Prognosis prediction and risk stratification of transarterial chemoembolization or intraarterial chemotherapy for unresectable hepatocellular carcinoma based on machine learning.

OBJECTIVE: To develop and validate a risk scoring scale model (RSSM) for stratifying prognostic risk after intra-arterial therapies (IATs) for hepatocellular carcinoma (HCC). METHODS: Between February 2014 and October 2022, 2338 patients with HCC who underwent initial IATs were consecutively enrolled. These patients were divided into training datasets (TD, n = 1700), internal validation datasets (ITD, n = 428), and external validation datasets (ETD, n = 200). Five-years death was used to predict outcome. Thirty-four clinical information were input and five supervised machine learning (ML) algorithms, including eXtreme Gradient Boosting (XGBoost), Categorical Gradient Boosting (CatBoost), Gradient Boosting Decision Tree (GBDT), Light Gradient Boosting Machine (LGBT), and Random Forest (RF), were compared using the areas under the receiver operating characteristic (AUC) with DeLong test. The variables with top important ML scores were used to build the RSSM by stepwise Cox regression. RESULTS: The CatBoost model achieved the best discrimination when 12 top variables were input, with the AUC of 0.851 (95% confidence intervals (CI), 0.833-0.868) for TD, 0.817 (95%CI, 0.759-0.857) for ITD, and 0.791 (95%CI, 0.748-0.834) for ETD. The RSSM was developed based on the immune checkpoint inhibitors (ICI) (hazard ratios (HR), 0.678; 95%CI 0.549, 0.837), tyrosine kinase inhibitors (TKI) (HR, 0.702; 95%CI 0.605, 0.814), local therapy (HR, 0.104; 95%CI 0.014, 0.747), response to the first IAT (HR, 4.221; 95%CI 2.229, 7.994), tumor size (HR, 1.054; 95%CI 1.038, 1.070), and BCLC grade (HR, 2.375; 95%CI 1.950, 2.894). Kaplan-Meier analysis confirmed the role of RSSM in risk stratification (p < 0.001). CONCLUSIONS: The RSSM can stratify accurately prognostic risk for HCC patients received IAT. On the basis, an online calculator permits easy implementation of this model. CLINICAL RELEVANCE STATEMENT: The risk scoring scale model could be easily implemented for physicians to stratify risk and predict prognosis quickly and accurately, thereby serving as a more favorable tool to strengthen individualized intra-arterial therapies and management in patients with unresectable hepatocellular carcinoma. KEY POINTS: • The Categorical Gradient Boosting (CatBoost) algorithm achieved the optimal and robust predictive ability (AUC, 0.851 (95%CI, 0.833-0.868) in training datasets, 0.817 (95%CI, 0.759-0.857) in internal validation datasets, and 0.791 (95%CI, 0.748-0.834) in external validation datasets) for prediction of 5-years death of hepatocellular carcinoma (HCC) after intra-arterial therapies (IATs) among five machine learning models. • We used the SHapley Additive exPlanations algorithms to explain the CatBoost model so as to resolve the black boxes of machine learning principles. • A simpler restricted variable, risk scoring scale model (RSSM), derived by stepwise Cox regression for risk stratification after intra-arterial therapies for hepatocellular carcinoma, provides the potential forewarning to adopt combination strategies for high-risk patients.

Postprogression treatment of lenvatinib plus PD-1 inhibitor in advanced hepatocellular carcinoma refractory to hepatic arterial infusion chemotherapy.

PURPOSE: This study compares the efficacy and safety of lenvatinib and programmed cell death protein (PD)-1 versus lenvatinib alone for advanced hepatocellular carcinoma (Ad-HCC) refractory to hepatic arterial infusion chemotherapy (HAIC). METHODS: From April 2016 to September 2021, 145 patients with Ad-HCC refractory to HAIC based on modified Response Evaluation Criteria in Solid Tumors criteria were enrolled by two radiologists and classified into the HAIC-lenvatinib group (H-L, n = 87) and HAIC-lenvatinib-PD-1 group (H-L-P, n = 58). A propensity score-matching method was used to reduce selective bias. The overall survival (OS) and postprogression-free survival (PPS) rates were compared using the Kaplan-Meier method with log-rank test. Multivariable analyses of independent prognostic factors were evaluated by means of the forward stepwise Cox regression model. RESULTS: After propensity score matching 1:1, the median OS was 43.6 months in the H-L-P group and was significantly longer than that (18.9 months) of the H-L group (p = .009). The median PPS was 35.6 months in the H-L-P group and was significantly longer than that (9.4 months) of the H-L group (p = .009). Multivariate analyses showed that the factors that significantly affected the OS were α-fetoprotein (hazard ratio [HR], 2.14; 95% CI, 1.26-3.98; p = .006), early response to HAIC (HR, 0.44; 95% CI, 1.20-3.85; p = .009), and H-L treatment (HR, 0.52; 95% CI, 0.30-0.86; p = .012). Modified albumin-bilirubin grade (HR, 1.32; 95% CI, 1.03-1.70; p = .026), early response to HAIC (HR, 0.44; 95% CI, 0.25-0.77; p = .004), and H-L (HR, 0.47 ; 95% CI, 0.28-0.78; p = .003) significantly affected the PPS. CONCLUSIONS: This combination therapy of PD-1 inhibitors plus lenvatinib has promising survival benefits in the management of patients with Ad-HCC refractory to HAIC. PLAIN LANGUAGE SUMMARY: Lenvatinib plus programmed death 1 inhibitor is an effective and safe postprogression treatment and improved significantly overall survival and postprogression-free survival compared with lenvatinib alone in patients with advanced hepatocellular carcinoma refractory to hepatic arterial infusion chemotherapy.

The impact of erythroblast enucleation efficiency on the severity of anemia in patients with myelodysplastic syndrome.

Anemia is the most common manifestation in myelodysplastic syndrome (MDS) patients, but the cause of ineffective hematopoiesis is not fully understood. Enucleation is an important event in the maturation process of erythroblasts. According to a series of morphological phenotypes of the pathological development of MDS erythroblasts, we speculate that there may be enucleation disorders. To verify this hypothesis, we cultured MDS bone marrow CD34+ cells in vitro and induced erythroblast development. The results showed that erythroblast enucleation in MDS was significantly lower than that in the normal group, and the rate of enucleation was positively correlated with hemoglobin concentration. Risk stratification of MDS was performed to further analyze the differences in enucleation among the normal group, low-middle risk group and high-risk group. The results showed that the enucleation rate of the high risk group was higher than that of the low-middle risk group but still lower than that of the normal group. Moreover, the expression of pERK and pAKT in MDS erythroblasts in the high risk group was higher than that in the normal group, while the expression of pERK and pAKT in the low-middle risk group was lower than that in the normal group. Furthermore, the enucleation of MDS was positively correlated with the phosphorylation degree of ERK and AKT. In conclusion, this study reveals that the enucleation of erythroblasts is one of the possible causes of anemia in MDS. Video Abstract.

Automatic prediction of hepatic arterial infusion chemotherapy response in advanced hepatocellular carcinoma with deep learning radiomic nomogram.

OBJECTIVES: Hepatic arterial infusion chemotherapy (HAIC) using the FOLFOX regimen (oxaliplatin plus fluorouracil and leucovorin) is a promising option for advanced hepatocellular carcinoma (Ad-HCC). As identifying patients with Ad-HCC who would obtain objective response (OR) to HAIC preoperatively remains a challenge, we aimed to develop an automatic and non-invasive model for predicting HAIC response. METHODS: A total of 458 patients with Ad-HCC who underwent HAIC were retrospectively included from three hospitals (310 for training, 77 for internal validation, and 71 for external validation). The deep learning and radiomic features were extracted from the automatically segmented liver region on contrast-enhanced computed tomography images. Then, a deep learning radiomic nomogram (DLRN) was constructed by integrating deep learning scores, radiomic scores, and significant clinical variables with multivariate logistic regression. Model performance was assessed by AUC and Kaplan-Meier estimator. RESULTS: After automatic segmentation, only a few modifications were needed (less than 30 min for 458 patients). The DLRN achieved an AUC of 0.988 in the training cohort, 0.915 in the internal validation cohort, and 0.896 in the external validation cohort, respectively, outperforming other models in HAIC response prediction. Moreover, survival risk stratification was also successfully performed by the DLRN. The overall survival (OS) of the predictive OR group was significantly longer than that of the predictive non-OR group (median OS: 26.0 vs. 12.3 months, p < 0.001). CONCLUSIONS: The DLRN provided a satisfactory performance for predicting HAIC response, which is essential to identify Ad-HCC patients for HAIC and may potentially benefit personalized pre-treatment decision-making. CLINICAL RELEVANCE STATEMENT: This study presents an accurate and automatic method for predicting response to hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma, and therefore help in defining the best candidates for this treatment. KEY POINTS: • Deep learning radiomic nomogram (DLRN) based on automatic segmentation of CECT can accurately predict hepatic arterial infusion chemotherapy (HAIC) response of advanced HCC patients. • The proposed prediction model can perform survival risk stratification and is an easy-to-use tool for personalized pre-treatment decision-making for advanced HCC patients.

A multitask deep learning radiomics model for predicting the macrotrabecular-massive subtype and prognosis of hepatocellular carcinoma after hepatic arterial infusion chemotherapy.

BACKGROUND: The macrotrabecular-massive (MTM) is a special subtype of hepatocellular carcinoma (HCC), which has commonly a dismal prognosis. This study aimed to develop a multitask deep learning radiomics (MDLR) model for predicting MTM and HCC patients' prognosis after hepatic arterial infusion chemotherapy (HAIC). METHODS: From June 2018 to March 2020, 158 eligible patients with HCC who underwent surgery were retrospectively enrolled in MTM related cohorts, and 752 HCC patients who underwent HAIC were included in HAIC related cohorts during the same period. DLR features were extracted from dual-phase (arterial phase and venous phase) contrast-enhanced computed tomography (CECT) of the entire liver region. Then, an MDLR model was used for the simultaneous prediction of the MTM subtype and patient prognosis after HAIC. The MDLR model for prognostic risk stratification incorporated DLR signatures, clinical variables and MTM subtype. FINDINGS: The predictive performance of the DLR model for the MTM subtype was 0.968 in the training cohort [TC], 0.912 in the internal test cohort [ITC] and 0.773 in the external test cohort [ETC], respectively. Multivariable analysis identified portal vein tumor thrombus (PVTT) (p = 0.012), HAIC response (p < 0.001), HAIC sessions (p < 0.001) and MTM subtype (p < 0.001) as indicators of poor prognosis. After incorporating DLR signatures, the MDLR model yielded the best performance among all models (AUC, 0.855 in the TC, 0.805 in the ITC and 0.792 in the ETC). With these variables, the MDLR model provided two risk strata for overall survival (OS) in the TC: low risk (5-year OS, 44.9%) and high risk (5-year OS, 4.9%). INTERPRETATION: A tool based on MDLR was developed to consider that the MTM is an important prognosis factor for HCC patients. MDLR showed outstanding performance for the prognostic risk stratification of HCC patients who underwent HAIC and may help physicians with therapeutic decision making and surveillance strategy selection in clinical practice.

Identification of Potential Mechanisms of Rk1 Combination with Rg5 in the Treatment of Type II Diabetes Mellitus by Integrating Network Pharmacology and Experimental Validation.

In this study, we aimed to explore the potential targets and functional mechanisms of Rk1 combined with Rg5 (Rk1+Rg5) against type II diabetes mellitus (T2DM). Network pharmacology and molecular docking were used to predict and verify the targets and signaling pathways of Rk1+Rg5 against T2DM. The results were further confirmed by a db/db mouse model and a model using PA-induced L6 cells. According to network pharmacology, a total of 250 core targets of Rk1+Rg5 towards T2DM were identified; the insulin resistance signaling pathways were enriched by KEGG. Results of molecular docking indicated good binding affinity of Rk1 and Rg5 to Akt1. In vivo and in vitro studies further showed that Rk1+Rg5 is an inhibitor of skeletal muscle insulin resistance. The results showed that Rk1+Rg5 significantly improved the hyperglycemic state of db/db mice, alleviated dyslipidemia, and promoted skeletal muscle glucose uptake. This phenomenon was closely related to the alleviation of the insulin resistance in skeletal muscles. Finally, the combination activated the Akt signaling pathway and promoted GLUT4 translocation to the cell membrane for glucose uptake. Altogether, our findings, for the first time, demonstrate that the combination of Rk1 and Rg5 could be beneficial for anti-T2DM, possibly involving ameliorated insulin resistance.

Deep learning radiomics of dual-energy computed tomography for predicting lymph node metastases of pancreatic ductal adenocarcinoma.

PURPOSE: Diagnosis of lymph node metastasis (LNM) is critical for patients with pancreatic ductal adenocarcinoma (PDAC). We aimed to build deep learning radiomics (DLR) models of dual-energy computed tomography (DECT) to classify LNM status of PDAC and to stratify the overall survival before treatment. METHODS: From August 2016 to October 2020, 148 PDAC patients underwent regional lymph node dissection and scanned preoperatively DECT were enrolled. The virtual monoenergetic image at 40 keV was reconstructed from 100 and 150 keV of DECT. By setting January 1, 2021, as the cut-off date, 113 patients were assigned into the primary set, and 35 were in the test set. DLR models using VMI 40 keV, 100 keV, 150 keV, and 100 + 150 keV images were developed and compared. The best model was integrated with key clinical features selected by multivariate Cox regression analysis to achieve the most accurate prediction. RESULTS: DLR based on 100 + 150 keV DECT yields the best performance in predicting LNM status with the AUC of 0.87 (95% confidence interval [CI]: 0.85-0.89) in the test cohort. After integrating key clinical features (CT-reported T stage, LN status, glutamyl transpeptadase, and glucose), the AUC was improved to 0.92 (95% CI: 0.91-0.94). Patients at high risk of LNM portended significantly worse overall survival than those at low risk after surgery (P = 0.012). CONCLUSIONS: The DLR model showed outstanding performance for predicting LNM in PADC and hold promise of improving clinical decision-making.

Thin-section computed tomography findings and longitudinal variations of the residual pulmonary sequelae after discharge in patients with COVID-19: a short-term follow-up study.

OBJECTIVES: This study analyzed and compared CT findings and longitudinal variations after discharge between severe and non-severe coronavirus disease (COVID-19) patients who had residual pulmonary sequelae at pre-discharge. METHODS: A total of 310 patients were included and stratified into severe and non-severe COVID-19 groups. Cross-sectional CT features across different time periods (T0: pre-discharge, T1: 1-4 weeks after discharge, T2: 5-8 weeks after discharge, T3: 9-12 weeks after discharge, T4: > 12 weeks after discharge) were compared, and the longitudinal variations of CT findings were analyzed and compared in both groups. RESULTS: The cumulative absorption rate of fibrosis-like findings in the severe and non-severe groups at T4 was 24.3% (17/70) and 52.0% (53/102), respectively. In both groups, ground-glass opacity (GGO) with consolidation showed a clear decreasing trend at T1, after which they maintained similar lower levels. The GGO in the severe group showed an increasing trend first at T1 and then decreasing at T4; however, the incidence decreased gradually in the non-severe group. Most fibrosis-like findings showed a tendency to decrease rapidly and then remained stable. Bronchial dilatation in the severe group persisted at an intermediate level. CONCLUSIONS: After discharge, the characteristics and changing trends of pulmonary sequelae caused by COVID-19 were significantly different between the two groups. Pulmonary sequelae were more serious and recovery was slower in patients with severe/critical disease than in patients with moderate disease. A portion of the fibrosis-like findings were completely absorbed in patients with moderate and severe/critical diseases. KEY POINTS: • Lung sequelae were more serious and recovery was slower in severe/critical COVID-19 patients. • Complete absorption of fibrosis-like findings after a short-term follow-up was observed in at least 17/70 (24.3%) of COVID-19 patients with severe/critical disease and 53/102 (52.0%) of COVID-19 patients with moderate disease. • The most common fibrosis-like findings was a parenchymal band; irregular interface was a nonspecific sign of COVID-19, and the percentage of bronchial dilatation in patients with severe/critical disease remained at a relatively stable medium level (range, 31.6 to 47.8%) at all stages.

Small single perivascular hepatocellular carcinoma: comparisons of radiofrequency ablation and microwave ablation by using propensity score analysis.

OBJECTIVES: We aimed to compare the therapeutic outcomes of radiofrequency ablation (RFA) and microwave ablation (MWA) as first-line therapies in patients with small single perivascular hepatocellular carcinoma (HCC). METHODS: A total of 144 eligible patients with small (≤ 3 cm) single perivascular (proximity to hepatic and portal veins) HCC who underwent RFA (N = 70) or MWA (N = 74) as first-line treatment were included. The overall survival (OS), disease-free survival (DFS), and local tumor progression (LTP) rates between the two ablation modalities were compared. The inverse probability of treatment weighting (IPTW) method was used to reduce selection bias. Subgroup analysis was performed according to the type of hepatic vessels. RESULTS: After a median follow-up time of 38.2 months, there were no significant differences in OS (5-year OS: RFA 77.7% vs. MWA 74.6%; p = 0.600) and DFS (5-year DFS: RFA 24.7% vs. MWA 40.4%; p = 0.570). However, a significantly higher LTP rate was observed in the RFA group than the MWA group (5-year LTP: RFA 24.3% vs. MWA 8.4%; p = 0.030). IPTW-adjusted analyses revealed similar results. The treatment modality (RFA vs. MWA: HR 7.861, 95% CI 1.642-37.635, p = 0.010) was an independent prognostic factor for LTP. We observed a significant interaction effect of ablation modality and type of peritumoral vessel on LTP (p = 0.034). For patients with periportal HCC, the LTP rate was significantly higher in the RFA group than in the MWA group (p = 0.045). However, this difference was not observed in patients with perivenous HCC (p = 0.116). CONCLUSIONS: In patients with a small single periportal HCC, MWA exhibited better tumor control than RFA. KEY POINTS: • Microwave ablation exhibited better local tumor control than radiofrequency ablation for small single periportal hepatocellular carcinoma. • There was a significant interaction between the treatment effect of ablation modality and type of peritumoral vessel on local tumor progression. • The type of peritumoral vessel is vital in choosing ablation modalities for hepatocellular carcinoma.

Four types of tumor progression after microwave ablation of single hepatocellular carcinoma of ≤5 cm: incidence, risk factors and clinical significance.

OBJECTIVES: To evaluate the incidence, risk factors and clinical significance of four types of tumor progression (TP) after microwave ablation (MWA) of single hepatocellular carcinoma (HCC) of <5 cm. METHODS: The data of 340 treatment-naïve, HCC patients with a single HCC of <5 cm underwent MWA between April 2012 and November 2017 were retrospectively reviewed. TPs including local tumor progression (LTP), intrahepatic distant recurrence (IDR), aggressive intrasegmental recurrence (AIR) and extrahepatic distant recurrence (EDR) were reviewed and compared between BCLC stage 0 and A. Univariate and multivariate analysis were performed on clinicopathological variables and different TPs to identify factors affecting long-term overall survival (OS). RESULTS: In a median follow-up period of 25.6 months (range, 3.1-61.4 months), the rate of LTP, IDR, AIR and EDR was 6.2% (21/340), 29.1% (98/340), 3.2% (11/340) and 7.9% (27/340). The four types of TP occurrence rates in BCLC stage 0 were comparable to those in BCLC stage A (p = 0.492, 0.971, 0.681 and 0.219). Univariate analysis showed that age (p < 0.001, hazard ratio [HR] = 2.783), comorbidities (p = 0.042, HR = 1.864), IDR, AIR and EDR (p = 0.027, HR = 1.719; p = 0.001, HR = 3.628; p = 0.009, HR = 2.638) were independently associated with OS. Multivariate analysis showed older age (p < 0.001, HR = 2.478), the occurrence of AIR (p < 0.001, HR = 2.648) and the occurrence of EDR (p = 0.002, HR = 2.222), were associated with poor OS. CONCLUSIONS: The occurrence rate of IDR is the highest of all TPs following MWA of a single HCC of <5cm. Old age, AIR and EDR had an adverse effect on long-term OS.

TET2 deficiency leads to stem cell factor-dependent clonal expansion of dysfunctional erythroid progenitors.

Myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis. Anemia is the defining cytopenia of MDS patients, yet the molecular mechanisms for dyserythropoiesis in MDSs remain to be fully defined. Recent studies have revealed that heterozygous loss-of-function mutation of DNA dioxygenase TET2 is 1 of the most common mutations in MDSs and that TET2 deficiency disturbs erythroid differentiation. However, mechanistic insights into the role of TET2 on disordered erythropoiesis are not fully defined. Here, we show that TET2 deficiency leads initially to stem cell factor (SCF)-dependent hyperproliferation and impaired differentiation of human colony-forming unit-erythroid (CFU-E) cells, which were reversed by a c-Kit inhibitor. We further show that this was due to increased phosphorylation of c-Kit accompanied by decreased expression of phosphatase SHP-1, a negative regulator of c-Kit. At later stages, TET2 deficiency led to an accumulation of a progenitor population, which expressed surface markers characteristic of normal CFU-E cells but were functionally different. In contrast to normal CFU-E cells that require only erythropoietin (EPO) for proliferation, these abnormal progenitors required SCF and EPO and exhibited impaired differentiation. We termed this population of progenitors "marker CFU-E" cells. We further show that AXL expression was increased in marker CFU-E cells and that the increased AXL expression led to increased activation of AKT and ERK. Moreover, the altered proliferation and differentiation of marker CFU-E cells were partially rescued by an AXL inhibitor. Our findings document an important role for TET2 in erythropoiesis and have uncovered previously unknown mechanisms by which deficiency of TET2 contributes to ineffective erythropoiesis.

3D visualization ablation planning system assisted microwave ablation for hepatocellular carcinoma (Diameter >3): a precise clinical application.

BACKGROUND: The aim of this retrospective study was to compare the feasibility and efficiency of ultrasound-guided percutaneous microwave ablation (US-PMWA) assisted by three-dimensional visualization ablation planning system (3DVAPS) and conventional 2D planning for hepatocellular carcinoma (HCC) (diameter > 3 cm). METHODS: One hundred thirty patients with 223 HCC nodules (5.0 ± 1.5 cm in diameter, [3.0-10.0 cm]) who met the eligibility criteria divided into 3D and 2D planning group were reviewed from April 2015 to August 2018. Ablation parameters and oncological outcomes were compared, including overall survival (OS), recurrence-free survival (RFS), and local tumor progression (LTP). Multivariate analysis was performed on clinicopathological variables to identify the risk factors for OS and LTP. RESULTS: The median follow-up period was 21 months (range 3-44). Insertion number (5.4 ± 1.2 VS. 4.5 ± 0.9, P = 0.034), ablation time (1249.2 ± 654.2 s VS. 1082.4 ± 584.7 s, P = 0.048), ablation energy (57,000 ± 11,892 J VS. 42,600 ± 10,271 J, P = 0.038) and success rate of first ablation (95.0% VS. 85.7%, P = 0.033) were higher in the 3D planning group compared with those in 2D planning group. There was no statistical difference in OS, and RFS between the two groups (P = 0.995, P = 0.845). LTP rate of 3D planning group was less than that of 2D planning group (16.5% VS 41.2%, P = 0.003). Multivariate analysis showed tumor maximal diameters (P < 0.001), tumor number (P = 0.003) and preoperative TACE (P < 0.001) were predictors for OS and sessions (P = 0.024), a-fetoprotein level (P = 0.004), and preoperative planning (P = 0.002) were predictors for LTP, respectively. CONCLUSIONS: 3DVAPS improves precision of US guided ablation resulting in lower LTP and higher 5 mm-AM for patients with HCC lesions larger than 3 cm in diameter.

A nomogram to predict survival of patients with intermediate-stage hepatocellular carcinoma after transarterial chemoembolization combined with microwave ablation.

OBJECTIVES: To develop a prognostic nomogram based on the albumin-bilirubin (ALBI) grade for prediction of the long-term survival of patients with intermediate-stage hepatocellular carcinoma (HCC) after transarterial chemoembolization combined with microwave ablation (TACE-MWA). METHODS: We retrospectively studied 546 consecutive patients with intermediate-stage HCC according to the Barcelona Clinic Liver Cancer guidelines who underwent TACE-MWA between January 2000 and December 2016. Overall survival (OS) and progression-free survival (PFS) were analyzed. The predictive value of the ALBI grade was investigated. The prognostic nomogram was constructed using the independent predictors assessed by the multivariate Cox proportional hazards model. RESULTS: After a median follow-up of 35.0 months (range, 4.0-221.0 months), 380 patients had died. The median OS was 35.0 months (95% confidence interval (CI), 30.84-39.16 months), and the median PFS was 6.5 months (95% CI, 6.13-6.87 months). The ALBI grade was validated as an independent predictor of OS (p < 0.001). Multivariate analyses showed that Eastern Cooperative Oncology Group performance status score more than 0, presence of liver cirrhosis, a-fetoprotein level above 400 ng/mL, tumor size greater than 5 cm, tumor number more than 3, advanced ALBI grade, and treatment sessions of TACE or MWA fewer than 3 were independently associated with overall mortality. The prognostic nomogram incorporating these eight predictors achieved good calibration and discriminatory abilities with a concordance index of 0.770 (95% CI, 0.746-0.795). CONCLUSIONS: The prognostic nomogram based on the ALBI grade resulted in reliable efficacy for prediction of individualized OS in patients with intermediate-stage HCC after TACE-MWA. KEY POINTS: • TACE-MWA was associated with a median overall survival of 35.0 months for patients with intermediate-stage HCC. • A prognostic nomogram was built to predict individualized survival of patients with intermediate-stage HCC after TACE-MWA. • The prognostic nomogram incorporating eight predictors achieved good calibration and discriminatory abilities with a concordance index of 0.770.

Nomograms to predict survival outcomes after microwave ablation in elderly patients (>65 years old) with early-stage hepatocellular carcinoma.

Objectives: To develop and validate the nomograms to predict survival outcomes after microwave ablation (MWA) in elderly patients(>65 years old) with early-stage hepatocellular carcinoma (EHCC).Methods: This retrospective study was approved by the institutional review board. A total of 265 EHCC patients (76 females, 189 males; average age 71.4 years ± 5.4 [standard deviation]) with 345 nodules subsequently underwent MWA from April 2006 to October 2019. Baseline characteristics were collected to identify the risk factors for the determination of survival outcomes after MWA. The nomograms were based on prognostic factors for overall survival (OS) and recurrence-free survival (RFS) from the multivariate Cox proportional hazards model and validated in external cohorts from another two institutions (n = 130). The nomograms were assessed for their predictive accuracy using Harrell's concordance index (C-index).Results: After a median follow-up time of 28.6 months, 29.8% (79/265) of the patients died, and 54.3% (144/265) of the patients experienced recurrence in the training set. The OS nomogram was developed based on the hepatitis B virus (HBV) presence, α-fetoprotein (AFP), and albumin, with a C-index of 0.757 (95% confidence interval [CI]: 0.645, 0.789).The scores of the nomogram ranged from 0 to 24. The RFS nomogram was developed based on tumor number, abutting major vessels and platelets, with a C-index of 0.733 (CI: 0.672, 0.774). The likelihood of 3- and 5-year OS and RFS were consistent between clinical observations and nomogram predictions in external cohorts.Conclusions: The nomogram models can be useful in determining the risk of OS and RFS in elderly patients with EHCC after MWA, which can guide individual patient management.Key pointsMWA is an effective and feasible treatment for elderly patients with EHCC and can improve survival outcomes.A calibrated and objective nomogram model for the prediction of survival outcomes in elderly patients (>65 years old) may guide patient selection and MWA treatment.Older age was not deemed to be a risk factor for survival outcomes when the elderly patients with EHCC underwent MWA.

Percutaneous microwave ablation versus surgical resection for ovarian cancer liver metastasis.

Objective: To compare the oncological outcomes between microwave ablation (MWA) and surgical resection (SR) in patients with ovarian cancer liver metastasis (OCLM).Materials and methods: In this retrospective study, a total of 29 female patients (mean age, 47.8 ± 12.9 years; range, 21-65 years) diagnosed with forty-three OCLM nodules between September 2008 and July 2016 were included. All patients with ovarian cancer received chemotherapy and cytoreductive surgery (CRS). Fifteen patients with 22 nodules underwent MWA, and 14 patients with 21 nodules underwent SR. Overall survival (OS), local tumor recurrence-free survival (LTRS), and operation-related parameters were compared between the two groups. Multivariate analyses were performed on clinicopathological variables to identify factors affecting OS and LTRS.Results: The median follow-up time was 70.2 months (range, 12.1-107.2 months). Fourteen patients died during this period. The 1-, 3-, and 5-year OS and LTRS rates after MWA were comparable to those after SR (p = .198 and p = .889, respectively). Compared with the SR group, the MWA group had a shorter surgical time (p < .001), less estimated blood loss (p < .001), shorter postoperative hospitalization (p < .001) and fewer costs (p = .015). The multivariate analysis showed that old age (p = .001) was a predictor of poor OS and that intrahepatic tumor size (p = .005) and intrahepatic tumor number (p = .001) were predictors of poor LTRS.Conclusion: Percutaneous MWA had comparable oncologic outcomes with those of SR and could be a safe and effective treatment for OCLM.

Acute kidney injury after nephron sparing surgery and microwave ablation: focus on incidence, survival impact and prediction.

Purpose: To compare acute kidney injury (AKI) incidence between nephron sparing surgery (NSS) and microwave ablation (MWA) for T1a RCC patients, reveal the effect of AKI on survival prognosis, construct AKI nomogram and use Law of Total Probability for survival probability (SP) prediction.Materials and methods: Patients were studied retrospectively after NSS (n = 1267) or MWA (n = 210) from January 1, 2011 to June 30, 2017. Using one to one Propensity Score Matching (PSM), 158 pairs of patients were identified for the cohort study. AKI incidence, risk factors and impact on survival outcomes were analyzed using Chi-square test, logistic and cox regression analysis. AKI risk and SP were predicted by nomogram and Law of Total Probability. The performance of the nomogram was assessed with respect to its discrimination, calibration, and clinical usefulness.Results: AKI occurred more commonly in NSS (27.85%) cohort, when compared to MWA (17.72%) cohort (p = 0.032), but treatment modality was not independently predictive of AKI occurrence (odds ratio [OR]: 0.598; 95% confidence interval [CI]: 0.282-1.265; p = 0.178). The 5-yr overall survival (OS) was lower in AKI patients (73.5%) compared with non-AKI patients (94.8%; p < 0.001). AKI was an independent risk factor for all-cause mortality in RCC patients (hazard ratio [HR]: 2.820; 95% confidence interval [CI]: 1.110-7.165; p = 0.029). Predictors for both NSS- and MWA-related AKI included tumor diameter, baseline eGFR and CCI score. RENAL score and tumor blood supply can predict AKI after NSS and MWA, respectively. The AKI normograms demonstrated good discrimination, with AUCs >0.86, excellent calibration and net benefits at the decision curve analysis with probabilities ≥5%. SP predicted by Law of Total Probability was comparable to actual OS.Conclusion: AKI was an early indicator for poor overall survival in RCC patients. It can be predicted by several oncological parameters. Nomogram and Law of Total Probability can accurately predict AKI risk and SP.

Ultrasound-guided percutaneous microwave ablation of hepatocellular carcinoma in challenging locations: oncologic outcomes and advanced assistive technology.

Purpose: To assess the oncologic outcomes of the hepatocellular carcinoma (HCC) patients in challenging locations (CLs) underwent ultrasound-guided percutaneous microwave ablation (US-PMWA) and the efficacy and safety of the advanced assistive technology (AAT).Materials and methods: Data for 489 treatment-naïve patients with HCC who met Milan criteria and subsequently underwent US-PMWA were reviewed from March 2012 to November 2016. According to the distance (<5 mm) between the tumor and surrounding structures, the patients were divided into two groups: a CL group and a non-CL group. Regarding MWA assisted by AAT, the CL group was further subdivided into two groups: an AAT group and a non-AAT group. Technique effectiveness, complications and survival outcomes (i.e., overall survival [OS] and recurrence-free survival [RFS]) were compared between CL and non-CL groups. Local tumor progression (LTP) was compared between AAT and non-AAT groups.Results: Technique effectiveness and complications in the CL group were similar to those in the non-CL group (p = .873 and p = .828, respectively). The OS and RFS in six types of CL groups were comparable with those in non-CL group (p = .131-.117) including adjacent vital structures, gallbladder, hepatic hilar regions, major vessels, diaphragm and capsule, respectively. The LTP rates in the AAT group were significantly higher than those in the non-AAT group (p = .001).Conclusions: US-PMWA assisted by AAT to treat HCC lesions in CLs was safe and effective; also, this technique had comparable success and survival outcomes with those of patients in non-CL.

Diversity and Antimicrobial Activity of Endophytic Fungi Isolated from Chloranthus japonicus Sieb in Qinling Mountains, China.

The plant Chloranthus japonicus Sieb is known for its anticancer properties and mainly distributed in China, Japan, and Korea. In this study, we firstly investigated the diversity and antimicrobial activity of the culturable endophytic fungi from C. japonicus. A total of 332 fungal colonies were successfully isolated from 555 tissue segments of the medicinal plant C. japonicus collected from Qinling Mountains, China. One hundred and thirty representative morphotype strains were identified according to ITS rDNA sequence analyses and were grouped into three phyla (Ascomycota, Basidiomycota, Mucoromycota), five classes (Dothideomycetes, Sordariomycetes, Eurotiomycetes, Agaricomycetes, Mucoromycetes), and at least 30 genera. Colletotrichum (RA, 60.54%) was the most abundant genus, followed by Aspergillus (RA, 11.75%) and Diaporthe (RA, 9.34%). The Species Richness Index (S, 56) and the Shannon-Wiener Index (H', 2.7076) indicated that C. japonicus harbored abundant fungal resources. Thirteen out of 130 endophytic fungal ethyl acetate extracts exhibited inhibitory activities against at least one pathogenic bacterium or fungus. Among of these, F8158, which was identified as Trichoderma cf. harzianum, exhibited good antagonistic capacities (the percent inhibition of mycelial growth ranged from 47.72~88.18) for different pathogens and has a potential application in biological control. In addition, it is noteworthy that the strain F8157 (Thanatephorus cucumeris, an opportunistic pathogen) showed antibacterial and antifungal activity, which is reported firstly in this study, and should be investigated further. Taken together, these results indicated that the endophytic fungi from C. japonicus may be of potential interest in screening bio-control agents and discovering of new bioactive compounds.

Tumor suppressor miR-139-5p targets Tspan3 and regulates the progression of acute myeloid leukemia through the PI3K/Akt pathway.

Dysregulation of microRNAs is closely implicated in the initiation and progression of human cancers including acute myeloid leukemia (AML). Though miR-139-5p was reported to be a potent tumor suppressor in adult AML, its underlying molecular mechanism in AML remains to be further defined. Herein, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were conducted to determine the expressions of miR-139-5p and tetraspanin3 (Tspan3) in AML patients and cells. Luciferase reporter assay, qRT-PCR, and Western blot analysis were carried out to detect the interaction between miR-139-5p and Tspan3. Cell proliferation, cell cycle distribution, invasion, and migration were evaluated by cell counting kit-8, flow cytometry, transwell invasion, and migration assays, respectively. Western blot analysis was conducted to determine phosphorylated-protein kinase B (Akt) and Akt levels. We found that a significant reduction in miR-139-5p expression and a prominent increase in Tspan3 expression were observed in AML patients and cells. Tspan3 was confirmed as a direct target of miR-139-5p and was negatively modulated by miR-139-5p. Rescue experiments showed that overexpression of miR-139-5p constrained cell proliferation, invasion and migration capabilities, and induced cell cycle arrest at the S phase in AML cells, which were partially reversed by Tspan3 overexpression. In addition, we found that miR-139-5p suppressed the phosphoinositide 3-kinase (PI3K)/Akt pathway in AML cells by targeting Tspan3. In conclusion, our study concluded that miR-139-5p suppressed the leukemogenesis in AML cells by targeting Tspan3 through inactivation of the PI3K/Akt pathway, providing a better understanding of AML progression.

Distinct roles for TET family proteins in regulating human erythropoiesis.

The ten-eleven translocation (TET) family of proteins plays important roles in a wide range of biological processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine. However, their function in erythropoiesis has remained unclear. We show here that TET2 and TET3 but not TET1 are expressed in human erythroid cells, and we explore the role of these proteins in erythropoiesis. Knockdown experiments revealed that TET2 and TET3 have different functions. Suppression of TET3 expression in human CD34+ cells markedly impaired terminal erythroid differentiation, as reflected by increased apoptosis, the generation of bi/multinucleated polychromatic/orthochromatic erythroblasts, and impaired enucleation, although without effect on erythroid progenitors. In marked contrast, TET2 knockdown led to hyper-proliferation and impaired differentiation of erythroid progenitors. Surprisingly, knockdown of neither TET2 nor TET3 affected global levels of 5mC. Thus, our findings have identified distinct roles for TET2 and TET3 in human erythropoiesis, and provide new insights into their role in regulating human erythroid differentiation at distinct stages of development. Moreover, because knockdown of TET2 recapitulates certain features of erythroid development defects characteristic of myelodysplastic syndromes (MDSs), and the TET2 gene mutation is one of the most common mutations in MDS, our findings may be relevant for improved understanding of dyserythropoiesis of MDS.