Multi-dataset identification of innovative feature genes and molecular mechanisms in keratoconus.

This study aimed to identify feature genes and explore the molecular mechanisms of keratoconus (KC). We downloaded data files from NCBI GEO public database. The Limma package was used for differential expression analysis of gene profiles. Lasso regression was used to identify the feature genes. The CIBERSORT algorithm was used to infer the proportion of immune-infiltrating cells and analyse the correlation between gene expression levels and immune cells. Related transcription factors and miRNAs of key genes were predicted using the Cistrome DB and Mircode databases. Analysis of expression differences in disease genes was based on the GeneCards database. The CMap was used to analyse targeted therapeutic drugs. IHC was performed to verify the expression levels of ATOH7 and MYRF in corneas. Exactly 593 upregulated and 473 downregulated genes were identified. Lasso regression analysis identified ATOH7, DBNDD1, RNF217-AS1, ARL11, MYRF and SNORA74B as feature genes for KC. All key genes were correlated with immune infiltration and the levels of activated memory CD4+ T cells and plasma cells were significantly increased. miRNA, IRF and STAT families were correlated to feature genes. The expression levels of key genes were significantly correlated to KC-related genes. Entinostat, ochratoxin-a, diphencyprone and GSK-3-inhibitor-II were predicted as potential KC medications. The expression of MYRF was significantly higher in the KC samples, contrary to the expression of ATOH7. KC is related to both immune infiltration and genetic factors. MYRF and ATOH7 were newly identified and verified feature genes of KC.

Recommended 10-Year Follow-Up Strategy for Small Hepatocellular Carcinoma After Radiofrequency Ablation: A Cost-Effectiveness Evaluation.

INTRODUCTION: An optimal follow-up schedule for small (≤3-cm) hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains unclear in clinical guidelines. We aimed to assess the cost-effectiveness of follow-up strategies in patients with small HCC after RFA. METHODS: In total, 11,243 patients were collected from global institutions to calculate recurrence rates. Subsequently, a Markov model covering a 10-year period was developed to compare 25 surveillance strategies involving different surveillance techniques (computed tomography [CT], magnetic resonance imaging or ultrasonography [US], and α-fetoprotein [AFP]) and intervals (3 or 6 months). The study endpoint was incremental cost-effectiveness ratio (ICER), which represented additional cost per incremental quality-adjusted life year. Sensitivity analysis was conducted by varying the values of input parameters to observe the ICER. RESULTS: In a base case analysis, the dominant strategy was CT every 3 months during an initial 2 years, followed by semiannual CT, and then switch to biannual the combination of US screening and AFP testing after 5 years (m3_CT-m6_CT-m6_USAFP), with an ICER of $68,570.92 compared with the "not followed" strategy. One-way sensitivity analysis showed the ICER consistently remained below the willingness-to-pay threshold of $100,000.00. In a probabilistic sensitivity analysis, m3_CT-m6_CT-m6_USAFP was the most cost-effective approach in 95.6% of simulated scenarios at a willingness-to-pay threshold. DISCUSSION: For small HCC after RFA, the recommended follow-up strategy is CT, with scans scheduled every 3 months for the first 2 years, every 6 months thereafter, and transition to biannual the combination of US screening and AFP testing after 5 years.

Group-Based Trajectory Modeling to Identify Patterns of Antipsychotic-Associated Weight Gain Among Children and Adolescents.

PURPOSE/BACKGROUND: Antipsychotic-associated weight gain (AAWG) is a common adverse effect of second-generation antipsychotic (SGA) medications among children and adolescents. This study applied group-based trajectory modeling to identify latent trajectories of AAWG among children and adolescents and associated risk factors. PROCEDURES: This was a retrospective analysis of the IQVIA Ambulatory EMR-US database from 2016 to 2021. The cohort consisted of patients aged 6 to 19 years who were SGA naive and received at least 90 days of continuous SGA prescriptions. Group-based trajectory modeling was used to identify latent trajectories of AAWG development during a 24-month period since SGA initiation, and multinomial logistic regression analysis was conducted to examine the risk factors associated with the identified AAWG trajectories. FINDINGS/RESULTS: A total of 16,262 patients were included. Group-based trajectory modeling identified the following 4 distinctive AAWG trajectories: persistent severe weight gain (4.2%), persistent moderate weight gain (20.1%), minor weight change (69.6%), and gradual weight loss (6.1%). Compared with the minor weight change group, younger age (12-17 vs 5-11: odds ratio [OR], 0.634; 95% confidence interval [CI], 0.521-0.771), lower baseline body mass index z -score (OR, 0.216; 95% CI, 0.198-0.236), and receiving olanzapine as the initial SGA (olanzapine vs aripiprazole: OR, 1.686; 95% CI, 1.673-1.699) were more likely to follow severe weight gain trajectories. The area under the receiver operating characteristic curves for comparing severe weight gain versus minor weight change groups and moderate weight vs minor weight change groups in the multinomial regression model were 0.91 and 0.8, respectively. IMPLICATIONS/CONCLUSIONS: A quarter of pediatric SGA recipients experienced persistent weight gain during the SGA treatment. The risk of having persistent AAWG can be predicted using patient characteristics collected before SGA initiation and the initial SGA agent.

Hepatic arterial infusion therapy for advanced hepatocellular carcinoma after systemic treatment failure: Multicenter, real-world study.

AIM: The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. METHODS: Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. RESULTS: The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5 months (95% confidence interval [CI], 8.1-12.9) and 6.0 months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p = 0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p = 0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p = 0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p = 0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p < 0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. CONCLUSIONS: Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.

Effect of Exosomal Protein Expression and Electrochemical Nano Interface in Morphine Analgesia Tolerance.

The current understanding of neurons cannot well explain the phenomenon of morphine tolerance, and even if some neuronal drugs are used in combination with morphine, they cannot achieve good results. In recent years, exosomal proteins have been the role of morphine tolerance and morphine-induced hyperalgesia is becoming more and more important. In clinical application, a larger dose is needed to achieve the desired analgesic effect, and large doses of morphine will aggravate the adverse drug reactions. The purpose of this experiment is to explore the role and mechanism of exosomal protein expression and electrochemical nanointerface in morphine analgesic tolerance and provide a theoretical basis for the application of exosomal protein in the clinical prevention and treatment of morphine tolerance. In this paper, adult male rats were randomly divided into groups and analyzed from four aspects: enhancing the analgesic effect of high-dose morphine, preventing morphine tolerance, the effect of morphine-induced hyperalgesia, and changes in mRNA levels of related genes. Experiments have shown that the mRNA levels of exosomal protein-related genes in the spinal cord of morphine-tolerant rats are significantly increased, and the rats given exosome protein inhibitors can prolong morphine analgesia and relieve morphine tolerance and hyperalgesia in behavior. It can inhibit the increase of exosomal protein-related genes. It shows that low-dose long-term morphine treatment can cause spinal endoplasmic reticulum stress, and the exosomal protein inhibitor 4-PBA or TUDCA can enhance the analgesic effect of morphine in neuropathic pain.

Intention to get naloxone among patients prescribed opioids for chronic pain.

BACKGROUND: Prescription opioids have been increasingly prescribed for chronic pain while the opioid-related death rates grow. Naloxone, an opioid antagonist, is increasingly recommended in these patients, yet there is limited research that investigates the intention to get naloxone. This study aimed to investigate intention toward getting naloxone in patients prescribed opioids for chronic pain and to assess the predictive utility of the theory of reasoned action (TRA) constructs in explaining intention to get naloxone. METHODS: This was a cross-sectional study of a panel of U.S. adult patients prescribed opioids for chronic pain using a Qualtrics®XM survey. These patients participated in the study during February to March 2020. The online internet survey assessed the main outcome of intention to get naloxone and constructs of TRA (attitudes and subjective norms); additional measures assessed the characteristics of patients' opioid overdose risk factors, knowledge of naloxone, and their demographics. The relationship between TRA constructs, namely, attitudes and subjective norms, and the intention variable was examined using logistic regression analyses with the intention outcome contrasted as follows: high intention (scores ≥ 5) and non-high intention (scores < 5). RESULTS: A total of 549 participants completed the survey. Most of them were female (53.01%), White or Caucasian (83.61%), non-Hispanic (87.57%) and had a mean age of 44.16 years (SD = 13.37). Of these, 167 (30.42%) had high intention to get naloxone. The TRA construct of subjective norm was significantly associated with increased likelihood of higher intentions to get naloxone (OR 3.04, 95% CI 2.50-3.70, P < 0.0001). CONCLUSIONS: Our study provides empirical support of the TRA in predicting intention to get naloxone among chronic pain patients currently taking opioids. Subjective norms significantly predicted intention to get naloxone in these patients. The interventions targeting important reference groups of these patients would have greater impact on increasing intention to get naloxone in this population. Future studies should test whether theory-based interventions focusing on strengthening subjective norms increase intention to get naloxone in this population.

Generation of Functional Immortalized Human Corneal Stromal Stem Cells.

In addition to their therapeutic potential in regenerative medicine, human corneal stromal stem cells (CSSCs) could serve as a powerful tool for drug discovery and development. Variations from different donors, their isolation method, and their limited life span in culture hinder the utility of primary human CSSCs. To address these limitations, this study aims to establish and characterize immortalized CSSC lines (imCSSC) generated from primary human CSSCs. Primary CSSCs (pCSSC), isolated from human adult corneoscleral tissue, were transduced with ectopic expression of hTERT, c-MYC, or the large T antigen of the Simian virus 40 (SV40T) to generate imCSSC. Cellular morphology, proliferation capacity, and expression of CSSCs specific surface markers were investigated in all cell lines, including TNFAIP6 gene expression levels in vitro, a known biomarker of in vivo anti-inflammatory efficacy. SV40T-overexpressing imCSSC successfully extended the lifespan of pCSSC while retaining a similar morphology, proliferative capacity, multilineage differentiation potential, and anti-inflammatory properties. The current study serves as a proof-of-concept that immortalization of CSSCs could enable a large-scale source of CSSC for use in regenerative medicine.

Surveillance Strategy after Complete Ablation of Initial Recurrent Hepatocellular Carcinoma: A Risk-Based Machine Learning Study.

PURPOSE: To investigate surveillance strategies for initial recurrent hepatocellular carcinoma (irHCC) after ablation to support clinical decision making, as there is no consensus regarding the monitoring strategy for irHCC after ablation. MATERIALS AND METHODS: Data from patients with irHCC who received ablation were retrospectively collected at 2 medical centers. The risk of tumor relapse in each month was calculated through random survival forest methodology, and follow-up schedules were arranged thereafter to maximize the capability of relapse detection at each visit. RESULTS: The cumulative 0.5-, 1-, 1.5-, and 2-year risk-adjusted probabilities in the training/validation cohorts were 26.2%/21.5%, 42.3%/39.4%, 55.5%/52.6%, and 61.3%/63.2%, respectively, with the highest recurrence rate occurring in the second month (maximum, 7.9%/7.4%). The surveillance regime primarily concentrated on the first year after treatment, especially the initial 6 months. The delay in detecting tumor recurrence gradually decreased when the total number of follow-up visits increased from 4 to 8. Compared with the control strategies, this schedule (follow-up visits at 2, 4, 6, 9, 12, and 18 months) reduced the delay in detection. The benefits of this surveillance regime were evident when the patients were followed up 6 times. The proposed 6-visit surveillance strategy significantly decreased the delay in detection compared with the control 7-visit approach (1.32 months vs 1.82 months, respectively; P < .001). CONCLUSIONS: The proposed new surveillance schedule minimized the delay in detecting recurrence in patients with irHCC after ablation. The risk-related machine learning method described in this study could be applied to develop follow-up strategies for other patients with hepatocellular carcinoma.

Hepatic Artery Infusion Chemotherapy Using Fluorouracil, Leucovorin, and Oxaliplatin versus Transarterial Chemoembolization as Initial Treatment for Locally Advanced Hepatocellular Carcinoma: A Propensity Score-Matching Analysis.

PURPOSE: To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with a modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) regimen with that of transarterial chemoembolization as a locoregional treatment for patients with locally advanced hepatocellular carcinoma (HCC). METHODS: This retrospective study included adult patients with locally advanced HCC who received first-line treatment with either HAIC-mFOLFOX or conventional transarterial chemoembolization monotherapy from January 2015 to December 2016. The outcomes, including tumor response rates, evaluated via imaging assessment using the modified response evaluation criteria in solid tumors; overall survival; progression-free survival; and safety, were compared. The propensity score-matching methodology was used to reduce the influence of confounding factors on the outcomes. RESULTS: The study included 131 patients with locally advanced HCC who underwent transarterial chemoembolization and 101 who received HAIC-mFOLFOX as initial treatment. After propensity score matching (n = 67 in each group), patients who received HAIC-mFOLFOX had a higher objective response rate (43.3% vs 13.4%, P = .001), longer median overall survival (13.9 vs 6.0 months, P < .001), and longer median progression-free survival (6.4 vs 2.8 months, P = .001) than those who underwent transarterial chemoembolization. The survival benefit with HAIC-mFOLFOX was strengthened in patients with HCC with vascular invasion (hazard ratio: 0.379; 95% confidence interval: 0.237-0.607). HAIC-mFOLFOX was associated with lower incidences of severe adverse events (8.9% vs 22.9%) and liver toxicity than transarterial chemoembolization. CONCLUSIONS: Compared with transarterial chemoembolization, HAIC-mFOLFOX is a potentially safer and more effective locoregional therapy for patients with locally advanced HCC.

The guiding value of microvascular invasion for treating early recurrent small hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) have worse survival. Whether the presence of MVI indicates the necessity of more aggressive locoregional treatments for recurrences remains to be elucidated. METHODS: We reviewed patients who underwent curative hepatectomy for primary HCC in our institution, and 379 patients with recurrent HCC up to three nodules smaller than 3 cm were enrolled. The Kaplan-Meier method was adopted to compare the secondary recurrence-free survival (sRFS) and post-recurrence survival (PRS) among patients undergoing hepatectomy, RFA and transarterial chemoembolization plus RFA (TACE-RFA). Cox regression analyses were performed to identify independent prognostic factors. RESULTS: Both the sRFS and PRS of the MVI (-) group were significantly longer than those of the MVI (+) group (p = 0.001 and 0.011). For patients with MVI (-), no significant difference was found in sRFS or PRS among recurrent HCC patients receiving hepatectomy, RFA or TACE-RFA (p = 0.149 and 0.821). A similar trend was found in patients with MVI (+) (p = 0.851 and 0.960). Further analysis found that TACE-RFA provided better sRFS than hepatectomy or RFA alone in patients with MVI (+) and early recurrence within two years (p = 0.036 and 0.044). CONCLUSION: For HCC patients with MVI (+) and early small recurrence, TACE-RFA could achieve better prognosis than hepatectomy or RFA alone, while RFA alone provided comparable survival benefits compared with hepatectomy or TACE-RFA in other HCC patients with small recurrence.

Calcitriol inhibits apoptosis via activation of autophagy in hyperosmotic stress stimulated corneal epithelial cells in vivo and in vitro.

BACKGROUND: Previously, calcitriol has been demonstrated as a potential therapeutic agent for dry eye, whilst its role on corneal epithelium death remains unclear. This study aims to investigate the relationship between apoptosis and autophagy on dry eye related scenario, as well as the effect of calcitriol and its potential mechanism. METHODS: In vitro, immortalized human corneal epithelial cells (iHCEC) were cultured in hyperosmotic medium with or without various concentrations of calcitriol and other reagents. In vivo, Wistar rats were applied with benzalkonium chloride to induce dry eye. Then rats were topically treated with calcitriol (10-6 M) for 14 days. Autophagy flux (LC3B-II and SQSTM1/P62) was examined by western blotting or immunostaining. To test cell apoptosis, western blotting for cleaved caspase-3, Annexin V/PI double staining and TUNEL assay were used. CCK-8 assay was performed to detect the cell viability. Small interfering RNA was used to knock down the expression of vitamin D receptor in iHCECs. RESULTS: Autophagy activation could protect iHCECs against HS induced apoptosis in vitro, and calcitriol was able to augment autophagy flux via VDR signaling, shown as the remarkably elevated expression of LC3B-II, as well as the declined p62 expression. In vivo results further supported the protective role of calcitriol on corneal epithelium apoptosis through promoting autophagy in dry eye rats. CONCLUSION: The current study indicated that autophagy was an adaptive change of corneal epithelial cells in response to hyperosmotic stress and calcitriol could prevent cells from apoptosis via further activation of autophagy through VDR pathway.

Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin in Hepatocellular Cancer with Extrahepatic Spread.

PURPOSE: To compare treatment with hepatic arterial infusion of chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) with both extrahepatic spread (EHS) and intrahepatic tumor and patients with intrahepatic tumor only. MATERIALS AND METHODS: This single-center retrospective study comprised 116 patients with advanced HCC with both intrahepatic tumor and EHS (EHS group; n = 50) or with intrahepatic tumor only (non-EHS group; n = 66) treated with HAIC including oxaliplatin, fluorouracil, and leucovorin between June 2014 and July 2016. Overall survival (OS) and radiologic responses to treatment were determined and compared between the 2 groups. RESULTS: Both the objective response rate and the clinical benefit rate were higher in the non-EHS group than in the EHS group (37.9% vs 16% objective response rate, P = .010; 81.8% vs 62% clinical benefit rate, P = .017). Median OS was not statistically different between the 2 groups (14.8 months vs 9.8 months, P = .068). Subgroup analysis of OS found that patients with lung metastases survived for a shorter time (OS 7 months) than patients with other metastatic sites (P = .003) and patients free of metastases (P = .001). CONCLUSIONS: HAIC is a potential treatment option for advanced HCC with limited extrahepatic metastases in a population with hepatitis B virus infection.

Survival benefits of computed tomography-guided thermal ablation for adrenal metastases from hepatocellular carcinoma.

Purpose: To evaluate the safety, efficacy, and survival outcomes of computed tomography (CT)-guided thermal ablation for adrenal metastases from hepatocellular carcinoma (HCC). Methods: This long-term retrospective study included 27 male patients (median age, 50 years; range, 34-77 years) with 29 adrenal metastatic tumors associated with HCC who underwent ablation between January 2004 and December 2015. The technical success rate, effectiveness rate, complications, and survival were recorded. Complications were assessed according to the Common Terminology Criteria for Adverse Events. Survival curves were estimated using the Kaplan-Meier method. A Cox regression model was used for the evaluation of factors predicting survival. Results: A total of 33 ablation sessions were performed for the 29 tumors. No ablation-related death was observed, and the incidence of complications was 87.9%. Grade 1-2 complications occurred in 23 of the 33 sessions (69.7%), and grade 3 hypertension was the only major complication, occurring in eight sessions (24.2%). The technical success and effectiveness rates were 93.1% (27 of 29 tumors) and 92.6% (25 of 27 patients), respectively. The median progression-free survival and overall survival (OS) durations for the 27 patients were 6.9 months and 16.8 months, respectively. The median OS duration was longer for patients with adrenal oligometastases (21.8 months) than for those with (12.8 months) multiple metastases (p = .037). Adrenal oligometastases were the only significant predictor of OS (p = .043). Conclusions: CT-guided ablation is a feasible and safe procedure for adrenal metastases from HCC, and it may be more beneficial for patients with adrenal oligometastases.

The Optimal Management for Sub-Centimeter Hepatocellular Carcinoma: Curative Treatments or Follow-Up?

BACKGROUND The optimal strategy for dealing with sub-centimeter hepatic nodules has not yet been established. This study aimed to assess whether there was a need to provide curative treatments for sub-centimeter hepatocellular carcinomas (HCCs) to patients at risk for high false positives. MATERIAL AND METHODS We identified patients with primary pathologically diagnosed HCC ≤2 cm from 2004 to 2015 in the Surveillance, Epidemiology and End Results (SEER) database. They were divided according to the interventions they received: local ablation, surgical resection, or liver transplantation. In each group, overall survival and cancer-specific survival were used as endpoints to compare the prognoses between patients with sub-centimeter HCC and patients with HCC measuring 1 to 2 cm by Kaplan-Meier. Propensity score matching was performed to reduce bias. We also compared the survival of patients with a primary solitary HCC based on interventions, in the different tumor size groups. Bootstrapping was performed to validate the findings. RESULTS Overall, 10.4% of patients (197 out of 1894) had HCCs <1 cm, and 89.6% of patients (1697 out of 1894) had HCCs in the 1 to 2 cm range. There was no significant difference in overall and cancer-specific survival between patients with HCCs <1 cm and those with HCCs in the 1 to 2 cm range, in all treatment groups. After adjusting confounding factors, no significant correlation was found between tumor size and survival time. In patients with HCCs measuring ≤2 cm, overall survival and cancer-specific survival were superior in liver transplantation compared with surgical resection and local ablation. Surgical resection provided better survival than local ablation. CONCLUSIONS Compared to patients with HCCs measuring 1 to 2 cm, the survival rates of patients with sub-centimeter HCCs was not improved through curative treatments, risking high false positives.

Mechanism and prognostic value of indoleamine 2,3-dioxygenase 1 expressed in hepatocellular carcinoma.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-metabolizing enzyme that is widely distributed in normal or malignant tissues and contributes to immunologic tolerance and immune escape. However, in hepatocellular carcinoma (HCC), the characteristics and mechanism of IDO1 expression have not been well defined. In this study, IDO1 expression in tumor cells (T-IDO1) was frequently detected (109/112) by immunohistochemistry in formalin-fixed paraffin-embedded specimens from HCC patients, and the expression patterns were mostly focal (102/109). Expression of T-IDO1 was significantly associated with the infiltration of CD8+ T cells (P = .043), as well as younger age (<50 years old, P = .02). It was also found that IDO1 had diffuse expression in inflammatory cells in all specimens, which were defined as antigen-presenting cells. Significant correlations among IDO1, IFNG, and CD8A transcriptional levels were observed in freshly resected HCC specimens; moreover, no constitutive IDO1 expression was detected in HCC cell lines until stimulated by interferon-γ through the JAK2-STAT1 signaling pathway, but not type I interferon. Survival analyses showed that increased T-IDO1 and CD8+ T cell infiltration were significantly associated with superior overall survival (OS) (T-IDO1, P = .003; CD8+ T cells, P = .004), and T-IDO1 expression is an independent prognosis factor in both OS and disease-free survival (OS, P = .007; disease-free survival, P = .044). These findings indicated that T-IDO1 expression in HCC is common and is dominantly driven by the host antitumor immune response, which is a favorable prognostic factor in HCC.

Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma.

BACKGROUND & AIMS: To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib. METHODS: This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models. RESULTS: The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001). CONCLUSION: HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding. LAY SUMMARY: We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.

Percutaneous CT-guided radiofrequency ablation for patients with extrahepatic oligometastases of hepatocellular carcinoma: long-term results.

BACKGROUND: The aim of this study was to evaluate the therapeutic outcome of percutaneous computed tomography (CT)-guided radiofrequency ablation (RFA) for extrahepatic oligometastases of hepatocellular carcinoma (HCC). METHODS: Institutional review board approval was obtained for this retrospective study, and all patients provided written informed consent. Between April 2004 and December 2015, 116 oligometastases (diameter, 5-50 mm; 20.3 ± 10.4) in 79 consecutive HCC patients (73 men and 6 women; average age, 50.3 years ±13.0) were treated with RFA. We focussed on patients with 1-3 extrahepatic metastases (EHM) confined to 1-2 organs (including the lung, adrenal gland, bone, lymph node and pleura/peritoneum) who were treated naïve with curative intent. Survival, technical success and safety were evaluated. The log-rank test and Cox proportional hazards regression models were used to analyse the survival data. RESULTS: No immediate technical failure occurred, and at 1 month, the technique effectiveness rate was determined to be 95.8%. After a median follow-up time of 28.0 months (range, 6-108 months), the 1-, 2- and 3-year overall survival (OS) rates were 91, 70 and 48%, respectively, with a median survival time of 33.5 months. Time to unoligometastatic progression (TTUP) of less than 6 months (p < 0.001) and a Child-Pugh score of more than 5 (p = 0.001) were significant indicators of shorter OS. The 1-, 2- and 3-year disease free survival (DFS) rates were 34, 21 and 8%, respectively, with a median DFS time of 6.8 months. DFS was better for those with lung metastases (p = 0.006). Major complication occurred in nine (9.5%, 9/95) RFA sessions without treatment-related mortality. CONCLUSIONS: CT-guided RFA for oligometastatic HCC may provide favourable efficacy and technical success with a minimally invasive approach.

[Roles of CX3CR1 in mediation of post-incision induced mechanical pain hypersensitivity: Effects of acupuncture-combined anesthesia].

Post-incision pain often occurs after surgery and is emergent to be treated in clinic. It hinders the rehabilitation of patients and easily leads to various types of postoperative complications. Acupuncture-combined anesthesia (ACA) is the combination of traditional acupuncture and modern anesthesia, which means acupuncture is applied at acupoints with general anesthesia. It was testified that ACA strengthened the analgesic effect and reduced the occurrence of postoperative pain, but its mechanism was not clear. Numerous reports have shown that chemokine receptor CX3CR1 is involved in the development and progression of many pathological pains. The present study was aimed to reveal whether ACA played the analgesic roles in the post-incision pain by affecting CX3CR1. A model of toe incision pain was established in C57BL/6J mice. The pain threshold was detected by behavioral test, and the expression of CX3CR1 protein was detected by immunohistochemical method and Western blot. The results showed that the significant mechanical allodynia and thermal hyperalgesia were induced by paw incision in the mice. Mechanical allodynia was significantly suppressed by ACA, but thermal hyperalgesia was not changed. CX3CR1 was mainly expressed in microglia in the spinal cord dorsal horn, and its protein level was significantly increased at 3 d after incision compared with that of naïve C57BL/6J mice. ACA did not affect CX3CR1 protein expression at 3 d after incision in the toe incision model mice. Paw withdrawal threshold was significantly increased at 3 d after incision in CX3CR1 knockout (KO) mice compared with that in the C57BL/6J mice. But the analgesic effect of ACA was disappeared in CX3CR1 KO mice. Accordingly, it was also blocked when neutralizing antibody of CX3CR1 was intrathecally injected (i.t.) 1 h before ACA in the C57BL/6J mice. These results suggest that CX3CR1 in microglia is involved in post-incision pain and analgesia of ACA.

[Analysis of the relationship of DNA mismatch repair with clinicopathologic features and prognosis of colon cancer].

OBJECTIVE: To explore the relationship between DNA mismatch repair (MMR) and clinicopathologic features and prognosis in patients with stages II and III colon cancers. METHODS: The clinical and pathological data of 440 patients with stage II/III colon cancer after radical resection were retrospectively reviewed and analyzed. Immunohistochemical staining was used to assess the expression of MMR proteins (MLH1, MSH2, MSH6 and PMS2), and the correlation between DNA MMR and clinicopathological features and prognosis of colon cancers was analyzed. RESULTS: Of the 440 tumor samples tested for DNA mismatch repair status, 90 (20.5%) demonstrated defective DNA mismatch repair and 350 (79.5%) had proficient DNA mismatch repair. Defective DNA mismatch repair (dMMR) was associated with young patients (≤ 60), proximal colon cancer, stage II, poorly differentiated adenocarcinoma and mucinous adenocarcinoma (P<0.05 for all). Among the 440 patients, 126 (28.6%) cases had recurrence or metastasis and 93 (21.1%) died during the median follow-up of 61.0 months. The five-year disease-free survival (DFS) rate was 82.2% among the patients with tumor exhibiting dMMR, significantly higher than that in patients with tumors exhibiting pMMR (68.9%, P=0.02). The univariate and mutlivariate analyses showed that the MMR status is an independent factor affecting 5-year disease-free survival and overall survival (OS) in colon cancer patients (P<0.05 for both). CONCLUSIONS: Defective DNA mismatch repair (dMMR) is associated with patients with proximal colon cancer, stage II and poorly defferentiated adenocarcinoma and mucinous adenocarcinoma. The prognosis for patients with dMMR is better than those with pMMR. dMMR may be a useful biomarker for the prognosis of colon cancer.