Network meta-analysis of triazole, polyene, and echinocandin antifungal agents in invasive fungal infection prophylaxis in patients with hematological malignancies.

BACKGROUND AND AIM: Triazole, polyene, and echinocandin antifungal agents are extensively used to treat invasive fungal infections (IFIs); however, the optimal prophylaxis option is not clear. This study aimed to determine the optimal agent against IFIs for patients with hematological malignancies. METHODS: Randomized controlled trials (RCTs) comparing the effectiveness of triazole, polyene, and echinocandin antifungal agents with each other or placebo for IFIs in patients with hematological malignancies were searched. This Bayesian network meta-analysis was performed for all agents. RESULTS: The network meta-analyses showed that all triazoles, amphotericin B, and caspofungin, but not micafungin, reduced IFIs. Posaconazole was superior to fluconazole [odds ratio (OR), 0.30; 95% credible interval (CrI), 0.12-0.60], itraconazole (OR, 0.40; 95% CrI, 0.15-0.85), and amphotericin B (OR, 4.97; 95% CrI, 1.73-11.35). It also reduced all-cause mortality compared with fluconazole (OR, 0.35; 95% CrI, 0.08-0.96) and itraconazole (OR, 0.33; 95% CrI, 0.07-0.94), and reduced the risk of adverse events compared with fluconazole (OR, 0.02; 95% CrI, 0.00-0.03), itraconazole (OR, 0.01; 95% CrI, 0.00-0.02), posaconazole (OR, 0.02; 95% CrI, 0.00-0.03), voriconazole (OR, 0.005; 95% CrI, 0.00 to 0.01), amphotericin B (OR, 0.004; 95% CrI, 0.00-0.01), and caspofungin (OR, 0.05; 95% CrI, 0.00-0.42) despite no significant difference in the need for empirical treatment and the proportion of successful treatment. CONCLUSIONS: Posaconazole might be an optimal prophylaxis agent because it reduced IFIs, all-cause mortality, and adverse events, despite no difference in the need for empirical treatment and the proportion of successful treatment.

Relationship of possible biomarkers with malignancy of thymic tumors: a meta-analysis.

BACKGROUND: Role of biomarkers for promotion of tumor proliferation (BPTPs) and for promotion of apoptosis (BPAs) in thymic malignant tumors is still unclear. The purpose of this study was to evaluate the relationship between BPTPs and/or BPAs and malignancy of thymic malignant tumors. METHODS: Studies on thymic malignant tumors and biomarkers were searched in PubMed, ISI Web of Knowledge, and Embase databases, and all statistical analyses were conducted using Review Manager. RESULTS: Twelve articles related to biomarkers and thymic malignant tumors were selected and analyzed. A relationship between BPAs and Masaoka stage was demonstrated for four markers, namely Bax, p73, Casp-9 and Bcl-2, included 138 stage I/II patients and 74 stage III/IV patients, and BPAs were significantly correlated with high Masaoka staging (P = 0.03). We further found a relationship between BPAs and degree of malignancy for four markers, namely Bax, p73, Casp-9 and Bcl-2, included 176 thymoma patients and 36 thymic carcinoma patients, and BPAs were significantly correlated with thymic carcinoma (P = 0.010). In addition, a relationship between BPTP and Masaoka staging was demonstrated for seven markers, namely Podoplanin, Glut-1, Muc-1, Egfr, Igf1r, c-Jun, and n-Ras, included 373 patients with stage I/II and 212 patients with stage III/IV, and BPTPs were significantly correlated with high Masaoka staging (P < 0.001). We also found a relationship between BPTPs and degree of malignancy for ten markers, namely Mesothelin, c-Kit (CD117), Egfr, Lat-1, Muc-1,Ema, Glut-1, Igf1r, c-Jun, and n-Ras, included 748 thymoma patients and 280 thymic carcinoma patients, and BPTPs were significantly correlated with thymic carcinoma (P < 0.001). CONCLUSION: These findings show that high levels of BPTPs or BPAs are more closely related to thymic carcinoma and Masaoka stage III/IV, suggesting that BPTPs and BPAs may play an important role in the occurrence and development of thymic malignant tumors.

Small RNA Sequencing Reveals Transfer RNA-derived Small RNA Expression Profiles in Retinal Neovascularization.

Retinal neovascularization (RNV) is characterized in retinopathy of prematurity (ROP), diabetic retinopathy (DR), and retinal vein occlusion (RVO), which leads to severe vision loss and even blindness. To reveal the altered transfer RNA-derived small RNA (tsRNA)s in RNV, and to investigate the underlying mechanisms of the altered tsRNAs involved in RNV, we carried out a small RNA sequencing to profile tsRNA expressions in the retinas of mice with oxygen-induced retinopathy (OIR) and control mice. A total of 45 tsRNAs were significantly changed (fold change ≥ 1.5 and P < 0.05) in the retinas of OIR mice compared with controls. Validation by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) in four selected tsRNAs was consistent with the results of small RNA sequencing. Bioinformatics analyses identified 153 altered target genes of the four validated tsRNAs. These altered target genes were largely enriched in developmental process, cell periphery and protein binding, as well as Th1 and Th2 cell differentiation pathway. Our study suggests tsRNAs play key roles in the pathogenesis of RNV, indicating their therapeutic potential to treat patients with RNV. Moreover, small RNA sequencing is a useful tool to identify changes in tsRNA expression, an important indicator of the progress of retinal diseases.

Altered Long Non-coding RNAs Involved in Immunological Regulation and Associated with Choroidal Neovascularization in Mice.

Choroidal neovascularization (CNV) is a severe complication of the wet form of age-related macular degeneration (AMD). Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of different ocular neovascular diseases. To identify the function and therapeutic potential of lncRNAs in CNV, we assessed lncRNAs and mRNA expression profile in a mouse model of laser-induced CNV by microarray analysis. The results of altered lncRNAs were validated by qRT-PCR. Bioinformatics analyses, including Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were performed to clarify the potential biological functions and signaling pathways with which altered genes are most closely related. Moreover, to identify the interaction of lncRNAs and mRNAs, we constructed a coding-non-coding gene co-expression (CNC) network. By microarray analysis, we identified 716 altered lncRNAs and 821 altered mRNAs in CNV mice compared to controls. A CNC network profile based on 7 validated altered lncRNAs (uc009ewo.1, AK148935, uc029sdr.1, ENSMUST00000132340, AK030988, uc007mds.1, ENSMUST00000180519) as well as 282 interacted and altered mRNAs, and were connected by 713 edges. GO and KEGG analyses suggested that altered mRNAs, as well as those lncRNA-interacted mRNAs were enriched in immune system process and chemokine signaling pathway. Thus, lncRNAs are significantly altered in this mouse model of CNV and are involved in immunological regulation, suggesting that lncRNAs may play a critical role in the pathogenesis of CNV. Thus, dysregulated lncRNAs and their target genes might be promising therapeutic targets to suppress CNV in AMD.

A novel frameshift mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome using targeted exome sequencing.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS. METHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls. RESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls. CONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.

Identifying circRNA-associated-ceRNA networks in retinal neovascularization in mice.

Retinal neovascularization is a complication which caused human vision loss severely. It has been shown that circular RNAs (circRNAs) play essential roles in gene regulation. However, circRNA expression profile and the underlying mechanisms in retinal neovascular diseases remain unclear. In the present study, we identified altered circRNAs in the retinas of oxygen-induced retinopathy (OIR) mouse model by microarray profiling. Microarray analysis revealed that 539 circRNAs were significantly altered in OIR retinas compared with controls. Among them, 185 up-regulated and 354 down-regulated circRNAs were identified. The expression levels of 4 altered circRNAs including mmu_circRNA_002573, mmu_circRNA_011180, mmu_circRNA_016108 and mmu_circRNA_22546 were validated by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Bioinformatic analysis with validated circRNAs such as competing endogenous RNA (ceRNA) regulatory networks with Gene Ontology (GO) enrichment analysis demonstrated that qRT-PCR validated circRNAs were associated with cellular process, cell part and phosphoric ester hydrolase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated that MAPK signaling pathway and renin-angiotensin system were related to validated circRNAs, suggesting these pathways may participate in pathological angiogenesis. The results together suggested that circRNAs were aberrantly expressed in OIR retinas and may play potential roles in retinal neovascular diseases.

Microarray Analysis of Long Non-Coding RNAs and Messenger RNAs in a Mouse Model of Oxygen-Induced Retinopathy.

Objective: Retinal neovascularization is a severe complication of many ocular diseases. To clarify the possible functions and therapeutic potential of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in retinal neovascularization, we assessed their expression profile in a mouse model of oxygen-induced retinopathy (OIR). Methods: Microarray analysis was performed to identify altered lncRNA and mRNA expressions between OIR and control mice. The microarray results were validated by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to determine biological functions and signaling pathways of the altered or interacted mRNAs. A coding-non-coding gene co-expression (CNC) network was constructed to identify the interaction of lncRNAs and mRNAs. Results: We identified 198 up-regulated and 175 down-regulated lncRNAs (fold change≥2.0, P<0.05), respectively in OIR mice compared to control mice. We also identified 412 up-regulated and 127 down-regulated mRNAs (fold change≥2.0, P<0.05), respectively in OIR mice compared to control mice. GO and KEGG analyses suggested that altered mRNAs were enriched in immune system process, exopeptidase activity, ECM-receptor interaction and protein digestion and absorption. Four validated lncRNAs (ENSMUST00000165968, ENSMUST00000153785, ENSMUST00000134409, and ENSMUST00000154285) and the nearby coding gene pairs were analyzed. A CNC network profile based on those validated altered lncRNAs as well as 410 interacted mRNAs was composed of 509 connections. Moreover, the GO and KEGG analyses demonstrated that these interacted mRNAs mainly enriched in blood vessel development, angiogenesis, cell adhesion molecules and leukocyte transendothelial migration pathways. Conclusion: Our data highlight the utility of altered lncRNA and mRNA profiling in understanding the pathogenesis of ischemia-induced retinal neovascularization and further suggest that therapeutic potential of altered lncRNA for retinal neovascularization.

A Missense Mutation in GJA8 Encoding Connexin 50 in a Chinese Pedigree with Autosomal Dominant Congenital Cataract.

Congenital cataract is leading cause of visual impairment and blindness in children worldwide. Approximately one-third of congenital cataract cases are familial, whose genetic etiology can be distinguished by targeted exome sequencing. Here, a three-generation congenital cataract pedigree was recruited, and physical and ophthalmologic examinations were taken. Targeted exome sequencing of 139 cataract-related genes was performed on the proband III:1. Sanger sequencing was used to validate the presence of variation identified via exome sequencing in family members and 200 controls. Conservative and functional prediction was performed with bioinformatic tools. We, thus, found a heterozygous missense mutation c.10T>A (p.W4R) in gap junction protein alpha 8 (GJA8) in the patients. However, this mutation was not present in normal family members and 200 unrelated controls. The GJA8 gene encodes a gap junction protein, connexin 50 (Cx50), in lens fibers that provide channels for exchange of ions and small molecules between adjacent cells. Conservative and functional prediction suggests that the W-to-R substitution at codon 4 may impair the function of the human Cx50 protein. Accordingly, we analyzed the distribution of Flag-tagged mutant Cx50 protein in HeLa cervical cancer cells. Immunofluorescent staining showed that the W-to-R substitution impaired Cx50 trafficking to the plasma membrane to form the gap junction. In conclusion, c.10T>A (p.W4R) in GJA8 is the newly identified genetic cause of familial congenital cataract. The W-to-R substitution near the amino-terminus may alter the localization of mutant Cx50, thereby impairing gap junction formation, which is the molecular pathogenic mechanism of this mutation.

Effects of nicotine on proliferation and survival in human umbilical cord mesenchymal stem cells.

Cigarette smoking is known to have negative effects on tissue repair and healing. The aim of this study is to investigate the effects of nicotine in human umbilical cord mesenchymal stem cells (MSCs). After nicotine treatment, MSCs became pyknotic, vacuoles appeared in the cytoplasm and nucleus, and the nuclear boundary became fuzzy as observed using atomic force microscopy. Cell proliferation was inhibited in a dose-dependent manner (P < 0.05 for all concentrations). The proportion of apoptotic MSCs was significantly increased in a dose-dependent manner. The mitochondrial membrane potential was significantly decreased (P < 0.05). Nicotine-treated MSCs had a significantly higher G0/G1 ratio (P < 0.05). Peptide mass fingerprinting identified 27 proteins that were differentially expressed between MSCs with and without nicotine treatment. These nicotine exerted toxic effects on MSCs are likely related, at least in part, to the altered expression of multiple proteins that are essential to the health and proliferation of these cells.

HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs.

Human epidermal growth factor receptor 3 (HER3), which is part of the HER family, is aberrantly expressed in various human cancers. Since HER3 only has weak tyrosine kinase activity, when HER3 ligand neuregulin 1 (NRG1) or neuregulin 2 (NRG2) appears, activated HER3 contributes to cancer development and drug resistance by forming heterodimers with other receptors, mainly including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Inhibition of HER3 and its downstream signaling, including PI3K/AKT, MEK/MAPK, JAK/STAT, and Src kinase, is believed to be necessary to conquer drug resistance and improve treatment efficiency. Until now, despite multiple anti-HER3 antibodies undergoing preclinical and clinical studies, none of the HER3-targeted therapies are licensed for utilization in clinical cancer treatment because of their safety and efficacy. Therefore, the development of HER3-targeted drugs possessing safety, tolerability, and sensitivity is crucial for clinical cancer treatment. This review summarizes the progress of the mechanism of HER3 in drug resistance, the HER3-targeted therapies that are conducted in preclinical and clinical trials, and some emerging molecules that could be used as future designed drugs for HER3, aiming to provide insights for future research and development of anticancer drugs targeting HER3.

Loss of Sarm1 reduces retinal ganglion cell loss in chronic glaucoma.

Glaucoma is one of the leading causes of irreversible blindness worldwide and vision loss in the disease results from the deterioration of retinal ganglion cells (RGC) and their axons. Metabolic dysfunction of RGC plays a significant role in the onset and progression of the disease in both human patients and rodent models, highlighting the need to better define the mechanisms regulating cellular energy metabolism in glaucoma. This study sought to determine if Sarm1, a gene involved in axonal degeneration and NAD+ metabolism, contributes to glaucomatous RGC loss in a mouse model with chronic elevated intraocular pressure (IOP). Our data demonstrate that after 16 weeks of elevated IOP, Sarm1 knockout (KO) mice retain significantly more RGC than control animals. Sarm1 KO mice also performed significantly better when compared to control mice during optomotor testing, indicating that visual function is preserved in this group. Our findings also indicate that Sarm1 KO mice display mild ocular developmental abnormalities, including reduced optic nerve axon diameter and lower visual acuity than controls. Finally, we present data to indicate that SARM1 expression in the optic nerve is most prominently associated with oligodendrocytes. Taken together, these data suggest that attenuating Sarm1 activity through gene therapy, pharmacologic inhibition, or NAD+ supplementation, may be a novel therapeutic approach for patients with glaucoma.

The prediction model for intraoperatively acquired pressure injuries in orthopedics based on the new risk factors: a real-world prospective observational, cross-sectional study.

Introduction: Orthopedic patients are at high risk for intraoperatively acquired pressure injuries (IAPI), which cause a serious issue and lead to high-expense burden in patient care. However, there are currently no clinically available scales or models to assess IAPI associated with orthopedic surgery. Methods: In this real-world, prospective observational, cross-sectional study, we identified pressure injuries (PI)-related risk factors using a systematic review approach and clinical practice experience. We then prepared a real-world cohort to identify and confirm risk factors using multiple modalities. We successfully identified new risk factors while constructing a predictive model for PI in orthopedic surgery. Results: We included 28 orthopedic intraoperative PI risk factors from previous studies and clinical practice. A total of 422 real-world cases were also included, and three independent risk factors-preoperative limb activity, intraoperative wetting of the compressed tissue, and duration of surgery-were successfully identified using chi-squared tests and logistic regression. Finally, the three independent risk factors were successfully used to construct a nomogram clinical prediction model with good predictive validity (area under the ROC curve = 0.77), which is expected to benefit clinical patients. Conclusion: In conclusion, we successfully identified new independent risk factors for IAPI-related injury in orthopedic patients and developed a clinical prediction model to serve as an important complement to existing scales and provide additional benefits to patients. Our study also suggests that a single measure is not sufficient for the prevention of IAPI in orthopedic surgery patients and that a combination of measures may be required for the effective prevention of IAPI.

Cholesterol Efflux Drives the Generation of Immunosuppressive Macrophages to Promote the Progression of Human Hepatocellular Carcinoma.

Cholesterol is often enriched in tumor microenvironment (TME); however, its impact on disease progression varies in different tissues and cells. Monocytes/macrophages (Mφ) are major components and regulators of the TME and play pivotal roles in tumor progression and therapeutic responses. We aimed to investigate the profile, effects, and regulatory mechanisms of Mφ cholesterol metabolism in the context of human hepatocellular carcinoma (HCC). Here, we found that patients with high serum levels of cholesterol had shorter survival times and lower response rates to anti-PD-1 treatment. However, the cholesterol content in tumor-infiltrating monocytes/Mφ was significantly lower than that in their counterparts in paired nontumor tissues. The expression of the cholesterol efflux transporter, ABCA1, was upregulated in tumor monocytes/Mφ, and ABCA1 upregulation positively associated with decreased cellular cholesterol content and increased serum cholesterol levels. Mechanistically, autocrine cytokines from tumor-treated monocytes increased LXRα and ABCA1 expression, which led to the generation of immature and immunosuppressive Mφ. Although exogenous cholesterol alone had little direct effect on Mφ, it did act synergistically with tumor-derived factors to promote ABCA1 expression in Mφ with more immunosuppressive features. Moreover, high numbers of ABCA1+ Mφ in HCC tumors associated with reduced CD8+ T-cell infiltration and predicted poor clinical outcome for patients. Our results revealed that dysregulated cholesterol homeostasis, due to the collaborative effects of tumors and exogenous cholesterol, drives the generation of immunosuppressive Mφ. The selective modulation of cholesterol metabolism in Mφ may represent a novel strategy for cancer treatment.

Levels of pretreatment serum lipids predict responses to PD-1 inhibitor treatment in advanced intrahepatic cholangiocarcinoma.

BACKGROUND: It has been identified that serum lipids can be used as prognostic biomarkers in several types of cancer and are associated with patient survival. We aimed to clarify the prognostic value of the serum lipids and to establish a novel effective nomogram for overall survival (OS) in intrahepatic cholangiocarcinoma (iCCA) patients receiving anti-PD1 therapy. METHODS: Pretreatment serum lipids were retrospectively analyzed for prognostic value, including apolipoprotein B (APOB), apolipoproteinA-1 (APOA1), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), which were assessed for prediction accuracy using Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC). Cox regression analysis with univariate and multivariate factors was used to identify prognostic factors predictive of OS, and prognostic nomograms were constructed. RESULTS: All the serum lipids showed good discriminatory ability in terms of OS (all P < 0.05), the higher the lipid levels, the better the prognosis, while APOA1 and TG were remarkable independent predictors for OS in multivariate analysis (hazard ratio, 2.177,2.035; confidence interval, 1.393-3.402, 1.184-3.498; P = 0.001, P = 0.01). Four (CA19-9, APOA1, tumor number and TG) independent prognostic factors were chosen to generate the nomogram for OS. The area under the ROC curve at 1-year and 2-year consistently demonstrated that the predictive value of the nomogram was superior to serum lipids. CONCLUSION: In our study, serum lipid levels were used as a prognostic nomogram in the prediction of anti-PD-1 therapy efficacy in patients with iCCA.

Comparable Clinical Outcomes Between Transarterial Chemoembolization or Hepatic Arterial Infusion Chemotherapy Combined with Tyrosine Kinase Inhibitors and PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma.

Purpose: To compare the treatment efficacy and safety of transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKIs) and programmed cell death protein-1 (PD-1) inhibitors for patients with unresectable hepatocellular carcinoma (HCC). Patients and Methods: 81 unresectable HCC patients were retrospectively analyzed, including 30 or 51 patients treated with either TKIs and PD-1 inhibitors combined with TACE (TTP) or HAIC (HTP), respectively. Tumor response and survival outcomes were compared. Results: The median overall survival (mOS) was 21.0 months in the TTP group and 15.0 months in the HTP group (P = 0.525; HR = 1.23; 95% CI 0.66-2.29). The median progression-free survival (mPFS) was 6.7 months in the TTP group and 9.9 months in the HTP group (P = 0.160; HR = 0.70; 95% CI 0.42-1.16). After Propensity Score Matching (PSM), the mOS was 21.0 months in the TTP group and 18.0 months in the HTP group (P = 0.644; HR = 1.20; 95% CI 0.56-2.58). The mPFS was 6.4 months in the TTP group and 15.0 months in the HTP group (P = 0.028; HR = 0.49; 95% CI 0.26-0.93). The disease control rate in overall response (90.2% vs 76.7%, P = 0.116, before PSM; 91.7% vs 75.0%, P = 0.121, after PSM) and intrahepatic response (94.1% vs 80.0%, P = 0.070, before PSM; 91.7% vs 79.2%, P = 0.220, after PSM) were higher in the HTP group than in the TTP group. Conclusion: Though including more advanced tumors, the clinical outcomes of HAIC combined with TKIs and PD-1 inhibitors are comparable to TACE-based combination therapy for unresectable HCC. Nevertheless, HTP significantly improved the PFS benefits in HCC patients with with large tumor burden or vascular invasion.

Cholesterol and C-reactive protein prognostic score predicted prognosis of immune checkpoint inhibitors based interventional therapies for intermediate-to-advanced hepatocellular carcinoma patients.

Serum cholesterol (CHO) and C-reactive protein (CRP) have been successfully used as prognostic predictors for several malignancies, respectively. However, the clinicopathological significance of CHO and CRP levels in hepatocellular carcinoma (HCC) patients treated with ICIs-based hepatic artery infusion chemotherapy (HAIC) remains unclear. Serum CHO and CRP levels were measured for a total of 152 HCC patients that had been treated with ICIs-based HAIC from February 2019 to April 2020. Efficacy was evaluated according to tumor response and survival. The median OS was not reached in the CHO-low subgroup and 17.7 months in the CHO-high subgroup (P = 0.015). The median OS was not reached in the CRP-low subgroup and 20.0 months in the CRP-high subgroup (P = 0.010). Univariate and multivariate Cox regression analysis demonstrated that both serum CHO and CRP levels were independent risk factors for the OS of HCC patients treated with ICIs-based HAIC (P < 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. CHO and CRP prognostic score (CCPS) combining CHO and CRP levels could significantly stratify HCC patients receiving ICIs-based HAIC into low-, intermediate-, and high-risk subgroups (P < 0.001). Patients in the risk subgroups reported similar disease control rates (P = 0.121) and significantly different overall response rates (low- vs intermediate- vs high-risk groups: 70.6 % vs 46.6 % vs 44.1 %, respectively, P = 0.038) according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). The results of this study support the association between CCPS high risk with the response and OS for HCC patients receiving ICIs-based HAIC.

Tenofovir vs. Entecavir on Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma after Radiofrequency Ablation.

For patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) treated with curative radiofrequency ablation (RFA), the effect of entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF) on recurrence-free survival (RFS) and overall survival (OS) remains unclear. We aimed to compare the outcomes of patients receiving ETV or TDF after RFA. This study consecutively collected patients who were treated with ETV (n = 202) or TDF (n = 102) for chronic hepatitis B (CHB) after curative RFA of HCC from December 2015 to January 2021 at Sun Yat-sen University Cancer Center. There were 130 patients in the ETV group and 77 patients in the TDF group after we performed 1-to-n propensity score matching. Kaplan−Meier and Cox regression analyses were performed to validate possible risk factors for RFS and OS. In addition, we estimated the curative effect of ETV and TDF for HBV-related hepatitis by recording the change in serum HBV DNA and ALBI grade after RFA. During the study period (median 34.1 (interquartile range: 19.6−47.4 months) months), 123 (40.5%) patients suffered HCC recurrence, and 15 (4.9%) died. In the full cohort, the probability of HCC recurrence (41.6% vs. 37.3%, p = 0.49) and overall survival (95% vs. 95.1%, p = 0.39) at 5 years were similar between the ETV and TDF groups. In the matched cohort, HCC recurrence (40.8% vs. 40.3%, p = 0.35) and overall survival (96.9% vs. 93.5%, p = 0.12) at 5 years were similar between the ETV and TDF groups. Furthermore, the early RFS (<2 years) did not differ significantly between the two groups in the full and matched cohorts (p = 0.26, p = 0.13). Compared with the ALBI grade before RFA, the ALBI grade of 80 patients (41%) remained stable or improved in the ETV group and 64 patients (64%) in the TDF group (p < 0.001). The mean time of serum HBV DNA reduction to 0 was 9.13 (95% CI: 5.92−12.33) and 2.75 (95% CI: 2.01−3.49) months in the ETV and TDF groups, respectively (p = 0.015). The RFS and OS of patients after curative RFA for HCC were not significantly different between the ETV and TDF groups. TDF therapy was associated with a better effect of protecting liver function and reducing the load of HBV. Further validation studies are needed.

Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models.

Neuroinflammation significantly contributes to the pathophysiology of several neurodegenerative diseases. This is also the case in glaucoma and may be a reason why many patients suffer from progressive vision loss despite maximal reduction in intraocular pressure. Pioglitazone is an agonist of the peroxisome proliferator-activated receptor gamma (PPARγ) whose pleiotrophic activities include modulation of cellular energy metabolism and reduction in inflammation. In this study we employed the DBA2/J mouse model of glaucoma with chronically elevated intraocular pressure to investigate whether oral low-dose pioglitazone treatment preserves retinal ganglion cell (RGC) survival. We then used an inducible glaucoma model in C57BL/6J mice to determine visual function, pattern electroretinographs, and tracking of optokinetic reflex. Our findings demonstrate that pioglitazone treatment does significantly protect RGCs and prevents axonal degeneration in the glaucomatous retina. Furthermore, treatment preserves and partially reverses vision loss in spite of continuously elevated intraocular pressure. These data suggest that pioglitazone may provide treatment benefits for those glaucoma patients experiencing continued vision loss.

A Nomogram Based on Preoperative Lab Tests, BMI, ICG-R15, and EHBF for the Prediction of Post-Hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma.

Background: Liver cancer is one of the most common malignant tumors, and worldwide, its incidence ranks sixth, and its morality third. Post-hepatectomy liver failure (PHLF) is the leading cause of death in patients who have undergone liver resection. This retrospective study investigated the risk factors for PHLF by predicting and constructing an index to evaluate the risk. This was achieved by combining the lab tests with an indocyanine green (ICG) clearance test. Methods: The study analyzed 1081 hepatocellular carcinoma (HCC) patients who had received liver resection at Sun Yat-sen University Cancer Center between 2005 and 2020. The patients were divided into a PHLF group (n = 113) and a non-PHLF group (n = 968), according to the International Study Group of Liver Surgery (ISGLS) criteria. Receiver operating characteristics (ROC) curves were then used to estimate the optimal cut-off values. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors. Finally, a nomogram was constructed where the calibration plot, the areas under the ROC curve (AUC), and the decision curve analysis (DCA) showed good predictive ability. Results: Correlation analysis revealed that body mass index (BMI) was positively correlated with ICG-R15 and with effective hepatic blood flow (EHBF). Univariate and multivariate logistics regression analysis revealed that BMI, ICG-R15, international normalized ratio (INR), tumor size, hepatic inflow occlusion (HIO) time, and operation method were independent predictive factors for PHLF. When these factors and EHBF were included in the nomogram, the nomogram showed a good predictive value, with a C-index of 0.773 (95% Confidence Interval [CI]: 0.729-0.818). The INR had the largest ROC areas (AUC INR = 0.661). Among the variables, ICG-R15 (AUC ICG-R15 = 0.604) and EHBF (AUC EHBF = 0.609) also showed good predictive power. Conclusions: The risk of PHLF in HCC patients can be precisely predicted by this model prior to the operation. By integrating EHBF into the model, HCC patients at higher risk for PHLF can be identified more effectively.

Inflammation-Based Scores Predict Responses to PD-1 Inhibitor Treatment in Intrahepatic Cholangiocarcinoma.

Purpose: Inflammatory response is related to tumor progression and patient survival. We aimed to clarify the prognostic value of the inflammation-based scores in intrahepatic cholangiocarcinoma (ICC) patients receiving anti-PD1 therapy. Patients and Methods: A total of 73 patients who received anti-PD-1 therapy from February 2019 to February 2021 were included in the study. Representative inflammation-based prognostic scores, including C-reactive protein (CRP), the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-CRP ratio (LCR), lymphocyte-to-monocyte ratio (LMR), systemic immune inflammation index (SII), CRP-to-albumin ratio (CAR), prognostic nutritional index (PNI), Glasgow Prognostic Score (GPS), and prognostic index (PI), were assessed for prediction accuracy using Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC). All the ten inflammation-based prognostic scores were measured before receiving anti-PD1 therapy. Results: All the ten inflammation-based prognostic scores showed good discriminatory ability in terms of overall survival (OS) (all P < 0.01), the higher the score, the worse the prognosis, while the CRP score was a remarkable independent predictor for OS in multivariate analysis (hazard ratio, 6.032; confidence interval, 2.467-14.752; P < 0.001). The area under the ROC curve at 6 months, 12 months, 18 months and 24 months consistently demonstrated that the predictive value of the CRP score was superior to other inflammation-based scores. Conclusion: Inflammation-based scores predict the efficacy of anti-PD-1 therapy in patients with ICC and CRP score superior to the other inflammation-based prognostic scores in terms of predictive ability.