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PURPOSE: Accurately and early detection of intestinal fibrosis in Crohn's disease (CD) is crucial for clinical management yet remains an unmet need. Fibroblast activation protein inhibitor (FAPI) PET/CT has emerged as a promising tool to assess fibrosis. We aimed to investigate the diagnostic capability of [18F]F-FAPI PET/CT in detecting intestinal fibrosis and compared it with[18F]F-FDG PET/CT and magnetization transfer MR imaging (MTI). METHODS: Twenty-two rats underwent TNBS treatment to simulate fibrosis development, followed by three quantitative imaging sessions within one week. Mean and maximum standardized uptake values (SUVmean and SUVmax) were calculated on[18F]F-FAPI and [18F]F-FDG PET/CT, along with normalized magnetization transfer ratio on MTI. Intestinal fibrosis was assessed pathologically, with MTI serving as imaging standard for fibrosis. The diagnostic efficacy of imaging parameters in fibrosis was compared using pathological and imaging standards. Ten patients with 34 bowel strictures were prospectively recruited to validate their diagnostic performance, using the identical imaging protocol. RESULTS: In CD patients, the accuracy of FAPI uptake (both AUCs = 0.87, both P ≤ 0.01) in distinguishing non-to-mild from moderate-to-severe fibrosis was higher than FDG uptake (both AUCs = 0.82, P ≤ 0.01) and comparable to MTI (AUCs = 0.90, P ≤ 0.001). In rats, FAPI uptake responded earlier to fibrosis development than FDG and MTI; consistently, during early phase, FAPI uptake showed a stronger correlation (SUVmean: R = 0.69) with pathological fibrosis than FDG (SUVmean: R = 0.17) and MTI (R = 0.52). CONCLUSION: The diagnostic efficacy of [18F]F-FAPI PET/CT in detecting CD fibrosis is superior to [18F]F-FDG PET/CT and comparable to MTI, exhibiting great potential for early detection of intestinal fibrosis.
Subject(s)
Crohn Disease , Disease Models, Animal , Fibrosis , Fluorodeoxyglucose F18 , Intestines , Magnetic Resonance Imaging , Positron Emission Tomography Computed Tomography , Crohn Disease/diagnostic imaging , Crohn Disease/complications , Animals , Positron Emission Tomography Computed Tomography/methods , Rats , Fibrosis/diagnostic imaging , Humans , Male , Female , Adult , Intestines/diagnostic imaging , Intestines/pathology , Prospective Studies , Middle AgedABSTRACT
Celiac disease (CD), triggered by exposure to gluten in genetically susceptible individuals, is an immune-mediated small bowel disease affecting about 1% of the population worldwide. But the prevalence of CD varies with age, sex, and location. A strict gluten-free diet remains the primary treatment for CD, currently. Most of patients with CD respond well to gluten-free diet with good prognosis, while some patients fail to get symptomatic relief or histological remission (e.g., nonresponsive or refractory CD). Because of heterogeneous clinical appearance, the diagnosis of CD is difficult. Moreover, malignant complications and poor outcomes accompanied with refractory CD present great challenges in disease management. Over the past three decades, cross-sectional imaging techniques (computed tomography [CT] and magnetic resonance imaging [MRI]) play an important role in small bowel inflammatory and neoplastic diseases. Compared with endoscopic techniques, cross-sectional imaging permits clearly presentation of both intraluminal and extraluminal abnormalities. It provides vascular and functional information, thus improving the possibility as diagnostic and follow-up tool. The value of cross-sectional imaging for patients with suspected or confirmed CD has been gradually demonstrated. Studies revealed that certain features suggested by cross-sectional imaging could help to establish the early diagnosis of CD. Besides, the potential contributions of cross-sectional imaging may lie in the evaluation of disease activity and severity, which helps guiding management strategies. The purpose of this review is to provide current overviews and future directions of cross-sectional imaging in adult CD, thus facilitating the understanding and application in clinical practice. CLINICAL RELEVANCE STATEMENT: In this review, we systematically summarized the existing knowledge of cross-sectional imaging in adult CD and analyzed their possible roles in clinical practice, including disease diagnosis, complication identification, treatment evaluation, and prognostic prediction. KEY POINTS: ⢠Regarding a condition described as "celiac iceberg", celiac disease remains underdiagnosed and undertreated. ⢠Cross-sectional imaging is helpful in clinical management of celiac disease, including disease diagnosis, complication identification, treatment evaluation, and prognostic prediction. ⢠Cross-sectional imaging should be considered as the valuable examination in patients suspected from celiac disease.
Subject(s)
Celiac Disease , Humans , Adult , Celiac Disease/diagnostic imaging , Celiac Disease/complications , Glutens/adverse effects , Diet, Gluten-Free , Intestine, Small/diagnostic imaging , PrognosisABSTRACT
AIM: Cervical cancer is one of common diseases among women. There are limited therapies for patients with metastatic or recurrent cervical cancer. This study sought to explore the role of monoacylglycerol lipase (MAGL), an important metabolic enzyme, in cervical cancer progression. METHODS: In in vitro experiments, MAGL expression was inhibited by si-MAGL or JZL184 in cervical cancer cells. Quantitative real-time polymerase chain reaction and western blotting were performed to measure the expression of target molecules. Proliferation of cervical cancer cells was assessed by CCK-8 and colony formation assays. Apoptosis and cell cycle progression were evaluated by flow cytometry. The migration and invasion were detected by transwell assay. The in vivo tumor growth was detected in nude mice. TUNEL was utilized to observe apoptotic cells in tumor tissues. RESULTS: MAGL was upregulated in cervical cancer tissues and cells. Further, MAGL inhibition suppressed the growth of cervical cancer cells in vitro and in vivo. In addition, apoptosis and G1-phase cell cycle arrest were induced by MAGL knockdown. MAGL silencing-mediated upregulation of Bax and cleaved caspase-3, and downregulation of Bcl-2 was responsible for triggering apoptosis. More importantly, the migration and invasion of cervical cancer cells were restrained by MAGL depletion. CONCLUSIONS: MAGL drives the progression of cervical cancer, which can be a promising candidate to identify effective therapy for cervical cancer.
Subject(s)
Monoacylglycerol Lipases , Uterine Cervical Neoplasms , Animals , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Female , Humans , Mice , Mice, Nude , Neoplasm Invasiveness , Neoplasm Recurrence, LocalABSTRACT
BACKGROUND: Differentiation of suprasellar meningiomas (SSMs) from non-functioning pituitary macroadenomas (NFPMAs) is useful for clinical management. We investigated the utility of 13N-ammonia combined with 18F-FDG positron emission tomography (PET)/computed tomography (CT) in distinguishing SSMs from NFPMAs retrospectively. METHODS: Fourteen NFPMA patients and eleven SSM patients with histopathologic diagnosis were included in this study. Every patient underwent both 18F-FDG and 13N-ammonia PET/CT scans. The tumor to gray matter (T/G) ratios were calculated for the evaluation of tumor uptake. RESULTS: The uptake of 18F-FDG was higher in NFPMAs than SSMs, whereas the uptake of 13N-ammonia was obviously lower in NFPMAs than SSMs. The differences of 18F-FDG and 13N-ammonia uptake between the two groups were significant respectively (0.92[0.46] vs 0.59[0.29], P < 0.05, 18F-FDG; 1.58 ± 0.56 vs 2.80 ± 1.45, P < 0.05, 13N-ammonia). Tumor classification demonstrated a high overall accuracy of 96.0% for differential diagnosis. When the two traces were combined, only 1 SSM was misclassified into the NFPMA group. CONCLUSION: SSMs and NFPMAs have different metabolic characteristics on 18F-FDG and 13N-ammonia PET images. The combination of these two tracers can effectively distinguish SSMs from NFPMAs.
Subject(s)
Adenoma/diagnosis , Meningeal Neoplasms/diagnosis , Meningioma/diagnosis , Pituitary Neoplasms/diagnosis , Radiopharmaceuticals/pharmacokinetics , Adult , Aged , Ammonia/administration & dosage , Ammonia/pharmacokinetics , Diagnosis, Differential , Female , Fluorodeoxyglucose F18/administration & dosage , Fluorodeoxyglucose F18/pharmacokinetics , Humans , Male , Meninges/diagnostic imaging , Middle Aged , Nitrogen Radioisotopes/administration & dosage , Nitrogen Radioisotopes/pharmacokinetics , Pituitary Gland/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Radiopharmaceuticals/administration & dosage , Retrospective StudiesABSTRACT
The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.
Subject(s)
Apoptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Nerve Tissue Proteins/antagonists & inhibitors , Quinazolinones/pharmacology , Receptors, Cell Surface/antagonists & inhibitors , Animals , Drug Synergism , Lymphoma , Mice , Mice, Transgenic , Transcription Factors/metabolismABSTRACT
Drug efficacy strongly depends on the presence of the drug substance at the target site. As vascularization is an important factor for the distribution of drugs in tissues, we analyzed drug distribution as a function of blood vessel localization in tumor tissue. To explore distribution of the anticancer drugs afatinib, erlotinib, and sorafenib, a combined approach of matrix-assisted laser desorption/ionization (MALDI) drug imaging and immunohistochemical vessel staining was applied and examined by digital image analysis. The following two xenograft models were investigated: (1) mice carrying squamous cell carcinoma (FaDu) xenografts (ntumor = 13) were treated with afatinib or erlotinib, and (2) sarcoma (A673) xenograft bearing mice (ntumor = 8) received sorafenib treatment. MALDI drug imaging revealed a heterogeneous distribution of all anticancer drugs. The tumor regions containing high drug levels were associated with a higher degree of vascularization than the regions without drug signals (p < 0.05). When correlating the impact of blood vessel size to drug abundance in the sarcoma model, a higher amount of small vessels was detected in the tumor regions with high drug levels compared to the tumor regions with low drug levels (p < 0.05). With the analysis of coregistered MALDI imaging and CD31 immunohistochemical data by digital image analysis, we demonstrate for the first time the potential of correlating MALDI drug imaging and immunohistochemistry. Here we describe a specific and precise approach for correlating histological features and pharmacokinetic properties of drugs at microscopic level, which will provide information for the improvement of drug design, administration formula or treatment schemes.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Immunohistochemistry/methods , Niacinamide/analogs & derivatives , Phenylurea Compounds/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Quinazolines/pharmacokinetics , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Afatinib , Animals , Carcinoma, Squamous Cell/drug therapy , Erlotinib Hydrochloride , Female , Mice , Mice, SCID , Niacinamide/pharmacokinetics , Sarcoma/drug therapy , Sorafenib , Tissue DistributionABSTRACT
Background: The immune microenvironment (IME) is closely associated with prognosis and therapeutic response of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). Multi-parametric magnetic resonance imaging (MRI) enables non-invasive assessment of IME and predicts prognosis in HBV-HCC. We aimed to construct an MRI prediction model of the immunocyte-infiltration subtypes and explore its prognostic significance. Methods: HBV-HCC patients at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) with radical surgery (between 1 October and 30 December 2021) were prospectively enrolled. Patients with pathologically proven HCC (between 1 December 2013 and 30 October 2019) were retrospectively enrolled. Pearson correlation analysis was used to examine the relationship between the immunocyte-infiltration counts and MRI parameters. An MRI prediction model of immunocyte-infiltration subtypes was constructed in prospective cohort. Kaplan-Meier survival analysis was used to analyse its prognostic significance in the retrospective cohort. Results: Twenty-four patients were prospectively enrolled to construct the MRI prediction model. Eighty-nine patients were retrospectively enrolled to determine its prognostic significance. MRI parameters (relative enhancement, ratio of the apparent diffusion coefficient value of tumoral region to peritumoral region [rADC], T1 value) correlated significantly with the immunocyte-infiltration counts (leukocytes, T help cells, PD1+Tc cells, B lymphocytes). rADC differed significantly between high and low immunocyte-infiltration groups (1.47 ± 0.36 vs 1.09 ± 0.25, P = 0.009). The area under the curve of the MRI model was 0.787 (95% confidence interval 0.587-0.987). Based on the MRI model, the recurrence-free time was longer in the high immunocyte-infiltration group than in the low immunocyte-infiltration group (P = 0.026). Conclusions: MRI is a non-invasive method for assessing the IME and immunocyte-infiltration subtypes, and predicting prognosis in post-operative HBV-HCC patients.
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OBJECTIVES: Differentiating intestinal tuberculosis (ITB) from Crohn's disease (CD) remains a diagnostic dilemma. Misdiagnosis carries potential grave implications. We aim to establish a multidisciplinary-based model using machine learning approach for distinguishing ITB from CD. METHODS: Eighty-two patients including 25 patients with ITB and 57 patients with CD were retrospectively recruited (54 in training cohort and 28 in testing cohort). The region of interest (ROI) for the lesion was delineated on magnetic resonance enterography (MRE) and colonoscopy images. Radiomic features were extracted by least absolute shrinkage and selection operator regression. Pathological feature was extracted automatically by deep-learning method. Clinical features were filtered by logistic regression analysis. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Delong's test was applied to compare the efficiency between the multidisciplinary-based model and the other four single-disciplinary-based models. RESULTS: The radiomics model based on MRE features yielded an AUC of 0.87 (95% confidence interval [CI] 0.68-0.96) on the test data set, which was similar to the clinical model (AUC, 0.90 [95% CI 0.71-0.98]) and higher than the colonoscopy radiomics model (AUC, 0.68 [95% CI 0.48-0.84]) and pathology deep-learning model (AUC, 0.70 [95% CI 0.49-0.85]). Multidisciplinary model, integrating 3 clinical, 21 MRE radiomic, 5 colonoscopy radiomic, and 4 pathology deep-learning features, could significantly improve the diagnostic performance (AUC of 0.94, 95% CI 0.78-1.00) on the bases of single-disciplinary-based models. DCA confirmed the clinical utility. CONCLUSIONS: Multidisciplinary-based model integrating clinical, MRE, colonoscopy, and pathology features was useful in distinguishing ITB from CD.
Subject(s)
Colonoscopy , Crohn Disease , Machine Learning , Magnetic Resonance Imaging , Tuberculosis, Gastrointestinal , Humans , Crohn Disease/diagnostic imaging , Tuberculosis, Gastrointestinal/diagnostic imaging , Diagnosis, Differential , Female , Male , Retrospective Studies , Adult , Magnetic Resonance Imaging/methods , Middle AgedABSTRACT
PURPOSE: To develop a CT-based radiomics model combining with VAT and bowel features to improve the predictive efficacy of IFX therapy on the basis of bowel model. METHODS: This retrospective study included 231 CD patients (training cohort, n = 112; internal validation cohort, n = 48; external validation cohort, n = 71) from two tertiary centers. Machine-learning VAT model and bowel model were developed separately to identify CD patients with primary nonresponse to IFX. A comprehensive model incorporating VAT and bowel radiomics features was further established to verify whether CT features extracted from VAT would improve the predictive efficacy of bowel model. Area under the curve (AUC) and decision curve analysis were used to compare the prediction performance. Clinical utility was assessed by integrated differentiation improvement (IDI). RESULTS: VAT model and bowel model exhibited comparable performance for identifying patients with primary nonresponse in both internal (AUC: VAT model vs bowel model, 0.737 (95% CI, 0.590-0.854) vs. 0.832 (95% CI, 0.750-0.896)) and external validation cohort [AUC: VAT model vs. bowel model, 0.714 (95% CI, 0.595-0.815) vs. 0.799 (95% CI, 0.687-0.885)), exhibiting a relatively good net benefit. The comprehensive model incorporating VAT into bowel model yielded a satisfactory predictive efficacy in both internal (AUC, 0.840 (95% CI, 0.706-0.930)) and external validation cohort (AUC, 0.833 (95% CI, 0.726-0.911)), significantly better than bowel alone (IDI = 4.2% and 3.7% in internal and external validation cohorts, both p < 0.05). CONCLUSION: VAT has an effect on IFX treatment response. It improves the performance for identification of CD patients at high risk of primary nonresponse to IFX therapy with selected features from RM. CRITICAL RELEVANCE STATEMENT: Our radiomics model (RM) for VAT-bowel analysis captured the pathophysiological changes occurring in VAT and whole bowel lesion, which could help to identify CD patients who would not response to infliximab at the beginning of therapy. KEY POINTS: ⢠Radiomics signatures with VAT and bowel alone or in combination predicting infliximab efficacy. ⢠VAT features contribute to the prediction of IFX treatment efficacy. ⢠Comprehensive model improved the performance compared with the bowel model alone.
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Background: Magnetic resonance imaging (MRI) has now become the best modality for the preoperative staging of cervical cancer. This study was to compare the value of high-resolution reduced field-of-view diffusion-weighted MR imaging (r-FOV DWI) with conventional field-of-view (c-FOV DWI) in the diagnosis of cervical cancer. Methods: Forty-five patients (25 patients with cervical cancer and 20 patients with normal cervix) received magnetic resonance (MR) scans (3.0T), including both r-FOV DWI and c-FOV DWI sequences. The image quality (IQ) of both sequences was subjectively assessed by two attending radiologists using a double-blind method and quantitatively by the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Moreover, apparent diffusion coefficient (ADC) values for cervical cancer were blindly measured by one technician on the ADC map. Results: The subjective scores of r-FOV DWI images were higher than those of c-FOV DWI (P<0.0001), and the interrater reliability was in good agreement [Cohen's kappa coefficient (κ) =0.547-0.914]. There was a significant difference in CNR between the two DWI image groups (r-FOV DWI 12.73±5.56 vs. c-FOV DWI 11.21±5.92, P=0.019). The difference in mean ADC values between the two DWI sequences was statistically significant [r-FOV DWI (0.690±0.195)×10-3 mm2/s vs. c-FOV DWI (0.794±0.167)×10-3 mm2/s, P<0.001]. The ADC value of cervical cancer lesions [(0.690±0.195)×10-3 mm2/s] was significantly lower than that of normal cervix ADC value [(1.506±0.188)×10-3 mm2/s]. Conclusions: r-FOV DWI can effectively improve the spatial resolution of the image while reducing distortion and artifacts. Furthermore, it can help to diagnose cervical cancer more accurately for the more realistic ADC values.
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Previous evidences have demonstrated that anti-tumor effect of high-dose ascorbic acid is associated with the generation of reactive oxygen species (ROS) via autoxidation. Hypoxia induces therapy resistance in castration-resistant prostate cancer. As a mitochondrial respiration inhibitor, metformin has the potential to improve tumor oxygenation. In this study, we evaluate the anti-tumor effect of ascorbic acid combined with metformin in prostate cancer. We demonstrated that ascorbic acid inhibits prostate cancer cells proliferation by generating ROS, and metformin enhances the anti-tumor effects of ascorbic acid. Mechanistically, metformin reduces oxygen consumption rate and NADP+/NADPH value in prostate cancer cells, thereby increases the ROS content induced by ascorbic acid. In addition, our data demonstrated that ascorbic acid inhibits p-AKT signaling in a ROS-dependent pathway, leading to inhibition of p-mTOR expression. And metformin inhibits the p-mTOR expression by activating the AMPK signaling pathway, exerting a synergistic effect on tumor suppression with ascorbic acid. Furthermore, metformin improves tumor oxygenation, and the combined treatment effect of ascorbic acid and metformin were demonstrated in a xenograft model of prostate cancer. Taken together, our data demonstrate that metformin enhances the anti-tumor proliferation effect of ascorbic acid by increasing ROS content in castration-resistant prostate cancer. This provides a new strategy for the clinical application of high-dose ascorbic acid as an anti-tumor drug. KEY MESSAGES: Ascorbic acid inhibits tumor growth by inducing ROS generation. As a mitochondrial respiration inhibitor, metformin inhibits cellular oxygen consumption rate to improve oxygenation of prostate cancer. Metformin enhances anti-tumor effect of ascorbic acid by increasing ROS content. Ascorbic acid inhibits the mTOR expression via PI3K-AKT pathway, and metformin inhibits the mTOR expression by inhibiting AMPK signaling in prostate cancer cells.
Subject(s)
Antineoplastic Agents , Metformin , Prostatic Neoplasms, Castration-Resistant , Humans , Male , AMP-Activated Protein Kinases/metabolism , Antineoplastic Agents/pharmacology , Apoptosis , Ascorbic Acid/pharmacology , Ascorbic Acid/therapeutic use , Cell Line, Tumor , Cell Proliferation , Metformin/pharmacology , Phosphatidylinositol 3-Kinases , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Respiration , TOR Serine-Threonine Kinases/metabolism , AnimalsABSTRACT
Background: Non-invasive glycogen quantification in vivo could provide crucial information on biological processes for glycogen storage disorder. Using dual-energy computed tomography (DECT), this study aimed to assess the viability of quantifying glycogen content in vitro. Methods: A fast kilovolt-peak switching DECT was used to scan a phantom containing 33 cylinders with different proportions of glycogen and iodine mixture at varying doses. The virtual glycogen concentration (VGC) was then measured using material composition images. Additionally, the correlations between VGC and nominal glycogen concentration (NGC) were evaluated using least-square linear regression, then the calibration curve was constructed. Quantitative estimation was performed by calculating the linearity, conversion factor (inverse of curve slope), stability, sensitivity (limit of detection/limit of quantification), repeatability (inter-class correlation coefficient), and variability (coefficient of variation). Results: In all conditions, excellent linear relationship between VGC and NGC were observed (P<0.001, coefficient of determination: 0.989-0.997; residual root-mean-square error of glycogen: 1.862-3.267 mg/mL). The estimated conversion factor from VGC to NGC was 3.068-3.222. In addition, no significant differences in curve slope were observed among different dose levels and iodine densities. The limit of detection and limit of quantification had respective ranges of 6.421-15.315 and 10.95-16.46 mg/mL. The data demonstrated excellent scan-repeat scan agreement (inter-class correlation coefficient, 0.977-0.991) and small variation (coefficient of variation, 0.1-0.2%). Conclusions: The pilot phantom analysis demonstrated the feasibility and efficacy of detecting and quantifying glycogen using DECT and provided good quantitative performance with significant stability and reproducibility/variability. Thus, in the future, DECT could be used as a convenient method for glycogen quantification to provide more reliable information for clinical decision-making.
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Background: Visceral adipose tissue (VAT) is involved in the pathogenesis of Crohn's disease (CD). However, data describing its effects on CD progression remain scarce. We developed and validated a VAT-radiomics model (RM) using computed tomography (CT) images to predict disease progression in patients with CD and compared it with a subcutaneous adipose tissue (SAT)-RM. Methods: This retrospective study included 256 patients with CD (training, n = 156; test, n = 100) who underwent baseline CT examinations from June 19, 2015 to June 14, 2020 at three tertiary referral centres (The First Affiliated Hospital of Sun Yat-Sen University, The First Affiliated Hospital of Shantou University Medical College, and The First People's Hospital of Foshan City) in China. Disease progression referred to the development of penetrating or stricturing diseases or the requirement for CD-related surgeries during follow-up. A total of 1130 radiomics features were extracted from VAT on CT in the training cohort, and a machine-learning-based VAT-RM was developed to predict disease progression using selected reproducible features and validated in an external test cohort. Using the same modeling methodology, a SAT-RM was developed and compared with the VAT-RM. Findings: The VAT-RM exhibited satisfactory performance for predicting disease progression in total test cohort (the area under the ROC curve [AUC] = 0.850, 95% confidence Interval [CI] 0.764-0.913, P < 0.001) and in test cohorts 1 (AUC = 0.820, 95% CI 0.687-0.914, P < 0.001) and 2 (AUC = 0.871, 95% CI 0.744-0.949, P < 0.001). No significant differences in AUC were observed between test cohorts 1 and 2 (P = 0.673), suggesting considerable efficacy and robustness of the VAT-RM. In the total test cohort, the AUC of the VAT-RM for predicting disease progression was higher than that of SAT-RM (AUC = 0.786, 95% CI 0.692-0.861, P < 0.001). On multivariate Cox regression analysis, the VAT-RM (hazard ratio [HR] = 9.285, P = 0.005) was the most important independent predictor, followed by the SAT-RM (HR = 3.280, P = 0.060). Decision curve analysis further confirmed the better net benefit of the VAT-RM than the SAT-RM. Moreover, the SAT-RM failed to significantly improve predictive efficacy after it was added to the VAT-RM (integrated discrimination improvement = 0.031, P = 0.102). Interpretation: Our results suggest that VAT is an important determinant of disease progression in patients with CD. Our VAT-RM allows the accurate identification of high-risk patients prone to disease progression and offers notable advantages over SAT-RM. Funding: This study was supported by the National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Nature Science Foundation of Shenzhen, and Young S&T Talent Training Program of Guangdong Provincial Association for S&T. Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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PURPOSE: Targeted therapy with α-particle emitting radionuclides is a promising new option in cancer therapy. Stable conjugates of the vascular tumour-homing peptide F3 with the α-emitter (213)Bi specifically target tumour cells. The aim of our study was to determine efficacy of combined (213)Bi-diethylenetriaminepentaacetic acid (DTPA)-F3 and paclitaxel treatment compared to treatment with either (213)Bi-DTPA-F3 or paclitaxel both in vitro and in vivo. METHODS: Cytotoxicity of treatment with (213)Bi-DTPA-F3 and paclitaxel, alone or in combination, was assayed towards OVCAR-3 cells using the alamarBlue assay, the clonogenic assay and flow cytometric analyses of the mode of cell death and cell cycle arrest. Therapeutic efficacy of the different treatment options was assayed after repeated treatment of mice bearing intraperitoneal OVCAR-3 xenograft tumours. Therapy monitoring was performed by bioluminescence imaging and histopathologic analysis. RESULTS: Treatment of OVCAR-3 cells in vitro with combined (213)Bi-DTPA-F3 and paclitaxel resulted in enhanced cytotoxicity, induction of apoptosis and G2/M phase arrest compared to treatment with either (213)Bi-DTPA-F3 or paclitaxel. Accordingly, i.p. xenograft OVCAR-3 tumours showed the best response following repeated (six times) combined therapy with (213)Bi-DTPA-F3 (1.85 MBq) and paclitaxel (120 µg) as demonstrated by bioluminescence imaging and histopathologic investigation of tumour spread on the mesentery of the small and large intestine. Moreover, mean survival of xenograft mice that received combined therapy with (213)Bi-DTPA-F3 and paclitaxel was significantly superior to mice treated with either (213)Bi-DTPA-F3 or paclitaxel alone. CONCLUSION: Combined treatment with (213)Bi-DTPA-F3 and paclitaxel significantly increased mean survival of mice with peritoneal carcinomatosis of ovarian origin, thus favouring future therapeutic application.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma/therapy , Chemoradiotherapy , Organometallic Compounds/therapeutic use , Paclitaxel/therapeutic use , Peritoneal Neoplasms/therapy , Radiopharmaceuticals/therapeutic use , Animals , Apoptosis/drug effects , Cell Division/drug effects , Cell Line, Tumor , G2 Phase Cell Cycle Checkpoints/drug effects , HEK293 Cells , HMGN2 Protein/chemistry , Humans , Mice , Mice, SCID , Neoplasm Transplantation , Organometallic Compounds/pharmacology , Paclitaxel/pharmacology , Protein Structure, Tertiary , Radiopharmaceuticals/pharmacology , Treatment OutcomeABSTRACT
Purpose: To develop an effective diagnostic model for bone metastasis of gastric cancer by combining 18F-FDG PET/CT and clinical data. Materials and Methods: A total of 212 gastric cancer patients with abnormal bone imaging scans based on 18F-FDG PET/CT were retrospectively enrolled between September 2009 and March 2020. Risk factors for bone metastasis of gastric cancer were identified by multivariate logistic regression analysis and used to create a nomogram. The performance of the nomogram was evaluated by using receiver operating characteristic curves and calibration plots. Results: The diagnostic power of the binary logistic regression model incorporating skeleton-related symptoms, anemia, the SUVmax of bone lesions, bone changes, the location of bone lesions, ALP, LDH, CEA, and CA19-9 was significantly higher than that of the model using only clinical factors (p = 0.008). The diagnostic model for bone metastasis of gastric cancer using a combination of clinical and imaging data showed an appropriate goodness of fit according to a calibration test (p = 0.294) and good discriminating ability (AUC = 0.925). Conclusions: The diagnostic model combined with the 18F-FDG PET/CT findings and clinical data showed a better diagnosis performance for bone metastasis of gastric cancer than the other studied models. Compared with the model using clinical factors alone, the additional 18F-FDG PET/CT findings could improve the diagnostic efficacy of identifying bone metastases in gastric cancer.
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Purpose: Glutamine synthetase (GS) is the only currently known enzyme responsible for synthesizing endogenous glutamine (Gln). GS exerts a critical role in the oncogenesis of endogenous Gln-dependent cancers, making it an attractive target for anti-tumor therapies. A mixed-function oxidation system consisting of vitamin C (VC), oxygen, and trace metals can oxidize GS and promote its degradation. The current study aims to explore the effect of pharmacological VC treatment on GS. Methods: Endogenous Gln-dependent cancer lines (breast cancer MCF7 and prostate cancer PC3) were selected to establish chronic Gln-deprived MCF7 and PC3 cell models. The expression of GS in parental and chronic Gln-deprived tumor cells exposed to VC treatment and control was determined by Western blot analysis. The anti-cancer effects of VC on parental and chronic Gln-deprived tumor cells were assessed by CCK-8 and annexin V-FITC/PI FACS assays. In addition, changes in cellular reactive oxygen species (ROS), glutathione (GSH) levels and NADPH/NADP + ratio were analyzed to explore the underlying mechanisms. Moreover, BALB/c nude mice xenografting with parental and chronic Gln-deprived prostate cancer cells were constructed to evaluate the in vivo therapeutic effect of VC. Finally, tumor 13N-ammonia uptake in mice bearing prostate cancer xenografts was analyzed following treatment with VC and the expression of GS in xenografts were detected by immunohistochemistry. Results: Cells overexpressing GS were obtained by chronic Gln deprivation. We found that the cytotoxic effect of VC on cancer cells was positively correlated with the expression of GS. Additionally, VC treatment led to a significant increase in ROS production, as well as GSH depletion and NADPH/NADP + reduction. These changes could be reversed by the antioxidant N-acetyl-L-cysteine (NAC). Furthermore, pharmacological VC treatment exhibited a more significant therapeutic effect on xenografts of prostate cancer cells overexpressing GS, that could be well monitored by 13N-ammonia PET/CT imaging. Conclusion: Our findings indicate that VC can kill cancer cells by targeting glutamine synthetase to induce oxidative stress. VC could be used as an anti-cancer treatment for endogenous glutamine-dependent cancers.
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The effective and economical therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) is still requested from patients, who are not available for Lu-177 or Ra-223 treatment. Drug repurposing as a cost-effective and time-saving alternative to traditional drug development has been increasingly discussed. Proton pump inhibitors (PPIs) such as pantroprazole, which are commonly used as antacids, have also been shown to be effective in cancer chemoprevention via induction of apoptosis in multiple cancer cell lines. Vitamin C is an essential micronutrient for human body, has been proposed as a potential anti-cancer agent. In this context, have we investigated the combination of vitamin C and pantoprazole for the management of metastatic castration-resistant prostate cancer (mCRPC). Six chosen human adenocarcinoma cell lines were used to investigate the influence of pantoprazole on the microenvironment of cancer cells (extracellular pH and production of exosomes). Tumor growth and tumor 18F-FDG uptake in PC3 xenografts were analyzed following varied treatment. Our in vitro Results have suggested that pantoprazole enhanced the cytotoxic activity of vitamin C by regulating pH values and production of exosomes in cancer cells. Moreover, the synergistic effect of pantoprazole and vitamin C was pH-dependent since pantoprazole was more effective at a slightly acidic pH. In vivo, the combined treatment using pantoprazole and vitamin C produced better therapeutic outcomes than treatment with vitamin C or pantoprazole alone, as demonstrated via tumor growth and uptake of 18F-FDG. Therefore, we suggest that pantoprazole combined with vitamin C could be as a possible strategy to manage mCRPC.
ABSTRACT
L-ascorbic acid (AA) was reported to have an anti-cancer effect over 40 years. In recent years, several ongoing clinical trials are exploring the safety and efficacy of intravenous high-dose AA for cancer treatment. The lack of appropriate imaging modality limits the identification of potentially suitable patients for AA treatment. This study focuses on identifying AA-sensitive tumor cells using molecular imaging. 6-Deoxy-6-[18F] fluoro-L-ascorbic Acid (18F-DFA), a structural analog of AA, was synthesized and labeled to visualize the metabolism of AA in vivo. Colorectal cancer (CRC) cell lines with high and low expression of sodium-dependent vitamin C transporters 2 (SVCT2) were used for a series of cellular uptake tests. PET imaging was performed on xenograft tumor-bearing mice. More AA uptake was observed in CRC cells with high SVCT2 expression than in cells with low SVCT2 expression. The substrate (unlabeled AA) can competitively inhibit the 18F-DFA tracer uptake by CRC cells. The biodistribution of 18F-DFA in mice showed high radioactivity was seen in organs such as adrenal glands, kidneys, and liver that were known to have high concentrations of AA. Both PET imaging and tissue distribution showed that cancer cells with high SVCT2 expression enhanced the accumulation of 18F-DFA in mice after tumor formation. Immunohistochemistry was used to verify the corresponding results. As a radiotracer, 18F-DFA can provide powerful imaging information to identify tumor with high affinity of AA, and SVCT2 can be a potential biomarker in this process.
ABSTRACT
Fibrostenosis is a serious complication of Crohn's disease (CD), affecting approximately one-half of all patients. Surgical resection is the typical clinical end due to ineffective antifibrotic therapy mainly through anti-inflammatory treatment and fibrosis can be reverted only at early stages. Mover, human fibrotic disorders is known to be associated with aging process. Thus, accurate monitoring of the progression of fibrosis is crucial for CD management as well as can be benefit to aging related fibrosis. The excessive deposition of type I collagen (ColI) is the core point in major complications of fibrosis, including that in patients with CD and aging related fibrosis. Therefore, a MR imaging probe (EP-3533) targeted ColI was employed to stage bowel fibrosis in CD using a rat model and to compare its efficiency with the common MR imaging contrast medium gadopentetatedimeglumine (Gd-DTPA). The bowel fibrotic rat model was established with different degrees of bowel fibrosis, were scanned using a 3.0-T MRI scanner with a specialized animal coil. MRI sequence including T 1 mapping and T1-weighed imaging were performed before and after injecting the MRI probe (EP-3533 or Gd-DTPA). The T 1 relaxation time (T 1 value) and change in the contrast-to-noise ratio (ΔCNR) were measured to evaluate bowel fibrosis. Masson's trichrome staining was performed to determine the severity of fibrosis. EP-3533 offered a better longitudinal relaxivity (r1) with 67.537 L/mmol·s, which was approximately 13 times that of Gd-DTPA. The T 1 value on bowel segments was reduced in the images from EP-3533 compared to that from Gd-DTPA (F = 16.478; p < 0.001). Additionally, a better correlation between ΔCNR calculated from EP-3533 imaging and bowel fibrosis (AUC = 0.846) was determined 10 min after enhanced media administration than with Gd-DTPA (AUC = 0.532). The 10th-minute ΔCNR performed using the ColI probe showed the best correlation with the severity of bowel fibrosis (r = 0.538; p = 0.021). Our results demonstrates that targeted MRI probe (EP-3533) supplies a better enhanced effect compared to Gd-DTPA and could be a promising method to evaluate the progression and monitor the therapeutic response of bowel fibrosis.
ABSTRACT
RATIONALE AND OBJECTIVES: This study investigated the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for predicting visceral pleural invasion (VPI) of subsolid nodule (SSN) stage I lung adenocarcinoma. MATERIALS AND METHODS: A retrospective analysis of 18F-FDG PET/CT data from 65 postsurgical cases with surgical pathology-confirmed SSN lung adenocarcinoma identified significant VPI predictors using multivariate logistic regression. RESULTS: Nodule and solid component sizes, solid component-to-tumor ratios, pleural indentations, distances between nodules and pleura, and maximum standardized uptake values (SUVmax) differed significantly between VPI-positive (nâ¯=â¯30) and VPI-negative (nâ¯=â¯35) cases on univariate analysis. The distance between the nodule and pleura and SUVmax were significant independent VPI predictors on multivariate analysis. Areas under the curve of the distance between the nodule and pleura and SUVmax on receiver operating characteristic curves were 0.76 and 0.79, respectively; both factors were 0.90. The area under the curve of combined predictors was significantly superior to the distance between the nodule and pleura only but not SUVmax alone. The threshold of the distance between the nodule and pleura, to predict VPI was 4.50 mm, with 96.67% sensitivity, and 57.14% specificity. The threshold of SUVmax to predict VPI was 1.05, with 100% sensitivity and 60% specificity. The sensitivity and specificity of model 2 using the independent predictive factors were 96.67%, and 71.43%, respectively. CONCLUSION: Distance between the nodule and pleura and SUVmax are independent predictors of VPI in SSN stage I lung adenocarcinoma. Further, combining these factors improves their predictive ability.