The value of multiparametric MRI combined with clinical prognostic parameters in predicting the 5-year survival of stage IIIC1 cervical squamous cell carcinoma.

OBJECTIVES: To explore the value of multiparametric magnetic resonance imaging（MRI）in predicting the 5-year progression-free survival (PFS) and overall survival (OS) of cervical squamous cell carcinoma (CSCC) in 2018 FIGO stage IIIC1. METHODS: This retrospective study collected156 patients with CSCC from Dec. 2014 to Jul. 2018. Sixty-one patients underwent radical hysterectomy (RH), and 95 patients underwent concurrent chemoradiotherapy (CCRT). Clinical and MR parameters of primary tumours were analysed. A 1:1 ratio propensity score matching (PSM) was performed for the RH group and CCRT group according to T stage. The Cox proportional hazard model was used to evaluate the associations between imaging or clinical variables and PFS and OS. RESULTS: The 5-year PFS and OS rates were 72.6% and 78.3%, respectively. The analysis results show that the treatment method, ADCmin < 0.604 × 10-3 mm2/s, and Ktrans < 0.699 min-1 correlated with worse PFS, while SCC-Ag > 6.7 ng/L, ADCmin < 0.604 × 10-3 mm2/s, and Ktrans < 0.699 min-1 correlated with worse OS. After PSM, we confirmed that the treatment methods did not affect the long-term survival of patients with stage IIIC1 disease, and a low Ktrans value was an independent poor prognostic factor. CONCLUSION: Functional MRI parameters and SCC-Ag have potential predictive value for the 5-year survival of 2018 FIGOIIIC1 CSCC. There were no significant differences in survival between CCRT and RH + adjuvant therapy for IIIC1 stage CSCC if the T stage was earlier.

Tianhuang formula reduces the oxidative stress response of NAFLD by regulating the gut microbiome in mice.

Background: The gut microbiome affects the occurrence and development of NAFLD, but its mechanism has not yet been fully elucidated. Chinese medicine is a new treatment strategy to improve NAFLD by regulating the gut microbiome. Tianhuang formula (TH) has been proved to have a lipid-lowering effect in which constituents of ginsenoside Rb1, ginsenoside Rg1, ginsenoside Rb, ginsenoside Re, and ginsenoside R1 from Panax notoginseng and berberine, palmatine, and coptisine from Coptis chinensis have low drug permeability, which results in poor intestinal absorption into the human body, and are thus able to come into contact with the gut microflora for a longer time. Therefore, it might be able to influence the gut microbial ecosystem, but it still needs to be investigated. Method: The characteristics of the gut microbiome were represented by 16S rRNA sequencing, and the metabolites in intestinal contents and liver were discovered by non-targeted metabolomics. Correlation analysis and fermentation experiments revealed the relationship between the gut microbiome and metabolites. Blood biochemical indicators, liver function indicators, and oxidation-related indicators were assayed. H&E staining and Oil Red O staining were used to analyze the characteristics of hepatic steatosis. RT-qPCR and western blotting were used to detect the expression of genes and proteins in liver tissues, and fecal microbial transplantation (FMT) was performed to verify the role of the gut microbiome. Results: Gut microbiome especially Lactobacillus reduced, metabolites such as 5-Methoxyindoleacetate (5-MIAA) significantly reduced in the liver and intestinal contents, the level of hepatic GSH and SOD reduced, MDA increased, and the protein expression of Nrf2 also reduced in NAFLD mice induced by high-fat diet (HFD). The normal diet mice transplanted with NAFLD mice feces showed oxidative liver injury, indicating that the NAFLD was closely related to the gut microbiome. TH and TH-treated mice feces both can reshape the gut microbiome, increase the abundance of Lactobacillus and the content of 5-MIAA in intestinal contents and liver, and improve oxidative liver injury. This indicated that the effect of TH improving NAFLD was related to the gut microbiome, especially Lactobacillus. 5-MIAA, produced by Lactobacillus, was proved with fermentation experiments in vitro. Further experiments proved that 5-MIAA activated the Nrf2 pathway to improve oxidative stress in NAFLD mice induced by HFD. TH reshaped the gut microbiome, increased the abundance of Lactobacillus and its metabolite 5-MIAA to alleviate oxidative stress, and improved NAFLD. Conclusion: The study has demonstrated a mechanism by which the gut microbiome modulated oxidative stress in NAFLD mice induced by HFD. The traditional Chinese medicine TH improved NAFLD by regulating the gut microbiome, and its mechanism was related to the "Lactobacillus-5-MIAA-Nrf2" pathway. It provided a promising way for the intervention of NAFLD.

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.

Treatment Strategies and Prognostic Factors of 2018 FIGO Stage IIIC Cervical Cancer: A Review.

Cervical cancer is the fourth most common malignant tumor globally in terms of morbidity and mortality. The presence of lymph node metastasis (LNM) is an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in cervical cancer patients. The International Federation of Gynecology and Obstetrics (FIGO) staging system was revised in 2018. An important revision designates patients with regional LNM as stage IIIC, pelvic LNM only as stage IIIC1, and para-aortic LNM as stage IIIC2. However, the current staging system is only based on the anatomical location of metastatic lymph nodes (LNs). It does not consider other LN status parameters, which may limit its prognostic significance to a certain extent and needs further exploration and confirmation in the future. The purpose of this review is to summarize the choice of treatment for stage IIIC cervical cancer and the effect of different LN status parameters on prognosis.

Combined dynamic contrast enhanced MRI parameter with clinical factors predict the survival of concurrent chemo-radiotherapy in patients with 2018 FIGO IIICr stage cervical cancer.

PURPOSE: Combined clinical prognostic factors and magnetic resonance imaging (MRI) parameters on predicting the prognosis after concurrent chemo-radiotherapy (CCRT)in patients with 2018 International Federation of Gynecology and Obstetrics (FIGO) IIICr stage patients. METHODS: A total of 117 patients with cervical cancer (2018 FIGO stage IIICr) who underwent CCRT were enrolled from Dec.2014 to Jul.2017. 47 patients developed outcome events, including 32 recurrences and 15 deaths. Clinical and MR parameters of primary tumors were analyzed, including apparent diffusion coefficient (ADC) values (ADCmean, ADCmin, and ADCmax) and dynamic contrast-enhanced MRI (DCE-MRI) parameters (Ktrans, Kep, Ve) were recorded. The short diameters of visible lymph nodes in the MRI and enhanced computed tomography (CT) images were measured. Progression-free survival (PFS) was compared by Kaplan-Meier analysis and independent predictors were identified using cox regression analysis. RESULTS: The median PFS was 35 months (6-68 month). The 1-year and 3-year PFS rates were was 90.4 %, 74.4 %, respectively. Multivariate analysis showed that 2018 FIGOIIIC2r stage (HR 2.701,95 %CI1.259to. 5.797; p = 0.011), Ktrans(HR 0.353;95 %CI 0.189 to 0.659; p = 0.001) and ADCmin (HR0.423,95 %CI0.229to0.783; p = 0.006) were highly correlated with poor PFS. CONCLUSION: In conclusion, we have identified IIIC2r stage, Ktrans value and ADCmin value as the most important factors in evaluating the survival rate and prognosis of patients with stage IIICr cervical cancer. For stage IIIC1r subgroup, Ktrans, ADCmin value and site of positive lymph node >2 were independent prognostic factors.

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.

Gut microbiota combined with metabolomics reveals the metabolic profile of the normal aging process and the anti-aging effect of FuFang Zhenshu TiaoZhi(FTZ) in mice.

The aging process is accompanied by changes in the gut microbiota and metabolites. This study aimed to reveal the relationship between gut microbiota and the metabolome at different ages, as well as the anti-aging effect of FTZ, which is an effective clinical prescription for the treatment of hyperlipidemia and diabetes. METHODS: In the present study, mice were randomly divided into different age and FTZ treatment groups. The aging-relevant behavioral phenotype the levels of blood glucose, cholesterol, triglycerides, low density lipoprotein cholesterol, free fatty acids, high density lipoprotein-cholesterol and cytokine TNF-α,IL-6, IL-8 in the serum were measured. Changes of serum metabolties were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-Q-TOF/MS). Gut microbiota were identified using 16S rDNA sequencing. RESULTS: Our results indicated that with age, the aging-relevant behavioral phenotype appeared, glucose and lipid metabolism disordered, secretion levels of cytokine TNF-α, IL-6 and IL-8 increased.The Firmicutes/Bacteroidetes ratio changed with age, first increasing and then decreasing, and the microbial diversity and the community richness of the aging mice were improved by FTZ. The abundance of opportunistic bacteria decreased (Lactobacillus murinus, Erysipelatoclostridium), while the levels of protective bacteria such as Butyricimonas, Clostridium and Akkermansia increased. Metabolic analysis identified 24 potential biomarkers and 10 key pathways involving arachidonic acid metabolism, phospholipid metabolism, fatty acid metabolism, taurine and hypotaurine metabolism. Correlation analysis between the gut microbiota and biomarkers suggested that the relative abundance of protective bacteria was negatively correlated with the levels of leukotriene E4, 20-HETE and arachidonic acid, which was different from protective bacteria. CONCLUSION: Shifts of gut microbiota and metabolomic profiles were observed in the mice during the normal aging process, and treatment with FTZ moderately corrected the aging, which may be mediated via interference with arachidonic acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, taurine and hypotaurine metabolism and gut microbiota in mice.

Study on Metabolic Trajectory of Liver Aging and the Effect of Fufang Zhenzhu Tiaozhi on Aging Mice.

The aim of this study was to investigate the metabolic trajectory of liver aging, the effect of FTZ against liver aging in aging mice, and its mechanism using ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Methods: A total of 80 C57BL/6J Narl mice were randomly divided into five groups: 3-month-old group, 9-month-old group, 14-month-old group, 20-month-old group, and FTZ treatment group (20 months old). The mice in the treatment group received a therapeutic dose of oral FTZ extract (1.0 g/kg, on raw material weight basis) once daily during the experiment. The other groups received the corresponding volume of oral normal saline solution. Liver samples of all five groups were collected after 12 weeks, and UPLC-Q-TOF/MS was used to analyze metabolic changes. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to analyze the resulting data. Additionally, cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), secretion levels of TNF-α, IL-6, 5-LOX, and COX-2, as well as their relative mRNA expression in the liver were determined. Results: The levels of TC, TG, AST, and ALT were increased, and liver tissue structure was damaged. The secretion levels of TNF-α, IL-6, 5-LOX, and COX-2, as well as their relative mRNA expression in the liver also increased with aging. FTZ administration reduced the symptoms of liver aging. The OPLS-DA score plot illustrated the effect of FTZ against liver aging, with N-acetyl-leukotriene E4, 20-hydroxy-leukotriene E4, leukotriene E4, and arachidonic acid among the key biomarkers. The pivotal pathways revealed by pathway analysis included arachidonic acid metabolism and biosynthesis of unsaturated fatty acids. The mechanism by which FTZ reduces the symptoms of liver aging in mice might be related to disorders of the abovementioned pathways. Conclusion: A metabolomic approach based on UPLC-Q-TOF/MS and multivariate statistical analysis was successfully applied to investigate the metabolic trajectory of liver aging. FTZ has a protective effect against liver aging, which may be mediated via interference with the metabolism of arachidonic acid, biosynthesis of unsaturated fatty acids, and downregulation of pro-inflammatory factors in the liver in mice in vivo.