Amide Proton Transfer-Weighted Imaging Combined With Intravoxel Incoherent Motion for Evaluating Microsatellite Instability in Endometrial Cancer.

BACKGROUND: Microsatellite instability (MSI), caused by mismatch repair (MMR) protein defects that lead to uncorrectable mismatch bases, results in the accumulation of gene mutations and ultimately to tumors. Preoperative prediction of MSI can provide a basis for personalized and precise treatment of endometrial cancer (EC) patients. PURPOSE: To investigate amide proton transfer weighting (APTw) imaging combined with intravoxel incoherent motion (IVIM) in the assessment of MSI in EC. STUDY TYPE: Retrospective. POPULATION: A total of 71 patients with EC (12 classified as the MSI group and 22 as the microsatellite stabilization [MSS] group after entering and leaving the group standard). FIELD STRENGTH/SEQUENCE: A 3.0 T/IVIM, diffusion-weighted imaging (DWI) and APTw. ASSESSMENT: Amide proton transfer (APT) value, apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudo diffusion coefficient (D*), and perfusion fraction (f) were calculated and compared between MSI and MSS groups. STATISTICAL TESTS: The Kendall's W test; Mann-Whitney U-test; Chi-square test or Fisher's exact test; logistic regression analysis; Area under the receiver operating characteristic (ROC) curve (AUC); The Delong test; Pearson or Spearman correlation coefficients. The significance threshold was set at P < 0.05. RESULTS: APT and D* values of the MSI group were significantly higher than those of the MSS group. While ADC, D, and f values in the MSI group were significantly lower than those in the MSS group. The multivariate analysis revealed that only APT and D* values were independent predictors to evaluate the MSI status. And the ROC curves indicated that the combination of APT and D* values could distinguish the MSI status of EC with the highest diagnostic efficacy (AUC = 0.973), even without significant difference to those by APT (AUC = 0.894) or D* (AUC = 0.920) value separately (P = 0.149 and 0.078, respectively). CONCLUSION: Combination of APTw and IVIM imaging may serve as an effective noninvasive method for clinical assessment of MSI in EC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

A multifunctional integrated biomimetic spore nanoplatform for successively overcoming oral biological barriers.

The biological barriers have seriously restricted the efficacious responses of oral delivery system in diseases treatment. Utilizing a carrier based on the single construction means is hard to overcome these obstacles simultaneously because the complex gastrointestinal tract environment requires carrier to have different or even contradictory properties. Interestingly, spore capsid (SC) integrates many unique biological characteristics, such as high resistance, good stability etc. This fact offers a boundless source of inspiration for the construction of multi-functional oral nanoplatform based on SC without further modification. Herein, we develop a type of biomimetic spore nanoplatform (SC@DS NPs) to successively overcome oral biological barriers. Firstly, doxorubicin (DOX) and sorafenib (SOR) are self-assembled to form carrier-free nanoparticles (DS NPs). Subsequently, SC is effectively separated from probiotic spores and served as a functional vehicle for delivering DS NPs. As expect, SC@DS NPs can efficaciously pass through the rugged stomach environment after oral administration and further be transported to the intestine. Surprisingly, we find that SC@DS NPs exhibit a significant improvement in the aspects of mucus penetration and transepithelial transport, which is related to the protein species of SC. This study demonstrates that SC@DS NPs can efficiently overcome multiple biological barriers and improve the therapeutic effect.

The Role of Multiparametric Magnetic Resonance Imaging in the Study of Primary Tumor and Pelvic Lymph Node Metastasis in Stage IB1-IIA1 Cervical Cancer.

OBJECTIVE: The aim of this study was to investigate the value of multiparametric magnetic resonance imaging (MRI) in demonstrating the metastatic potential of primary tumor and differentiating metastatic lymph nodes (MLNs) from nonmetastatic lymph nodes (non-MLNs) in stage IB1-IIA1 cervical cancer. METHODS: Fifty-seven stage IB1-IIA1 subjects were included. The apparent diffusion coefficient (ADC) values and dynamic contrast-enhanced MRI (DCE-MRI) parameters of primary tumors and lymph nodes and the conventional imaging features of the lymph nodes were measured and analyzed. Mann-Whitney test and χ test were used to analyze statistically significant parameters, logistic regression was used for multivariate analysis, and receiver operating characteristic analysis was used to compare the diagnostic performance of the MLNs. RESULTS: Nineteen subjects had lymph node metastasis. A total of 94 lymph nodes were evaluated, including 30 MLNs and 64 non-MLNs. There were no significant difference in ADC and DCE-MRI parameters between metastatic and nonmetastatic primary tumors. The heterogeneous signal was more commonly seen in MLNs than in non-MLNs (P = 0.001). The values of ADCmean, ADCmin, and ADCmax of MLNs were lower than those of non-MLNs (P < 0.001). The values of short-axis diameter, K, Kep, and Ve of MLNs were higher than those of non-MLNs (P < 0.05). Compared with individual MRI parameters, the combined evaluation of short-axis diameter, ADCmean, and K showed the highest area under the curve of 0.930. CONCLUSIONS: Diffusion-weighted imaging and DCE-MRI could not demonstrate the metastatic potential of primary tumor in stage IB1-IIA1 cervical cancer. Compared with individual MRI parameters, the combination of multiparametric MRI could improve the diagnostic performance of lymph node metastasis.

Loss of Cochlear Ribbon Synapse Is a Critical Contributor to Chronic Salicylate Sodium Treatment-Induced Tinnitus without Change Hearing Threshold.

Tinnitus is a common auditory disease worldwide; it is estimated that more than 10% of all individuals experience this hearing disorder during their lifetime. Tinnitus is sometimes accompanied by hearing loss. However, hearing loss is not acquired in some other tinnitus generations. In this study, we injected adult rats with salicylate sodium (SS) (200 mg/kg/day for 10 days) and found no significant hearing threshold changes at 2, 4, 8, 12, 14, 16, 20, or 24 kHz (all p > 0.05). Tinnitus was confirmed in the treated rats via Behaviour Testing of Acoustic Startle Response (ASR) and Gap Prepulse Inhibition Test of Acoustic Startle Reflex (GPIAS). A immunostaining study showed that there is significant loss of anti-CtBP2 puncta (a marker of cochlear inner hair cell (HC) ribbon synapses) in treated animals in apical, middle, and basal turns (all p < 0.05). The ABR wave I amplitudes were significantly reduced at 4, 8, 12, 14, 16, and 20 kHz (all p < 0.05). No significant losses of outer HCs, inner HCs, or HC cilia were observed (all p > 0.05). Thus, our study suggests that loss of cochlear inner HC ribbon synapse after SS exposure is a contributor to the development of tinnitus without changing hearing threshold.

CRKL regulates alternative splicing of cancer-related genes in cervical cancer samples and HeLa cell.

BACKGROUND: Aberrant spliced isoforms are specifically associated with cancer progression and metastasis. The cytoplasmic adaptor CRKL (v-crk avian sarcoma virus CT10 oncogene homolog-like) is a CRK like proto-oncogene, which encodes a SH2 and SH3 (src homology) domain-containing adaptor protein. CRKL is tightly linked to leukemia via its binding partners BCR-ABL and TEL-ABL, upregulated in multiple types of human cancers, and induce cancer cell proliferation and invasion. However, it remains unclear whether signaling adaptors such as CRKL could regulate alternative splicing. METHODS: We analyzed the expression level of CRKL in 305 cervical cancer tissue samples available in TCGA database, and then selected two groups of cancer samples with CRKL differentially expressed to analyzed potential CRKL-regulated alternative splicing events (ASEs). CRKL was knocked down by shRNA to further study CRKL-regulated alternative splicing and the activity of SR protein kinases in HeLa cells using RNA-Seq and Western blot techniques. We validated 43 CRKL-regulated ASEs detected by RNA-seq in HeLa cells, using RT-qPCR analysis of HeLa cell samples and using RNA-seq data of the two group of clinical cervical samples. RESULTS: The expression of CRKL was mostly up-regulated in stage I cervical cancer samples. Knock-down of CRKL led to a reduced cell proliferation. CRKL-regulated alternative splicing of a large number of genes were enriched in cancer-related functional pathways, among which DNA repair and G2/M mitotic cell cycle, GnRH signaling were shared among the top 10 enriched GO terms and KEGG pathways by results from clinical samples and HeLa cell model. We showed that CRKL-regulated ASEs revealed by computational analysis using ABLas software in HeLa cell were highly validated by RT-qPCR, and also validated by cervical cancer clinical samples. CONCLUSIONS: This is the first report of CRKL-regulation of the alternative splicing of a number of genes critical in tumorigenesis and cancer progression, which is consistent with CRKL reported role as a signaling adaptor and a kinase. Our results underline that the signaling adaptor CRKL might integrate the external and intrinsic cellular signals and coordinate the dynamic activation of cellular signaling pathways including alternative splicing regulation.

NADPH Oxidase 2-Mediated Insult in the Auditory Cortex of Zucker Diabetic Fatty Rats.

Clinical data has confirmed that auditory impairment may be a secondary symptom of type 2 diabetes mellitus (T2DM). However, mechanisms underlying pathologic changes that occur in the auditory system, especially in the central auditory system (CAS), remain poorly understood. In this study, Zucker diabetic fatty (ZDF) rats were used as a T2DM rat model to observe ultrastructural alterations in the auditory cortex and investigate possible mechanisms underlying CAS damage in T2DM. The auditory brainstem response (ABR) of ZDF rats was found to be markedly elevated in low (8 kHz) and high (32 kHz) frequencies. Protein expression of NADPH oxidase 2 (NOX2) and its matching subunits P22phox, P47phox, and P67phox was increased in the auditory cortex of ZDF rats. Expression of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of DNA oxidative damage, was also increased in the neuronal mitochondria of the auditory cortex of ZDF rats. Additionally, decreases in the mitochondrial total antioxidant capabilities (T-AOC), adenosine triphosphate (ATP) production, and mitochondrial membrane potential (MMP) were detected in the auditory cortex of ZDF rats, suggesting mitochondrial dysfunction. Transmission electron microscopy results indicated that ultrastructural damage had occurred to neurovascular units and mitochondria in the auditory cortex of ZDF rats. Furthermore, cytochrome c (Cyt c) translocation from mitochondria to cytoplasm and caspase 3-dependent apoptosis were also detected in the auditory cortex of ZDF rats. Consequently, the study demonstrated that T2DM may cause morphological damage to the CAS and that NOX2-associated mitochondrial oxidative damage and apoptosis may be partly responsible for this insult.

Amide proton transfer weighted combined with diffusion kurtosis imaging for predicting lymph node metastasis in cervical cancer.

OBJECTIVE: To investigate the value of amide proton transfer weighted (APTw) combined with diffusion kurtosis imaging (DKI) in quantitative prediction of lymph node metastasis (LNM) in cervical carcinoma (CC). METHODS: Data of 19 LNM(+) and 50 LNM(-) patients with CC were retrospectively analyzed. 3.0 T MRI scan was performed before the operation, including APTw and DKI. After post-processing, quantitative magnetization transfer ratio asymmetric at 3.5 ppm [MTRasym (3.5 ppm)], mean kurtosis (MK), and mean diffusivity (MD) maps were obtained. The MTRasym(3.5 ppm), MK, and MD values were respectively measured by two observers, and intra-class correlation coefficients (ICC) were used to test the consistency of the results. The independent samples t-test or Mann-Whitney U test was used to compare the differences in the values of each parameter. The ROC curve was used to analyze the predictive performance of parameters with significant differences and their combination parameter. RESULTS: The two observers had good agreement in the measurement of each data (ICC > 0.75). The MTRasym(3.5 ppm) and MK values of the LNM(+) group(3.260 ± 0.538% and 0.531 ± 0.202) were higher than those of the LNM(-) group(2.698 ± 0.597% and 0.401 ± 0.148) (P < 0.05), while there was no significant difference in MD values between the two groups(P > 0.05). The area under the curves (AUCs) of MTRasym(3.5 ppm), MK value, and MTRasym(3.5 ppm) + MK value were 0.763, 0.716, and 0.813, respectively, when predicting LNM status of CC. CONCLUSION: APTw and DKI can quantitatively predict LNM status of CC, which is of importance in clinical diagnosis and treatment.

Two-pronged microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention for synergistic tumor immunotherapy.

Immunotherapy is an emerging treatment modality for tumors after surgery, radiotherapy, and chemotherapy. Despite the potential for eliminating primary tumor cells and depressing cancer metastasis, immunotherapy has huge challenges including low tumor immunogenicity and undesirable immunosuppressive tumor microenvironment (TME). Herein, the two-pronged microenvironmental modulation nanoplatform is developed to overcome these limitations. Specifically, hollow mesoporous MnO2 (HM) nanoparticles with pH responsive property are prepared and modified with glucose oxidase (GOX) by amide bond, which are further loaded with a potent glutaminase inhibitor CB839 to obtain HM-GOX/CB839. Under the low pH values in TME, HM was disintegrated, thereby releasing Mn2+, GOX and CB839. On the one hand, Mn2+ can convert H2O2 that increased by GOX catalysis in tumors into highly toxic hydroxyl radicals (•OH) and further induce immunogenic cell death (ICD) through the metal-oxidase cascade catalytic reaction, enhancing immunogenicity. On the other hand, GOX and CB839 can block glycolytic and glutamine metabolism pathways, respectively, which effectively reduce the number of immunosuppressive cells and reshape TME, improving anti-tumor immune efficacy. It is demonstrated that HM-GOX/CB839 can effectively activate the body's immunity and inhibit tumor growth and metastasis, providing a potential strategy for comprehensive tumor therapy. STATEMENT OF SIGNIFICANCE: Integrated microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention offers a potential avenue for tumor immunotherapy. Under this premise, we constructed a two-pronged microenvironmental modulation nanoplatform (HM-GOX/CB839). On the one hand, the metal oxidase cascade could catalyze the generation of hydroxyl radicals (•OH) and induce immunogenic cell death (ICD), enhancing immunogenicity; on the other hand, metabolic intervention reprogrammed tumor microenvironment to relieve immunosuppression and thereby enhancing anti-tumor immune response. The resulting data demonstrated that HM-GOX/CB839 effectively inhibited tumor growth and metastasis, providing therapeutic potential for cancer immunotherapy.

A biomimetic spore nanoplatform for boosting chemodynamic therapy and bacteria-mediated antitumor immunity for synergistic cancer treatment.

Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer. However, the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations. Furthermore, monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors. In this study, based on our discovery that spore shell (SS) of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity, we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy, chemodynamic therapy and antitumor immunity for synergistic cancer treatment. In detail, SS is separated from probiotic spores and then attached to the surface of liposome (Lipo) that was loaded with hemoglobin (Hb), glucose oxidase (GOx) and JQ1 to construct SS@Lipo/Hb/GOx/JQ1. In tumor tissue, highly toxic hydroxyl radicals (•OH) are generated via sequential catalytic reactions: GOx catalyzing glucose into H2O2 and Fe2+ in Hb decomposing H2O2 into •OH. The combination of •OH and SS adjuvant can improve tumor immunogenicity and activate immune system. Meanwhile, JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response. In this manner, SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis. To summarize, the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.

Acceleration of uterine 3D T2 weighted imaging by compressed SENSE--a multicenter study.

OBJECTIVES: To find the optimal acceleration factor (AF) of the compressed SENSE (CS) technique for uterine isotropic high-resolution 3D T2-weighted imaging (3D-ISO-T2WI). METHODS: A total of 91 female volunteers from the XXX, XXX and XXX were recruited. A total of 44 volunteers received uterus sagittal 3D-ISO-T2WI scans on 3.0 T MRI device with different CS AFs (including SENSE3, CS3, CS4, CS5, CS6, and CS7), 51 received 3D-ISO-T2WI scans with different degrees of fat suppression (none, light, moderate, and severe), while 4 volunteers received both series of scans. Image quality was subjectively evaluated with a three-point scoring system. Junction zone signal-to-noise ratio (SNR) and contrast to noise ratio (CNR) and myometrial SNR were also calculated. Intraclass correlation coefficients (ICC) were used to analyze the consistency of the measurement results by two observers. ANOVA test or Friedman rank sum test was used to compare the differences in subjective scores, SNR and CNR under different AFs/different degrees of fat suppression. RESULTS: Images by AFs of CS3, CS4, and CS5 had the highest SNR and CNR. Among them, CS5 had the shortest scan time. CS5 also had one of the highest subjective scores. There was no significant difference in SNR and CNR among images acquired with different degrees of fat suppression. Also, images with moderate fat suppression had the highest subjective scores. CONCLUSION: The CS5 combined with moderate fat suppression is recommended for routine female pelvic 3D-ISO-T2WI scan. ADVANCES IN KNOWLEDGE: The CS5 has the highest images quality and has the shortest scan time, which is the best AF. Moderate fat suppression has the highest subjective scores. The CS5 and moderate fat suppression are the best combination for female pelvic 3D-ISO-T2WI scan.

Diffusion kurtosis imaging with multiple quantitative parameters for predicting microsatellite instability status of endometrial carcinoma.

PURPOSE: To explore the value of Diffusion kurtosis imaging (DKI) with multiple quantitative parameters in predicting microsatellite instability (MSI) status in endometrial carcinoma (EC). METHODS: Data of 38 patients with EC were retrospectively analyzed, including 12 MSI and 26 microsatellite stability (MSS). All patients underwent preoperative 1.5T MR examination. The quantitative values of the DKI sequence in the tumor parenchyma of the two groups, including mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr), fractional anisotropy (FA), fractional anisotropy of kurtosis (FAk), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr) were measured by two observers, respectively. RESULTS: The MK, Ka, Kr, FA, FAk, MD, Da, and Dr values of the MSI group were 1.074 ± 0.162, 1.253 ± 0.229, 0.886 ± 0.205, 0.207 ± 0.041, 0.397 ± 0.129, 0.890 ± 0.158 µm2/ms, 1.083 ± 0.218 µm2/ms, and 0.793 ± 0.133 µm2/ms, and 0.956 (0.889,1.002), 1.048 ± 0.211, 0.831 ± 0.099, 0.188 ± 0.061, 0.334 (0.241,0.410), 1.043 ± 0.217 µm2/ms, 1.235 ± 0.229 µm2/ms, and 0.946 ± 0.215 µm2/ms in the MSS group. The MK and Ka values of the MSI group were higher than those of the MSS group (P<0.05), while the MD and Dr values were lower than those of the MSS group (P<0.05). The AUC of MK, Ka, MD, and Dr values in predicting MSI status of EC was 0.763, 0.729, 0.731, 0.748, respectively. The sensitivity was 58.3%, 50.0%, 65.4%, 61.5%, and the specificity was 96.2%, 92.3%, 75.0%, 83.3%, respectively. CONCLUSION: DKI can provide multiple quantitative parameters for predicting the MSI status of EC, and assist gynecologist to optimize the treatment plan for the patients.

Dynamic regulation of drug biodistribution by turning tumors into decoys for biomimetic nanoplatform to enhance the chemotherapeutic efficacy of breast cancer with bone metastasis.

Breast cancer with bone metastasis accounts for serious cancer-associated pain which significantly reduces the quality of life of affected patients and promotes cancer progression. However, effective treatment using nanomedicine remains a formidable challenge owing to poor drug delivery efficiency to multiple cancer lesions and inappropriate management of cancer-associated pain. In this study, using engineered macrophage membrane (EMM) and drugs loaded nanoparticle, we constructed a biomimetic nanoplatform (EMM@DJHAD) for the concurrent therapy of bone metastatic breast cancer and associated pain. Tumor tropism inherited from EMM provided the targeting ability for both primary and metastatic lesions. Subsequently, the synergistic combination of decitabine and JTC801 boosted the lytic and inflammatory responses accompanied by a tumoricidal effect, which transformed the tumor into an ideal decoy for EMM, resulting in prolonged troop migration toward tumors. EMM@DJHAD exerted significant effects on tumor suppression and a pronounced analgesic effect by inhibiting µ-opioid receptors in bone metastasis mouse models. Moreover, the nanoplatform significantly reduced the severe toxicity induced by chemotherapy agents. Overall, this biomimetic nanoplatform with good biocompatibility may be used for the effective treatment of breast cancer with bone metastasis.

Orchestrating antigen delivery and presentation efficiency in lymph node by nanoparticle shape for immune response.

Activating humoral and cellular immunity in lymph nodes (LNs) of nanoparticle-based vaccines is critical to controlling tumors. However, how the physical properties of nanovaccine carriers orchestrate antigen capture, lymphatic delivery, antigen presentation and immune response in LNs is largely unclear. Here, we manufactured gold nanoparticles (AuNPs) with the same size but different shapes (cages, rods, and stars), and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas. Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes. On lymphatic delivery, both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention. A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity, which is mediated by CD4+ T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study. Interestingly, cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8+ T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study. These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs, and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.

Multi-parametric MRI-based radiomics for preoperative prediction of multiple biological characteristics in endometrial cancer.

Purpose: To develop and validate multi-parametric MRI (MP-MRI)-based radiomics models for the prediction of biological characteristics in endometrial cancer (EC). Methods: A total of 292 patients with EC were divided into LVSI (n = 208), DMI (n = 292), MSI (n = 95), and Her-2 (n = 198) subsets. Total 2316 radiomics features were extracted from MP-MRI (T2WI, DWI, and ADC) images, and clinical factors (age, FIGO stage, differentiation degree, pathological type, menopausal state, and irregular vaginal bleeding) were included. Intra-class correlation coefficient (ICC), spearman's rank correlation test, univariate logistic regression, and least absolute shrinkage and selection operator (LASSO) were used to select radiomics features; univariate and multivariate logistic regression were used to identify clinical independent risk factors. Five classifiers were applied (logistic regression, random forest, decision tree, K-nearest neighbor, and Bayes) to construct radiomics models for predicting biological characteristics. The clinical model was built based on the clinical independent risk factors. The combined model incorporating the radiomics score (radscore) and the clinical independent risk factors was constructed. The model was evaluated by ROC curve, calibration curve (H-L test), and decision curve analysis (DCA). Results: In the training cohort, the RF radiomics model performed best among the five classifiers for the three subsets (MSI, LVSI, and DMI) according to AUC values (AUCMSI: 0.844; AUCLVSI: 0.952; AUCDMI: 0.840) except for Her-2 subset (Decision tree: AUC=0.714), and the combined model had higher AUC than the clinical model in each subset (MSI: AUCcombined =0.907, AUCclinical =0.755; LVSI: AUCcombined =0.959, AUCclinical =0.835; DMI: AUCcombined = 0.883, AUCclinical =0.796; Her-2: AUCcombined =0.812, AUCclinical =0.717; all P<0.05). Nevertheless, in the validation cohort, significant differences between the two models (combined vs. clinical model) were found only in the DMI and LVSI subsets (DMI: AUCcombined =0.803, AUCclinical =0.698; LVSI: AUCcombined =0.926, AUCclinical =0.796; all P<0.05). Conclusion: The radiomics analysis based on MP-MRI and clinical independent risk factors can potentially predict multiple biological features of EC, including DMI, LVSI, MSI, and Her-2, and provide valuable guidance for clinical decision-making.

MRI outcome evaluation in patients with IB2 and IIA2 squamous cervical cancer stages: preliminary results.

OBJECTIVES: To evaluate the therapeutic effect of neoadjuvant therapy (NAT) followed by radical hysterectomy and concurrent chemoradiotherapy (CCRT) in stage IB2 and IIA2 squamous cervical cancer (SCC) and investigate the value of apparent diffusion coefficient (ADC) in outcome evaluation of different treatment strategies in the patients. METHODS: A total of 149 patients with IB2 and IIA2 SCC who underwent pretreatment MRI and DWI scan were included. Patients were treated with NAT + RH or CCRT. Clinical indices and pathological factors were recorded. The imaging indices were measured including tumor size and tumor ADC values. Intraclass correlation coefficient was employed to evaluate the consistency of the indices measured by two observers. ROC curves were used to evaluate the cutoff values of clinical and imaging indices. Kaplan-Meier and Cox proportional hazard model were used to analyze the independent factors of disease-free survival (DFS). RESULTS: The median follow-up period was 42.3 months. SCC-Ag, ADCmax and ADCmin were independent factors for DFS in the entire cohort. SCC-Ag, ADCmin and vascular invasion were independent factors for DFS in NAT + RH group. ADCmax and ADCmin were independent factors for DFS in CCRT group. ADCmin was the strongest independent factor for DFS in NAT + RH group, while ADCmax was that in CCRT group. CONCLUSION: The NAT + RH patients had similar DFS to that of CCRT in IB2 and IIA2 SCC, which could be a potential feasible alternative treatment. ADCmin and ADCmax were more valuable in evaluating the outcome of patients who underwent NAT + RH or CCRT, respectively.

Pelvic bones ADC could help to predict severe hematologic toxicity in patients undergoing concurrent chemoradiotherapy for cervical cancer.

BACKGROUND: Hematologic toxicity (HT) during concurrent chemoradiotherapy (CCRT) for cervical cancer can lead to treatment breaks and compromise efficacy. PURPOSE: To evaluate the association between severe hematologic toxicity (HT) and clinical factors and pelvic apparent diffusion coefficient (ADC) during CCRT of cervical cancer patients. METHODS: Data from 120 patients with cervical cancer who were treated with CCRT from January 2016 and December 2018 were retrospectively analyzed. The clinical data (age, menopausal status, clinical stage, body mass index, chemotherapy regimen and chemotherapy cycle) of the patients were collected, and the cohort were divided into two groups based on the HT grade: HT3+ group (HT grade ≥ 3; 66 patients) and HT3- group (HT grade<3; 54 patients). All patients performed MRI before CCRT, and pelvic (ilium, pubis, ischium) ADC value was measured on ADC map. The correlation between severe HT and clinical parameters and pelvic ADC value were analyzed by univariate analysis, and the diagnostic performance was further assessed by receiver operating characteristic (ROC) analysis. RESULTS: In univariate analysis, the menopausal status (p = 0.012) and chemotherapy regimen (p = 0.011) were significantly correlated with severe HT in overall patients, and menopausal patients or patients receiving paclitaxel plus cisplatin (TP) regimen were more likely to develop severe HT. HT3+ group showed a significantly lower pelvic ADC value than HT3- group. The ADC value cut-offs derived from our study for predicting severe HT was 0.317 × 10-3 mm2/s in overall patients. Neither clinical parameters nor pelvic ADCs were associated with severe HT in menopausal patients when analyzed separately (p > 0.05). CONCLUSIONS: Severe HT was significantly associated with menopausal status and chemotherapy regimen in patients with cervical cancer treated with CCRT, and HT3+ group showed a lower pelvic ADC value.

Value of MRI and diffusion-weighted imaging in diagnosing normal-sized pelvic lymph nodes metastases in patients with cervical cancer.

OBJECTIVES: To investigate the value of conventional MRI and diffusion-weighted imaging (DWI) in diagnosing normal-sized pelvic lymph nodes metastases in patients with cervical cancer. METHODS: 102 patients with cervical cancer who underwent MRI and DWI scan were included. 137 lymph nodes were analyzed, including 44 metastatic lymph nodes (MLNs) and 93 non-metastatic lymph nodes (non-MLNs). The morphology and apparent diffusion coefficient (ADC) value of lymph nodes were measured including short-axis diameter (DS), long-axis diameter (DL), ratio of short-to-long-axis diameter (DR), fatty hilum, asymmetry, ADCmax, ADCmean and ADCmin. The Mann-Whitney U-test, independent sample t-test and Chi-square test were employed to compare the differences of all criteria between MLNs and non-MLNs. Logistic regression and decision tree were used to develop the combined diagnostic model. ROC analyses were used to evaluate the diagnostic performance. RESULTS: The DS and DR of MLNs were significantly higher than those of non-MLNs (p < 0.05), the ADCmax, ADCmean and ADCmin of MLNs were significantly lower than those of non-MLNs (p < 0.05). Presence of fatty hilum and asymmetric lymph nodes between MLNs and non-MLNs were significantly different (p＜0.05). Combined measurement of ADCmin, DS and DR had the highest AUC 0.937 with 90.9% sensitivity and 87.1% specificity. The accuracy of decision tree was 88.3%. CONCLUSION: MRI with DWI had potential in diagnosing normal-sized pelvic lymph nodes metastases in patients with cervical cancer. The combined evaluation of DS, DR and ADCmin of lymph nodes and decision tree of the combined measure showed better diagnostic performances than sole criteria. ADVANCES IN KNOWLEDGE: The short-axis diameter, ratio of short-to-long-axis diameter and ADCmin of lymph nodes have moderate value in the diagnosis of the metastases of the normal-sized lymph nodes for the patient with cervical cancer as the sole indices. The combined evaluation of DS, DR and ADCmin is much more valuable in the detection of metastatic lymph nodes.

Hyperthermia based individual in situ recombinant vaccine enhances lymph nodes drainage for de novo antitumor immunity.

The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes (LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin (SV) adjuvant loaded Au nanocages (AuNCs) as cores (AuNCs/SV) and folic acid modified thermal-sensitive liposomes (FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy (PTT) induced the release of tumor-derived protein antigens (TDPAs) and the shedding of FA-TSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine (AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.

Amide proton transfer weighted imaging combined with dynamic contrast-enhanced MRI in predicting lymphovascular space invasion and deep stromal invasion of IB1-IIA1 cervical cancer.

Objectives: To investigate the value of amide proton transfer weighted (APTw) imaging combined with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting intermediate-risk factors of deep stromal invasion (DSI) and lymphovascular vascular space invasion (LVSI) in cervical cancer. Methods: Seventy patients with cervical cancer who underwent MRI before operation from July 2019 to February 2022 were retrospectively included in this study. Clinical information including age, histologic subtype etc. were recorded for patients. ATPw imaging parameter APTmean and DCE-MRI parameters Ktrans, Kep and Ve were measured and analyzed. The independent-sample t-test, Mann-Whitney U test, or Chi-square test was used to compare the differences of parameters between DSI/LVSI positive and negative groups. Logistic analysis was used to develop a combined predictive model. The receiver operating characteristic curve was for predictive performance. ANOVA and Kruskal-Wallis test were used to compare the differences of consecutive parameters among multiple groups. Results: Ktrans and SCC-Ag were independent factors in predicting DSI; Ktrans+SCC-Ag had the highest AUC 0.819 with sensitivity and specificity of 71.74% and 91.67%, respectively. APTmean and Ktrans were independent factors in predicting LVSI; APTmean+Ktrans had the highest AUC 0.874 with sensitivity and specificity of 92.86% and 75.00%, respectively. Ktrans and Ve could discriminate coexistence of DSI and LVSI from presence of single one, APTmean could discriminate the presence of DSI or LVSI from no risk factor presence. Conclusion: The combination of APTw and DCE-MRI is valuable in predicting intermediate-risk factors of DSI and LVSI in cervical cancer.

MRI-based radiomics nomogram for the preoperative prediction of deep myometrial invasion of FIGO stage I endometrial carcinoma.

BACKGROUND: Endometrial carcinoma (EC) is one of the most common gynecological malignancies with an increasing incidence, and an accurate preoperative diagnosis of deep myometrial invasion (DMI) is crucial for personalized treatment. OBJECTIVE: To determine the predictive value of a magnetic resonance imaging (MRI)-based radiomics nomogram for the presence of DMI in the International Federation of Gynecology and Obstetrics (FIGO) stage I EC. METHODS: We retrospectively collected 163 patients with pathologically confirmed stage I EC from two centers and divided all samples into a training group (Center 1) and a validation group (Center 2). Clinical and routine imaging indicators were analyzed by logistical regression to construct a conventional diagnostic model (M1). Radiomics features extracted from the axial T2-weighted and axial contrast-enhanced T1-weighted (CE-T1W) images were treated with the intraclass correlation coefficient, Mann-Whitney U test, least absolute shrinkage and selection operator, and logistic regression analysis with Akaike information criterion to build a combined radiomics signature (M2). A nomogram (M3) was constructed by M1 and M2. Calibration and decision curves were drawn to evaluate the nomogram in the training and validation cohorts. The diagnostic performance of each indicator and model was evaluated by the area under the receiver operating characteristic curve (AUC). RESULT: The four most significant radiomics features were finally selected from the CE-T1W MRI. For the diagnosis of DMI, the AUCT /AUCV of M1 was 0.798/0.738, the AUCT /AUCV of M2 was 0.880/0.852, and the AUCT /AUCV of M3 was 0.936/0.871 in the training and validation groups, respectively. The calibration curves showed that M3 was in good agreement with the ideal values. The decision curve analysis suggested potential clinical application values of the nomogram. CONCLUSION: A nomogram based on MRI radiomics and clinical imaging indicators can improve the diagnosis of DMI in patients with FIGO stage I EC.