered by Weighted gene co-expression network analysis (WGCNA) based on dynamic tree cutting algorithm. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment were subsequently implemented, and hub genes were described in each module. Finally, QPCR analysis was employed to validate RNA-seq data. The results showed that adipocyte area increased and adipocyte number decreased with development of backfat tissue. A total of 1,024 DEGs were identified in five comparison groups (120 days vs. 60 days, 180 days vs. 120 days, 240 days vs. 180 days, 300 days vs. 240 days, and 360 days vs. 300 days). The turquoise, red, pink, paleturquoise, darkorange, and darkgreen module had the highest correlation coefficient with 60, 120, 180, 240, 300, and 360 days developmental stage, while the tan, black and turquoise module had strong relationship with backfat thickness, adipocyte area, and adipocyte number, respectively. Thirteen hub genes (ACSL1, ACOX1, FN1, DCN, CHST13, COL1A1, COL1A2, COL6A3, COL5A1, COL14A1, OAZ3, DNM1, and SELP) were recognized. ACSL1 and ACOX1 might perform function in the early developmental stage of backfat tissue (60 days), and FN1, DCN, COL1A1, COL1A2, COL5A1, COL6A3, and COL14A1 have unignorable position in backfat tissue around 120 days developmental stage. Besides, hub genes SELP and DNM1 in modules significantly associated with backfat thickness and adipocyte area might be involved in the process of backfat tissue development. These findings contribute to understand the integrated mechanism underlying backfat tissue development and promote the progress of genetic improvement in Ningxiang pigs.

Evaluation of bladder filling effects on the dose distribution during radiotherapy for cervical cancer based on daily CT images.

PURPOSE: This study aimed to assess the effects of bladder filling during cervical cancer radiotherapy on target volume and organs at risk (OARs) dose based on daily computed tomography (daily-CT) images and provide bladder-volume-based dose prediction models. METHODS: Nineteen patients (475 daily-CTs) comprised the study group, and five patients comprised the validation set (25 daily-CTs). Target volumes and OARs were delineated on daily-CT images and the treatment plan was recalculated accordingly. The deviation from the planning bladder volume (DVB), the correlation between DVB and clinical (CTV)/planning (PTV) target volume in terms of prescribed dose coverage, and the relationship of small bowel volume and bladder dose with the ratio of bladder volume (RVB) were analyzed. RESULTS: In all cases, the prescribed dose coverage in the CTV was >95% when DVB was <200 cm3 , whereas that in the PTV was >95% when RVB was <160%. The ratio of bladder V45 Gy to the planning bladder V45 Gy (RBV45 ) exhibited a negative linear relationship with RVB (RBV45  = -0.18*RVB + 120.8; R2  = 0.80). Moreover, the ratio of small bowel volume to planning small bowel volume (RVS) exhibited a negative linear relationship with RVB (RVS = -1.06*RVB +217.59; R2  = 0.41). The validation set results showed that the linear model predicted well the effects of bladder volume changes on target volume coverage and bladder dose. CONCLUSIONS: This study assessed dosimetry and volume effects of bladder filling on target and OARs based on daily-CT images. We established a quantitative relationship between these parameters, providing dose prediction models for cervical cancer radiotherapy.

Improved accuracy of auto-segmentation of organs at risk in radiotherapy planning for nasopharyngeal carcinoma based on fully convolutional neural network deep learning.

OBJECTIVE: We examined a modified encoder-decoder architecture-based fully convolutional neural network, OrganNet, for simultaneous auto-segmentation of 24 organs at risk (OARs) in the head and neck, followed by validation tests and evaluation of clinical application. MATERIALS AND METHODS: Computed tomography (CT) images from 310 radiotherapy plans were used as the experimental data set, of which 260 and 50 were used as the training and test sets, respectively. An improved U-Net architecture was established by introducing a batch normalization layer, residual squeeze-and-excitation layer, and unique organ-specific loss function for deep learning training. The performance of the trained network model was evaluated by comparing the manual-delineation and the STAPLE contour of 10 physicians from different centers. RESULTS: Our model achieved good segmentation in all 24 OARs in nasopharyngeal cancer radiotherapy plan CT images, with an average Dice similarity coefficient of 83.75%. Specifically, the mean Dice coefficients in large-volume organs (brainstem, spinal cord, left/right parotid glands, left/right temporal lobes, and left/right mandibles) were 84.97% - 95.00%, and in small-volume organs (pituitary, lens, optic nerve, and optic chiasma) were 55.46% - 91.56%. respectively. Using the STAPLE contours as standard contour, the OrganNet achieved comparable or better DICE in organ segmentation then that of the manual-delineation as well. CONCLUSION: The established OrganNet enables simultaneous automatic segmentation of multiple targets on CT images of the head and neck radiotherapy plans, effectively improves the accuracy of U-Net based segmentation for OARs, especially for small-volume organs.

Comparison of intratumor and local immune response between MV X-ray FLASH and conventional radiotherapies.

Background/Purpose: Investigating the antitumor effect and intratumor as well as local immune response in breast cancer-bearing mice after MV X-ray ultra-high dose rate radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT). Materials/Methods: Six-week-old female C57BL/6 mice were inoculated subcutaneously with Py8119 and Py230 breast tumor cells in the inguinal mammary gland and administered 10 Gy abdominal 6 MV X-ray FLASH-RT (125 Gy/s) or CONV-RT (0.2 Gy/s) 15 days after tumor inoculation. Tumor and spleen tissues were obtained at different time points post-irradiation (PI) for analysis of immune cell infiltration using flow cytometry and immunohistochemical (IHC) staining. Intestine tissues were collected 3 days PI to evaluate normal tissue damage and immune cell infiltration. Results: Both FLASH-RT and CONV-RT significantly delayed tumor growth. Flow cytometry showed increased CD8+/CD3 + and CD8+/CD4 + ratios, and IHC confirmed a similar increased CD8 + T cell infiltration at 2 weeks PI in Py8119 tumor tissues in both irradiation groups. No statistical difference was observed between the irradiation groups in terms of tumor growth and increased T cell infiltration in the tumor. Unexpectedly, significantly smaller spleen weight and substantially higher CD8+/CD3 + and lower CD4+/CD3 + ratios were observed in the spleens of the FLASH-RT group than in the spleens of the non-irradiated control and CONV-RT groups 4 weeks PI. Pathological analysis revealed severe red pulp expansion in several spleens from the CONV-RT group, but not in the spleens of the FLASH-RT group. Reduced intestinal damage, macrophage and neutrophil infiltration were observed in the FLASH-RT group compared with CONV-RT group. Conclusions: FLASH-RT and CONV-RT effectively suppressed tumor growth and promoted CD8 + T cell influx into tumors. FLASH-RT can induce different splenic immune responses and reduce radiation-induced damage in the spleen and intestine, which may potentially enhance the therapeutic ratio of FLASH-RT.

Comprehensive analysis of miRNAs, lncRNAs and mRNAs profiles in backfat tissue between Daweizi and Yorkshire pigs.

OBJECTIVE: Daweizi (DWZ) is a famous indigenous pig breed in China and characterized by tender meat and high fat percentage. However, the expression profiles and functions of transcripts in DWZ pigs is still in infancy. The object of this study was to depict the transcript profiles in DWZ pigs and screen the potential pathway influence adipogenesis and fat deposition. METHODS: Histological analysis of backfat tissue was firstly performed between DWZ and lean-type Yorkshire pigs, and then RNA sequencing technology was utilized to explore miRNAs, lncRNAs and mRNAs profiles in backfat tissue. 18 differentially expressed (DE) transcripts were randomly selected for quantitative real-time polymerase chain reaction (QPCR) to validate the reliability of the sequencing results. Finally, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were conducted to investigate the potential pathways influence adipocyte differentiation, adipogenesis and lipid metabolism, and a schematic model was further proposed. RESULTS: A total of 1,625 differentially expressed transcripts were identified in DWZ pigs, including 27 upregulated and 45 downregulated miRNAs, 64 upregulated and 119 downregulated lncRNA, 814 upregulated and 556 downregulated mRNAs. QPCR analysis exhibited strong consistency with the sequencing data. GO and KEGG analysis elucidated that the differentially expressed transcripts were mainly associated with cell growth and death, signal transduction, peroxisome proliferator-activated receptors (PPAR), AMP-activated protein kinase (AMPK), PI3K-Akt, adipocytokine and foxo signaling pathways, all of which are strongly involved in cell development, lipid metabolism and adipogenesis. Further analysis indicated that the BGIR9823_87926/miR-194a-5p/AQP7 network may be effective in the process of adipocyte differentiation or adipogenesis. CONCLUSION: Our study provides comprehensive insights into the regulatory network of backfat deposition and lipid metabolism in pigs from the point of view of miRNAs, lncRNAs and mRNAs.

Patient-specific daily updated deep learning auto-segmentation for MRI-guided adaptive radiotherapy.

BACKGROUND AND PURPOSE: Deep Learning (DL) technique has shown great potential but still has limited success in online contouring for MR-guided adaptive radiotherapy (MRgART). This study proposed a patient-specific DL auto-segmentation (DLAS) strategy using the patient's previous images and contours to update the model and improve segmentation accuracy and efficiency for MRgART. METHODS AND MATERIALS: A prototype model was trained for each patient using the first set of MRI and corresponding contours as inputs. The patient-specific model was updated after each fraction with all the available fractional MRIs/contours, and then used to predict the segmentation for the next fraction. During model training, a variant was fitted under consistency constraints, limiting the differences in the volume, length and centroid between the predictions for the latest MRI within a reasonable range. The model performance was evaluated for both organ-at-risks and tumors auto-segmentation for a total of 6 abdominal/pelvic cases (each with at least 8 sets of MRIs/contours) underwent MRgART through Dice Similarity Coefficient (DSC) and 95% Hausdorff Distance (HD95), and was compared with deformable image registration (DIR) and frozen DL model (no updating after pre-training). The contouring time was also recorded and analyzed. RESULTS: The proposed model achieved superior performance with higher mean DSC (0.90, 95 % CI: 0.88-0.95), as compared to DIR (0.63, 95 %CI: 0.59-0.68) and frozen DL models (0.74, 95 % CI: 0.71-0.79). As for tumors, the proposed method yielded a median DSC of 0.95, 95 % CI: 0.94-0.97, and a median HD95 of 1.63 mm, 95 % CI: 1.22 mm-2.06 mm. The contouring time was reduced significantly (p < 0.05) using the proposed method (73.4 ± 6.5 secs) compared to the manual process (12 âˆ¼ 22 mins). The online ART time was reduced to 1650 ± 274 seconds with the proposed method, as compared to 3251.8 ± 447 seconds using the original workflow. CONCLUSION: The proposed patient-specific DLAS method can significantly improve the segmentation accuracy and efficiency for longitudinal MRIs, thereby facilitating the routine practice of MRgART.

MR-based synthetic CT image for intensity-modulated proton treatment planning of nasopharyngeal carcinoma patients.

PURPOSE: To develop an advanced deep convolutional neural network (DCNN) architecture to generate synthetic CT (SCT) images from MR images for intensity-modulated proton therapy (IMPT) treatment planning of nasopharyngeal cancer (NPC) patients. METHODS: T1-weighted MR images and paired CT (PCT) images were obtained from 206 NPC patients. For each patient, deformable image registration was performed between MR and PCT images to create an MR-CT image pair. Thirty pairs were randomly chosen as the independent test set and the remaining 176 pairs (14 for validation and 162 for training) were used to build two conditional generative adversarial networks (GANs): 1) GAN3D: using a 3D U-net enhanced with residual connections and attentional mechanism as the generator and 2) GAN2D: using a 2D U-net as the generator. For each test patient, SCT images were generated using the generators with the MR images as input and were compared with respect to the corresponding PCT image. A clinical IMPT plan was created and optimized on the PCT image. The dose was recalculated on the SCT images and compared with the one calculated on the PCT image. RESULTS: The mean absolute errors (MAEs) between the PCT and SCT, within the body, were (64.89 ± 5.31) HU and (64.31 ± 4.61) HU for the GAN2D and GAN3D. Within the high-density bone (HU > 600), the GAN3D achieved a smaller MAE compared with the GAN2D (p < 0.001). Within the body, the absolute point dose deviation was reduced from (0.58 ± 1.61) Gy for the GAN2D to (0.47 ± 0.94) Gy for the GAN3D. The (3 mm/3%) gamma passing rates were above 97.32% for all SCT images. CONCLUSIONS: The SCT images generated using GANs achieved clinical acceptable dosimetric accuracy for IMPT of NPC patients. Using advanced DCNN architecture design, such as residual connections and attention mechanism, SCT image quality was further improved and resulted in a small dosimetric improvement.

Impact on xerostomia for nasopharyngeal carcinoma patients treated with superficial parotid lobe-sparing intensity-modulated radiation therapy (SPLS-IMRT): A prospective phase II randomized controlled study.

PURPOSE: To compare the incidence of xerostomia in nasopharyngeal carcinoma (NPC) patients treated with superficial parotid lobe-sparing intensity-modulated radiation therapy (SPLS-IMRT) and conventional IMRT (C-IMRT). METHODS: Patients with histologically confirmed NPC who met the eligibility criteria were randomly assigned to receive either SPLS-IMRT or C-IMRT. The primary endpoint was the incidence of xerostomia at 12 months post-IMRT. The secondary endpoints included the xerostomia questionnaire (XQ) score, unstimulated salivary flow rate (USFR), stimulated salivary flow rate (SSFR), and survival outcomes. RESULTS: Ninety patients were enrolled. Eighty-two patients were included for xerostomia analysis (42 in the SPLS-IMRT group and 40 in the C-IMRT group). At 12 months post-IMRT, the incidence of xerostomia in the SPLS-IMRT group was significantly lower than that in the C-IMRT group (83.4% vs 95.0%; P = 0.007), especially the grade 3 xerostomia (0% vs 12.5%; P < 0.001). The median change in XQ score was similar between the two groups (11.9 points vs 14.1 points; P = 0.194). There was a significantly higher median fractional USFR (0.67 vs 0.35; P = 0.024) and SSFR (0.66 vs 0.32; P = 0.021) in the SPLS-IMRT group than the C-IMRT group. The 3-year LRRFS, DMFS, and OS in the SPLS-IMRT and C-IMRT groups were 92.5% vs 90.9%, 83.8% vs 81.7%, and 88.9% vs 88.2% (all P > 0.05). CONCLUSION: SPLS-IMRT significantly reduced the incidence of xerostomia at 12 months post-IMRT in NPC by recovering parotid gland function earlier than C-IMRT, without compromising survivals. Phase III clinical trials are warranted. (ClinicalTrials.gov, number NCT05020067).

Adjuvant Apatinib in Nasopharyngeal Carcinoma With Residual Epstein-Barr Virus DNA After Radiation Therapy: A Biomarker-Driven, Phase 2 Trial.

PURPOSE: We previously demonstrated that real-time monitoring of plasma Epstein-Barr virus DNA (EBV DNA) during chemoradiation therapy defined 4 distinct phenotypic clusters of nasopharyngeal carcinoma. In particular, the treatment-resistant group, defined as detectable EBV DNA at the end of radiation therapy, had the worst prognosis and is thought to have minimal residual disease. METHODS AND MATERIALS: This is the first phase 2 trial to use a targeted agent, apatinib (an inhibitor of vascular endothelial growth factor receptor 2 tyrosine kinase), in the treatment-resistant group. Eligible patients had plasma EBV DNA > 0 copies/mL at the end of radiation therapy (±1 week). Patients received apatinib (500 mg, once daily) until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was disease-free survival (DFS). RESULTS: Twenty-five patients were enrolled and 23 patients who received apatinib were included in the analyses. Three-year DFS was 47.8% and overall survival was 73.9%. Patients with plasma vascular endothelial growth factor-A ≤150 pg/mL at 28 days after the initiation of treatment had significantly better 3-year DFS (66.7% vs 14.3%; P = .041) and overall survival (88.9% vs 42.9%; P = .033). The most common adverse event of grade ≥3 was nasopharyngeal necrosis (26%), oral/pharyngeal pain (22%), and hand-foot syndrome (22%). Nineteen patients had serial EBV DNA data. Fourteen patients had plasma EBV DNA clearance (turn to 0), and 5 (36%) of these 14 patients had disease recurrence or death, whereas all 5 patients without EBV DNA clearance had disease recurrence or death (3-year DFS: 64.3% vs 0%; P = .001). CONCLUSIONS: The use of antiangiogenic agents shortly after radiation therapy might increase the risk of necrosis. This approach needs to be avoided until translational and preclinical studies reveal the underlying mechanism of interaction between radiation therapy and antiangiogenic agents.

Radioprotective effect of X-ray abdominal FLASH irradiation: Adaptation to oxidative damage and inflammatory response may be benefiting factors.

BACKGROUND: Ultrahigh dose-rate irradiation (FLASH-IR) was reported to be efficient in tumor control while reducing normal tissue radiotoxicity. However, the mechanism of such phenomenon is still unclear. Besides, the FLASH experiments using high energy X-ray, the most common modality in clinical radiotherapy, are rarely reported. This study aims to investigate the radiobiological response using 6 MV X-ray FLASH-IR or conventional dose-rate IR (CONV-IR). METHODS: The superconducting linac of Chengdu THz Free Electron Laser (CTFEL) facility was used for FLASH-IR, a diamond radiation detector and a CeBr3 scintillation detector were used to monitor the time structure and dose rate of FLASH pulses. BALB/c nude mice received whole abdominal 6 MV X-ray FLASH-IR or CONV-IR, the prescribed dose was 15 Gy or 10 Gy and the delivered absolute dose was monitored with EBT3 films. The mice were either euthanized 24 h post-IR to evaluate acute tissue responses or followed up for 6 weeks to observe late-stage responses and survival probability. Complete blood count, histological analyses, and measurement of cytokine expression and redox status were performed. RESULTS: The mean dose rate of >150 Gy/s and instantaneous dose rate of >5.5 × 105  Gy/s was reached in FLASH-IR at the center of mice body. After 6 weeks' follow-up of mice that received 15 Gy IR, the FLASH group showed faster body weight recovery and higher survival probability than the CONV group. Histological analysis showed that FLASH-IR induced less acute intestinal damage than CONV-IR. Complete blood count and cytokine concentration measurement found that the inflammatory blood cell counts and pro-inflammatory cytokine concentrations were elevated at the acute stage after both FLASH-IR and CONV-IR. However, FLASH irradiated mice had significantly fewer inflammatory blood cells and diminished pro-inflammatory cytokine at the late stage. Moreover, higher reactive oxygen species (ROS) signal intensities but significantly reduced lipid peroxidation were found in the FLASH group than in the CONV group in the acute stage. CONCLUSIONS: The radioprotective effect of 6 MV X-ray FLASH-IR was observed. The differences in inflammatory responses and redox status between the two groups may be the factors responsible for reduced radiotoxicities following FLASH-IR. Further studies are required to thoroughly evaluate the impact of ROS on FLASH effect.

Long-term Survivals, Toxicities and the Role of Chemotherapy in Early-Stage Nasopharyngeal Carcinoma Patients Treated with Intensity-Modulated Radiation Therapy: A Retrospective Study with 15-Year Follow-up.

PURPOSE: This study was aimed to investigate long-term survivals and toxicities of early-stage nasopharyngeal carcinoma (NPC) in endemic area, evaluating the role of chemotherapy in stage II patients. MATERIALS AND METHODS: Totally 187 patients with newly diagnosed NPC and restaged American Joint Committee on Cancer/International Union Against Cancer 8th T1-2N0-1M0 were retrospectively recruited. All received intensity-modulated radiotherapy (IMRT)±chemotherapy (CT) from 2001 to 2010. RESULTS: With 15.7-year median follow-up, 10-year locoregional recurrence-free survival, distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were 93.3%, 93.5%, 92.9% and 88.2%, respectively. Multivariable analyses showed cervical lymph nodes positive and pre-treatment prognostic nutritional index ≥ 52.0 could independently predict DMFS (p=0.036 and p=0.011), DSS (p=0.014 and p=0.026), and OS (p=0.002 and p < 0.001); Charlson comorbidity index < 3 points could predict DSS (p=0.011); age > 45 years (p=0.002) and pre-treatment lactate dehydrogenase ≥ 240 U/L (p < 0.001) predicted OS. No grade 4 late toxicity happened; grade 3 late toxicities included subcutaneous fibrosis (4.3%), deafness or otitis (4.8%), skin dystrophy (2.1%), and xerostomia (1.1%). No differences on survivals were shown between IMRT+CT vs. IMRT alone in stage II patients, even in T2N1M0 (p > 0.05). Unsurprising, patients in IMRT+CT had more acute gastrointestinal reaction, myelosuppression, mucositis, late ear toxicity, and cranial nerve injury (all p < 0.05) than IMRT alone group. CONCLUSION: Superior tumor control and satisfying long-term outcomes could be achieved with IMRT in early-stage NPC with mild late toxicities. As CT would bring more toxicities, it should be carefully performed to stage II patients.

Multivariate NTCP Model of Hypothyroidism After Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma.

OBJECTIVE: To evaluate the incidence of hypothyroidism in patients with nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT), analyze its correlation with multiple influencing factors such as thyroid exposure dose, thyroid volume, and gender, and construct a multivariate-based normal tissue complication probability (NTCP) model for the occurrence of hypothyroidism after IMRT. MATERIALS AND METHODS: The thyroid hormone levels of patients at different points in time before and after radiotherapy were tested, and statistics on the incidence of hypothyroidism after treatment were obtained. The dose-volume data of patients' thyroids were converted into EQD2 equivalent dose values. The correlation between hypothyroidism after radiotherapy and thyroid exposure dose, thyroid volume, gender, and other factors was analyzed, and an NTCP model was constructed. RESULTS: A total of 69 patients with nasopharyngeal carcinoma were enrolled in this study. Twelve months after radiotherapy, a total of 24 patients (34.8%) developed hypothyroidism. Univariate analysis and multivariate analysis revealed that the average thyroid dose and thyroid volume are the most important factors affecting hypothyroidism after radiotherapy. The NTCP model constructed based on the average dose and thyroid volume has a good degree of fit. CONCLUSION: The volume and average dose of the thyroid gland are the key factors affecting the occurrence of hypothyroidism in patients with nasopharyngeal carcinoma after radiotherapy. The NTCP model constructed based on multivariate construction suggests that reducing the average dose of the thyroid to the greatest extent is an effective way to protect thyroid functions.

Comparison of combinations of irradiation techniques and jaw conditions in intensity-modulated radiotherapy for lung cancer.

PURPOSE: To assist in the selection of a suitable combination of an irradiation technique and jaw condition in intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc radiotherapy (VMAT) for lung cancer treatment plans. MATERIALS AND METHODS: Thirty patients with lung cancer who underwent radiotherapy were enrolled retrospectively. They were categorized as having central lung cancer, peripheral lung cancer with mediastinal lymph node metastasis (peripheral E lung cancer), and peripheral lung cancer without mediastinal lymph node metastasis (peripheral N lung cancer). Four treatment plans were designed for each patient: fixed jaw and adaptive jaw IMRT technique (FJ-IMRT and JA-IMRT), and fixed jaw and jaw tracking VMAT technique (FJ-VMAT and JT-VMAT). The dose parameters of the four group plans were compared and analyzed. RESULTS: Compared to FJ-IMRT, JA-IMRT significantly reduced the mean dose (Dmean ) and volume percentage of 5 Gy (V5Gy ) of the total lung in central and peripheral N lung cancer. Similarly, compared to FJ-VMAT, JT-VMAT provided better protection to most organs at risk (OARs), particularly for total lung and heart. In comparison with IMRT, VMAT significantly improved the conformity index (CI) of the planning target volume for the three lung cancer classifications, and it reduced the dose of almost all OARs except V5Gy and Dmean of the total lung. Moreover, the mean monitor units of the VMAT groups were far lower than the IMRT groups. CONCLUSION: Based on the dosimetric findings and considering clinical data published on lung and heart side effects, we propose recommendations on the preferred treatment technique based on tumor location and pulmonary function. For central lung cancer with normal pulmonary function, we advise JT-VMAT techniques. Conversely, for central lung cancer with poor pulmonary function, we recommend JA-IMRT techniques. We advocate JA-IMRT for peripheral E lung cancer. For peripheral N lung cancer, JT-VMAT techniques are strongly recommended.

Computed Tomography-Based Evaluation of Volume and Position Changes of the Target Region and Organs at Risk During Radiotherapy for Esophageal Cancer: A Pilot Study.

OBJECTIVE: To analyze changes in volume and position of target regions and organs at risk (OARs) during radiotherapy for esophageal cancer patients. METHODS: Overall, 16 esophageal cancer patients who underwent radiotherapy, including 10 cases of intensity-modulated radiation therapy (IMRT) and six of three-dimensional conformal radiotherapy (3D-CRT), were enrolled. The prescription doses for the planning target volumes (PTVs) were as follows: PTV1, 64 Gy/32 fractions; and PTV2, 46 Gy/23 fractions. Repeat computed tomography (CT) was performed for patients after the 5th, 10th, 15th, 20th, and 25th fractions. Delineation of the gross tumor volume (GTV) and OAR volume was determined using five repeat CTs performed by the same physician. The target and OAR volumes and centroid positions were recorded and used to analyze volume change ratio (VCR), center displacement (ΔD), and changes in the distance from the OAR centroid positions to the planned radiotherapy isocenter (distance to isocenter, DTI) during treatment. RESULTS: No patient showed significant changes in target volume (TV) after the first week of radiotherapy (five fractions). However, TV gradually decreased over the following weeks, with the rate slowing after the fourth week (40 Gy). The comparison of TV from baseline to 40 Gy (20 fractions) showed that average GTVs decreased from 130.7 ± 63.1 cc to 92.1 ± 47.2 cc, with a VCR of -29.21 ± 13.96% (p<0.01), while the clinical target volume (CTV1) decreased from 276.7 ± 98.2 cc to 246.7 ± 87.2 cc, with a VCR of -10.34 ± 7.58% (p<0.01). As TVs decreased, ΔD increased and DTI decreased. After the fourth week of radiotherapy (40 Gy), centroids of GTV, CTV1, and prophylactic CTV (CTV2) showed average deviations in ΔD of 7.6 ± 4.0, 6.9 ± 3.4, and 6.0 ± 3.0 mm, respectively. The average DTI of the heart decreased by 4.53 mm (from 15.61 ± 2.96 cm to 15.16 ± 2.27 cm). CONCLUSION: During radiotherapy for esophageal cancer, Targets and OARs change significantly in volume and position during the 2nd-4th weeks. Image-guidance and evaluation of dosimetric changes are recommended for these fractions of treatment to appropriate adjust treatment plans.