Metabolic Enzyme SLC27A5 Regulates PIP4K2A pre-mRNA Splicing as a Noncanonical Mechanism to Suppress Hepatocellular Carcinoma Metastasis.

Solute carrier family 27 member 5, a key enzyme in fatty acid transport and bile acid metabolism in the liver, is frequently expressed in low quantities in patients with hepatocellular carcinoma, resulting in poor prognosis. However, it is unclear whether SLC27A5 plays non-canonical functions and regulates HCC progression. Here, an unexpected non-canonical role of SLC27A5 is reported: regulating the alternative splicing of mRNA to inhibit the metastasis of HCC independently of its metabolic enzyme activity. Mechanistically, SLC27A5 interacts with IGF2BP3 to prevent its translocation into the nucleus, thereby inhibiting its binding to target mRNA and modulating PIP4K2A pre-mRNA splicing. Loss of SLC27A5 results in elevated levels of the PIP4K2A-S isoform, thus positively regulating phosphoinositide 3-kinase signaling via enhanced p85 stability in HCC. SLC27A5 restoration by AAV-Slc27a5 or IGF2BP3 RNA decoy oligonucleotides exerts an inhibitory effect on HCC metastasis with reduced expression of the PIP4K2A-S isoform. Therefore, PIP4K2A-S may be a novel target for treating HCC with SLC27A5 deficiency.

Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid.

Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5-/- ) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4 ) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re-expression of hepatic SLC27A5 by an adeno-associated virus or the reduction of CA levels in the liver using A4250, an apical sodium-dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5-/- mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA-induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment.

Prediction model of no-response before the first transarterial chemoembolization for hepatocellular carcinoma: TACF score.

Previous clinic models for patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) mainly focused on the overall survival, whereas a simple-to-use tool for predicting the response to the first TACE and the management of risk classification before TACE are lacking. Our aim was to develop a scoring system calculated manually for these patients. A total of 437 patients with hepatocellular carcinoma (HCC) who underwent TACE treatment were carefully selected for analysis. They were then randomly divided into two groups: a training group comprising 350 patients and a validation group comprising 77 patients. Furthermore, 45 HCC patients who had recently undergone TACE treatment been included in the study to validate the model's efficacy and applicability. The factors selected for the predictive model were comprehensively based on the results of the LASSO, univariate and multivariate logistic regression analyses. The discrimination, calibration ability and clinic utility of models were evaluated in both the training and validation groups. A prediction model incorporated 3 objective imaging characteristics and 2 indicators of liver function. The model showed good discrimination, with AUROCs of 0.735, 0.706 and 0.884 and in the training group and validation groups, and good calibration. The model classified the patients into three groups based on the calculated score, including low risk, median risk and high-risk groups, with rates of no response to TACE of 26.3%, 40.2% and 76.8%, respectively. We derived and validated a model for predicting the response of patients with HCC before receiving the first TACE that had adequate performance and utility. This model may be a useful and layered management tool for patients with HCC undergoing TACE.

Comparison of endoscopic submucosal dissection outcomes between early gastric cardiac and non-cardiac cancers: a retrospective single-center study.

OBJECTIVES: This study aims to compare the efficacy of endoscopic submucosal dissection (ESD) between early gastric cardiac cancer (EGCC) and early gastric non-cardiac cancer (EGNCC), and investigate associated risk factors for non-curative resection. METHODS: Early gastric cancer (EGC) patients who underwent ESD from January 2015 to September 2020 in Beijing Friendship Hospital were consecutively enrolled. The clinical, histopathological and endoscopic data were retrospectively analyzed. The study was registered in Chinese Clinical Trial Registry (ChiCTR1800017117). RESULTS: Among 500 patients with 534 EGC lesions, 117 patients with 118 lesions were allocated to the EGCC group, and 383 patients with 416 lesions to the EGNCC group. The rates of en bloc resection, complete resection and curative resection in the EGCC group were 97.5%, 78.8% and 71.2%, respectively, significantly lower than those in the EGNCC group (99.8%, 94.5% and 90.4%, p = .010, <.001 and <.001). Among non-curative resected lesions, EGCC had more cases in both endoscopic curability (eCura) C-1 and C-2 groups than EGNCC (10.2% and 18.6% vs. 2.4% and 7.2%, p < .001). Multivariate analysis showed that tumor size (OR 2.393, 95% CI 1.388-4.126) and submucosal invasion (OR 11.498, 95% CI 3.759-35.175) were risk factors for non-curative resection in the EGCC group. For EGCC larger than 3 cm, none achieved curative resection, 86.7% were classified as eCura C-2 and 46.7% exhibited deep submucosal infiltration. CONCLUSIONS: The curative resection rate of ESD for EGCC was lower than that for EGNCC. ESD for EGCC larger than 3 cm should be cautiously considered.

Phage Display-Derived Peptides and Antibodies for Bacterial Infectious Diseases Therapy and Diagnosis.

The emergence of antibiotic-resistant-bacteria is a serious public health threat, which prompts us to speed up the discovery of novel antibacterial agents. Phage display technology has great potential to screen peptides or antibodies with high binding capacities for a wide range of targets. This property is significant in the rapid search for new antibacterial agents for the control of bacterial resistance. In this paper, we not only summarized the recent progress of phage display for the discovery of novel therapeutic agents, identification of action sites of bacterial target proteins, and rapid detection of different pathogens, but also discussed several problems of this technology that must be solved. Breakthrough in these problems may further promote the development and application of phage display technology in the biomedical field in the future.

Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGFß signalling pathway.

BACKGROUND: Glucuronic acid metabolism participates in cellular detoxification, extracellular matrix remodeling and cell adhesion and migration. Here, we aimed to explore the crosstalk between dysregulated glucuronic acid metabolism and crucial metastatic signalling in glutathione S-transferase zeta 1 (GSTZ1)-deficient hepatocellular carcinoma (HCC). METHODS: Transwell, HCC xenograft and Gstz1-/- mouse models were used to examine the role of GSTZ1 in HCC metastasis. Non-targeted and targeted metabolomics and global transcriptomic analyses were performed to screen significantly altered metabolic and signalling pathways in GSTZ1 overexpressing hepatoma cells. Further, RNA-binding protein immunoprecipitation, Biotin-RNA pull-down, mRNA decay assays and luciferase reporter assays were used to explore the interaction between RNA and RNA-binding proteins. RESULTS: GSTZ1 was universally silenced in both human and murine HCC cells, and its deficiency contributed to HCC metastasis in vitro and in vivo. UDP-glucose 6-dehydrogenase (UGDH)-mediated UDP-glucuronic acid (UDP-GlcUA) accumulation promoted hepatoma cell migration upon GSTZ1 loss. UDP-GlcUA stabilized TGFßR1 mRNA by enhancing its binding to polypyrimidine tract binding protein 3, contributing to the activation of TGFß/Smad signalling. UGDH or TGFßR1 blockade impaired HCC metastasis. In addition, UGDH up-regulation and UDP-GlcUA accumulation correlated with increased metastatic potential and decreased patient survival in GSTZ1-deficient HCC. CONCLUSIONS: GSTZ1 deficiency and subsequent up-regulation of the glucuronic acid metabolic pathway promotes HCC metastasis by increasing the stability of TGFßR1 mRNA and activating TGFß/Smad signalling. UGDH and a key metabolite, UDP-GlcUA, may serve as prognostic markers. Targeting UGDH might be a promising strategy for HCC therapy.

Amphipathic dendritic poly-peptides carrier to deliver antisense oligonucleotides against multi-drug resistant bacteria in vitro and in vivo.

BACKGROUND: Outbreaks of infection due to multidrug-resistant (MDR) bacteria, especially Gram-negative bacteria, have become a global health issue in both hospitals and communities. Antisense oligonucleotides (ASOs) based therapeutics hold a great promise for treating infections caused by MDR bacteria. However, ASOs therapeutics are strangled because of its low cell penetration efficiency caused by the high molecular weight and hydrophilicity. RESULTS: Here, we designed a series of dendritic poly-peptides (DPP1 to DPP12) to encapsulate ASOs to form DSPE-mPEG2000 decorated ASOs/DPP nanoparticles (DP-AD1 to DP-AD12) and observed that amphipathic DP-AD2, 3, 7 or 8 with a positive charge ≥ 8 showed great efficiency to deliver ASOs into bacteria, but only the two histidine residues contained DP-AD7 and DP-AD8 significantly inhibited the bacterial growth and the targeted gene expression of tested bacteria in vitro. DP-AD7anti-acpP remarkably increased the survival rate of septic mice infected by ESBLs-E. coli, exhibiting strong antibacterial effects in vivo. CONCLUSIONS: For the first time, we designed DPP as a potent carrier to deliver ASOs for combating MDR bacteria and demonstrated the essential features, namely, amphipathicity, 8-10 positive charges, and 2 histidine residues, that are required for efficient DPP based delivery, and provide a novel approach for the development and research of the antisense antibacterial strategy.

Efficacy of oral steroid gel in preventing esophageal stricture after extensive endoscopic submucosal dissection: a randomized controlled trial.

BACKGROUND AND AIMS: Esophageal stricture is a distressing issue for patients with early esophageal cancer following extensive endoscopic submucosal dissection (ESD), and the current steroid-based approaches are unsatisfactory for stricture prophylaxis. We evaluated the efficacy of oral hydrocortisone sodium succinate and aluminum phosphate gel (OHA) for stricture prophylaxis after extensive ESD. METHODS: Patients undergoing > 3/4 circumferential ESD were randomized to either the endoscopic loco-regional triamcinolone acetonide injection (ETI) plus oral prednisone group or the OHA group. The primary endpoint was incidence of esophageal stricture, and the secondary endpoints included adverse events (AEs) and endoscopic balloon dilations (EBDs). RESULTS: The incidence of esophageal stricture in OHA group (per-protocol analysis, 9.4%, 3/32; intention-to-treat analysis, 12.1%, 4/33) was significantly less than that of control group (per-protocol analysis, 35.5%, 11/31, P = 0.013; intention-to-treat analysis, 39.4%, 13/33, P = 0.011). Two sessions of EBD were necessary to release all strictures in the OHA group, while the similar EBDs (median 2, range 1-4) for 11 of the control. Operation-related AEs included infection (control vs. OHA group = 9.7% vs. 31.3%, P = 0.034), operation-related hypokalemia (19.4% vs. 31.3%, P = 0.278), perforation (3.2% vs. 3.1%), post-ESD hemorrhage (6.5% vs. 0%), and cardiac arrhythmia (0% vs. 6.3%). Steroid-related AEs included steroid-related hypokalemia (16.1% vs. 25%) and bone fracture (3.2% vs. 0%). Multivariate logistic regression analysis demonstrated that OHA was an independent protective factor for stricture (OR 0.079; 95%CI 0.011, 0.544; P = 0.01) and mucosal defect > 11/12 circumference was an independent risk factor (OR 49.91; 95%CI 6.7, 371.83; P < 0.001). CONCLUSIONS: OHA showed significantly better efficacy in preventing esophageal stricture after > 3/4 circumferential ESD compared to ETI plus oral prednisone.

Surfactin isoforms isolated from a mushroom derived Bacillus halotolerans DMG-7-2.

A new iso-C14 [Val2, Val7] surfactin isoform (1) together with eight known ones (2-9), was isolated from the culture of a mushroom derived bacterium, Bacillus halotolerans DMG-7-2. The structures of them were mainly elucidated by NMR and MS data, and the NMR data of 5 also was reported for the first time. The absolute configuration of 1 was determined by Marfey's analysis (for amino acid residues) and the 13C NMR calculation of the two plausible epimers of 1 (for fatty acid). Compounds 1-9 showed moderate cytotoxicity against two human cancer cell lines (A549, MCF-7) and mice microglial BV2 cells, the IC50 values ranged from 8.91 to 33.00 µM, and the IC50 values of the positive control 5-FU were 99.94, 71.49 and 0.12 µM, respectively.[Formula: see text].

Chemical characters and protective effect of Baqi Lingmao formula on experimental liver injury.

OBJECTIVE: To investigate the chemical characters of water-extract of Baqi Lingmao formula (BQLM formula) and its effects on anti-liver injury in model mice and live cells. METHODS: BQLM formula was composed of ten herbal medicines. We determined the contents of alkaloids, saponins, phenolic acids and flavonoid in BQLM formula by UV spectrophotometry. The active components of alkaloids and phenolic acids in BQLM formula were identified by HPLC chromatography. The anti-hepatic injury effects of BQLM formula were investigated with concanavalin A (ConA)-induced hepatitis model of mice, human liver LO2 and HepG2.2.15 cells. RESULTS: BQLM formula (2 and 10 g/kg, orally) significantly improved the damages of liver tissues and functions caused by ConA in mice, reduced the infiltration of inflammatory cells into liver and inhibited the inflammatory cytokine secretion of interferon-γ, tumor necrosis factor-α and interleukin-6. BQLM formula simultaneously decreased the levels of alanine aminotransferase and aspartate aminotransferase of liver and serum, and recovered the superoxide dismutase and catalase activities of liver to normal levels in ConA-induced hepatic-injury mice. The serum of BQLM formula group stimulated the human liver LO2 cell proliferation in vitro. Further, BQLM formula obviously promoted the proliferation of normal hepatocytes (LO2 cells) and inhibited the hepatocytes death induced by ConA. It also significantly inhibited the proliferation of HepG2.2.15 cells and decreased the secretion of HBsAg and HBeAg in vitro. CONCLUSIONS: BQLM formula has anti-inflammation and anti-hepatitis virus Beffects, and is capable of improving liver injury in vivo and in vitro.

Clinical Efficacy of Treating Endometrial Cancer with Xiaoaiping Tablets under Comprehensive Nursing Intervention and Their Effect on Quality of Life.

OBJECTIVE: To explore the clinical efficacy of treating endometrial cancer with Xiaoaiping tablets under comprehensive nursing intervention and their effect on quality of life. METHODS: The clinical data of 120 endometrial cancer patients treated at the Affiliated Hospital of Southwest Medical University from February 2019 to February 2020 were retrospectively analyzed, and the patients were split into the experimental group and the control group according to their admission order, with 60 cases each. Conventional treatment and Xiaoaiping tablet regimen were received by all patients, those in the control group accepted the general nursing, and those in the experimental group accepted the comprehensive nursing intervention for 12 months, so as to compare their clinical efficacy, quality of life (Functional Assessment of Cancer Therapy, FACT), negative emotion scores (Hospital Anxiety and Depression Scale, HAD), and Medical Coping Modes Questionnaire (MCMQ) scores between the two groups. RESULTS: No statistical differences in the patients' general information between the two groups were observed (P > 0.05); compared with the control group after nursing, the experimental group obtained a significantly higher objective remission rate (80.0%), significantly higher disease control rate (90.0%) (P < 0.05), significantly better QOL (P < 0.001), significantly lower negative emotion scores (P < 0.001), and significantly better MCMQ scores (P < 0.001). CONCLUSION: Adopting Xiaoaiping tablets under comprehensive nursing intervention can improve the negative emotions of patients with endometrial cancer, enhance their confidence in medical treatment, present better efficacy, and obviously promote their QOL. Therefore, comprehensive nursing intervention should be promoted and applied in practice.

Difficult endoscopic resection of a giant esophageal fibrovascular polyp: case report and literature review.

Esophageal fibrovascular polyp is rare in esophageal neoplasms and usually very large. Here, we present a case of giant esophageal fibrovascular polyp. The patient had dysphagia and choking sensation at presentation. She underwent positron emission-computed tomography (PET-CT), endoscopy, endoscopic ultrasonography, and fine needle aspiration. She was clinically diagnosed as having an esophageal benign tumor and underwent endoscopic submucosal dissection. The polyp was successfully resected; however, the process was very difficult, and the lesion was too large to pass through the upper esophagus. Finally, we removed the lesion surgically. Fibrovascular polyps are often large, and if endoscopic resection is chosen, it is necessary to consider the difficulties that may be encountered during resection, before initiating treatment.

A prognostic index model for predicting long-term recurrence of uterine leiomyoma after myomectomy.

INTRODUCTION: Uterine leiomyoma (UL) is a common benign pelvic tumor in women that has a high recurrence rate. Our aim is to propose a prognostic index (PI) model for predicting the long-term recurrence risk of uterine leiomyoma (UL). METHODS: A total of 725 women who underwent myomectomy were enrolled in this retrospective multicenter study. Patients were contacted for follow-up. A PI model was proposed based on the multivariate Cox regression analysis in the model group. The predictive value of this model was tested in both internal and external validation group. RESULTS: PI formula = 1.5(if 3-5 leiomyomas) or 2(if >5 leiomyomas)+1(if residue)+1(if not submucosal)+1(if combined endometriosis). The PI value was divided into low-risk, intermediate-risk, and high-risk group by cut-off values 1.25 and 3.75. In the model group, the high-risk group had a significantly 4.55 times greater recurrence risk of UL than that in the low-risk group [cumulative recurrence rate (CR): 82.1% vs 29.5%, HR = 4.55, 95% CI 2.821-7.339]; the intermediate-risk group had a significantly 2.81 times greater recurrence risk of UL than that in the low-risk group (CR: 62.3% vs 29.5%, HR = 2.81, 95% CI 2.035-3.878). The differences between any two risk groups were also significant (P< 0.05) in both internal and external validation groups. CONCLUSION: The model was proved to be effective in predicting recurrence of UL after myomectomy.

High L1CAM expression predicts poor prognosis of patients with endometrial cancer: A systematic review and meta-analysis.

BACKGROUD: Previous studies have reported that the levels of L1 cell adhesion molecule (L1CAM) indicate poor prognosis of patients with various solid tumors. However, the prognostic significance of L1CAM in endometrial cancer has remained controversial. Herein, we conducted a systematic review and meta-analysis to evaluate the prognostic value of L1CAM in endometrial cancer. METHODS: All studies related to the association between L1CAM expression and clinical characteristics of endometrial cancer were identified by searching the PubMed, MEDLINE, EMBASE, and Web of Science databases. Primary outcomes of the meta-analysis were the hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS). Secondary outcomes were odds ratios (ORs) for clinicopathological characteristics. Publication bias and sensitivity analysis were conducted to ensure reliability of the results. RESULTS: Overall, 17 studies encompassing 7146 patients were eligible for the meta-analysis. Results showed L1CAM overexpression to be significantly associated with decreased overall survival (HR = 2.87, 95% CI; 1.81-4.55, P < .001) and disease-free survival (HR = 3.32, 95% CI; 1.99-5.55, P < .001) in patients with endometrial cancer. High L1CAM expression was also related to adverse clinicopathological characteristics. CONCLUSION: This systematic review demonstrated that high L1CAM expression is correlated with poor survival outcomes and adverse clinicopathological parameters in patients with endometrial cancer.

Longibramides A-E, Peptaibols Isolated from a Mushroom Derived Fungus Trichoderma longibrachiatum Rifai DMG-3-1-1.

Five new peptaibols, longibramides A-E (1-5) with 11 amino acid residues, were isolated from a fungus Trichoderma longibrachiatum Rifai DMG-3-1-1, which was isolated from a mushroom Clitocybe nebularis (Batsch) P. Kumm collected from coniferous forest in the subboreal area of northeast China. The structures of longibramides A-E were determined by their spectroscopic data (NMR and MS-MS spectra), their absolute configurations were determined by X-ray diffractions and Marfey's analyses. The X-ray diffractions of longibramides A, B, and the similar CD spectra of A-E showed that they all had α-helix conformations. Longibramides B and E showed moderate cytotoxicities against BV2 and MCF-7 cells and also showed some inhibitory effects against methicillin-resistant Staphylococcus aureus MRSA T144. L-trans-Hyp was not commonly found in natural peptaibols, which was the 6th or 10th amino acid residue in longibramides C-E. The X-ray diffractions of longibramides A and B afforded the accuracy conformations of their secondary structures, which maybe help to interpret the structure-activity relationships of the family of peptaibols in the future.

Dietary fiber regulates intestinal flora and suppresses liver and systemic inflammation to alleviate liver fibrosis in mice.

OBJECTIVES: Liver fibrosis is a common pathologic process related to chronic liver disease. However, there are currently no effective methods to reverse liver fibrosis. Chronic liver disease is typically associated with a major imbalance in the intestinal flora, and targeting the regulation of the intestinal flora structure may facilitate the prevention and treatment of chronic liver disease. Therefore, in this study, we explored the effects of dietary fiber on the prevention of liver fibrosis in mice. METHODS: C57BL/6J mice were randomly divided into 4 groups: olive oil group (control), fibrosis (CCl4) group, resistant maltodextrin (RM) + CCl4 group, and wheat fiber (WF) + CCl4 group. In the latter 3 groups, liver fibrosis was established by treatment with CCl4. In the RM + CCl4 and WF + CCl4 groups, the mice were treated with soluble dietary fiber (RM) or insoluble dietary fiber (WF) for 3 wk before receiving CCl4. The effects of dietary fiber on various indexes of liver fibrosis in mice induced by CCl4 were observed. RESULTS: The results showed that increasing dietary fiber intake prevented liver fibrosis in mice, reduced serum levels of proinflammatory factors (e.g., tumor necrosis factor-alpha, interleukin [IL] 1-beta and IL-6) and increased IL-10 and interferon-gamma levels. Moreover, increased dietary fiber intake also reduced the infiltration of cluster of differentiation (CD) 3+, 4+, and 8+ T lymphocytes in the liver, regulated the structure of the intestinal flora, and increased the Bacteroidetes/Firmicutes ratio. CONCLUSIONS: Our findings revealed the complex relationships between dietary fiber, intestinal flora, and immunity, and suggested that dietary therapy could alleviate liver fibrosis.

Targeting Six Hallmarks of Cancer in Ovarian Cancer Therapy.

Normal cells must overcome multiple protective mechanisms to develop into cancer cells. Their new capabilities include self-sufficiency in growth signals and insensitivity to antigrowth signals, evasion of apoptosis, a limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis; these are also termed the six hallmarks of cancer. A deep understanding of the genetic and protein alterations involved in these processes has enabled the development of targeted therapeutic strategies and clinical trial design in the search for ovarian cancer treatments. Clinically, significantly longer progression-free survival has been observed in the single use of PARP, MEK, VEGF and Chk1/Chk2 inhibitors. However, the clinical efficacy of the targeted agents is still restricted to specific molecular subtypes and no trials illustrate a benefit in overall survival. Exploring novel drug targets or combining current feasible biological agents hold great promise to further improve outcomes in ovarian cancer. In this review, we intend to provide a comprehensive description of the molecular alterations involved in ovarian cancer carcinogenesis and of emerging biological agents and combined strategies that target aberrant pathways, which might shed light on future ovarian cancer treatment.

Poly (ADP-ribose) polymerase (PARP) inhibitor regimens for ovarian cancer in phase III randomized controlled trials: a network meta-analysis.

INTRODUCTION: We aimed to evaluate poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) regimens in BRCA-mutated ovarian cancer for patients responsive to front-line platinum (bevacizumab and olaparib, veliparib and chemotherapy, olaparib) or platinum-sensitive relapsed (olaparib, rucaprib, niraparib) patients in phase III randomized controlled trials. METHODS: A network meta-analysis was utilized to generate the direct and indirect comparisons. The primary outcomes for network meta-analysis were efficacy (hazard ratios for progression-free survival in BRCA mutation cohort) and toxicity (odds ratios for all grade 3-4 adverse events). The American Society of Clinical Oncology (ASCO) value framework was used to assess the cost-effectiveness of the PARPi regimens. RESULTS: Network meta-analysis indicated no statistically significant differences in efficacy and toxicity among the assessed upfront or relapsed PARPi regimens (95% CI included 1). The ASCO value framework indicated that current PARPi regimens were similar in clinical benefits, toxicity, and net health benefit in the upfront (bevacizumab and olaparib, veliparib and chemotherapy, olaparib) and relapsed setting (olaparib, rucaprib, niraparib). The addition of bevacizumab to olaparib ($353.72) increased the cost per unit net health benefit for patients compared with olaparib monotherapy ($260.57). The upfront PARPi regimens had lower toxic scores than the regimens used at relapse. CONCLUSIONS: The choice of PARPi regimens both in the upfront and relapsed setting should consider not only efficacy and toxicity but also costs in BRCA mutation patients. Current combining PARPi regimens are not recommended for such patients in the upfront setting from the cost-effective perspective. Upfront PARPi regimens are less toxic than those used at relapse.

Comparison of laparoscopic versus open radical hysterectomy in patients with early-stage cervical cancer: a multicenter study in China.

INTRODUCTION: Recently, the safety of minimally invasive surgery in the treatment of cervical cancer has been questioned. This study was designed to compare the disease-free survival and overall survival of abdominal radical hysterectomy and laparoscopic radical hysterectomy in patients with early-stage cervical cancer. METHODS: A total of 1065 patients with early-stage cervical cancer who had undergone abdominal/laparoscopic radical hysterectomy between January 2013 and December 2016 in seven hospitals were retrospectively analyzed. The 1:1 propensity score matching was performed in all patients. Patients with tumor size ≥2 cm and <2 cm were stratified and analyzed separately. Disease-free survival and overall survival were compared between matched groups. After confirming the normality by the Shapiro-Wilks test, the Mann-Whitney U test and the χ2 test were used for the comparison of continuous and categorical variables, respectively. The survival curves were generated by the Kaplan-Meier method and compared by log-rank test. RESULTS: After matching, a total of 812 patients were included in the disease-free survival and overall survival analyses. In the entire cohort, the laparoscopic radical hysterectomy group had a significantly shorter disease-free survival (HR 1.65, 95% CI 1.00 to 2.73; p=0.048) but not overall survival (HR 1.60, 95% CI 0.89 to 2.88; p=0.12) when compared with the abdominal radical hysterectomy group. In patients with tumor size ≥2 cm, the laparoscopic radical hysterectomy group had a significantly shorter disease-free survival (HR 1.93, 95% CI 1.05 to 3.55; p=0.032) than the abdominal radical hysterectomy group, whereas no significant difference in overall survival (HR 1.90, 95% CI 0.95 to 3.83; p=0.10) was found. Additionally, in patients with tumor size <2 cm, the laparoscopic radical hysterectomy and abdominal radical hysterectomy groups had similar disease-free survival (HR 0.71, 95% CI 0.24 to 2.16; p=0.59) and overall survival (HR 0.59, 95% CI 0.11 to 3.13; p=0.53). CONCLUSION: Laparoscopic radical hysterectomy was associated with inferior disease-free survival compared with abdominal radical hysterectomy in the entire cohort, as well as in patients with tumor size ≥2 cm. For the surgical treatment of patients with early-stage cervical cancer, priority should be given to open abdominal radical hysterectomy.