Tumor-derived Exosomal ENO2 Modulates Polarization of Tumor-associated Macrophages through Reprogramming Glycolysis to Promote Progression of Diffuse Large B-cell Lymphoma.

Macrophages can be polarized into functional classically activated (M1) or alternatively activated (M2) phenotype. Tumor-associated macrophages (TAMs) mainly exhibit M2 phenotype. Previous works determined that up-regulation of enolase 2 (ENO2) in diffuse large B-cell lymphoma (DLBCL) cells can promote macrophages to an M2-like phenotype, thereby consequently promoting the progression of DLBCL. Exosomes are a subset of extracellular vesicles, carrying various bioactive molecules, mediate signals transduction and regulate immune cells. In our study, we investigated the role and related mechanisms of DLBCL-derived exosomal ENO2 in regulating macrophage polarization during DLBCL progression via bioinformatics analysis and a series of experiments. The results of bioinformatics analysis indicated that high expression of ENO2 was positively correlated with DLBCL progression and macrophages M2/M1 ratio. ENO2 protein levels were increased in the exosomes of the sera of DLBCL patients and DLBCL cells. Moreover, the DLBCL-derived exosomes were assimilated by macrophages and then regulated macrophage polarization. The results of in vitro and in vivo experiments showed that DLBCL-derived exosomal ENO2 modulated macrophages polarization (increased M2 phenotype and decreased M1 phenotype), thereby promoting DLBCL proliferation, migration, and invasion. We then revealed that the modulation of macrophages polarization by DLBCL-derived exosomal ENO2 depended on glycolysis and was promoted through GSK3ß/ß-catenin/c-Myc signaling pathway. These findings suggested that DLBCL-derived exosomal ENO2 accelerated glycolysis via GSK3ß/ß-catenin/c-Myc signaling pathway to ultimately promote macrophages to an M2-like phenotype, which can promote the proliferation, migration and invasion of DLBCL, suggesting that exosomal ENO2 may be a promising therapeutic target and prognostic biomarker for DLBCL.

Design and Optimization of Planar Spiral Coils for Powering Implantable Neural Recording Microsystem.

This paper presents a design and optimization method utilizing inductive coupling coils for wireless power transfer in implantable neural recording microsystems, aiming at maximizing power transfer efficiency, which is essential for reducing externally transmitted power and ensuring biological tissue safety. The modeling of inductive coupling is simplified by combining semi-empirical formulations with theoretical models. By introducing the optimal resonant load transformation, the coil optimization is decoupled from an actual load impedance. The complete design optimization process of the coil parameters is given, which takes the maximum theoretical power transfer efficiency as the objective function. When the actual load changes, only the load transformation network needs to be updated instead of rerunning the entire optimization process. Planar spiral coils are designed to power neural recording implants given the challenges of limited implantable space, stringent low-profile restrictions, high-power transmission requirements and biocompatibility. The modeling calculation, electromagnetic simulation and measurement results are compared. The operating frequency of the designed inductive coupling is 13.56 MHz, the outer diameter of the implanted coil is 10 mm and the working distance between the external coil and the implanted coil is 10 mm. The measured power transfer efficiency is 70%, which is close to the maximum theoretical transfer efficiency of 71.9%, confirming the effectiveness of this method.

Long Noncoding RNA SNHG5 Induces the NF-KB Pathway by Regulating miR-181c-5p/CBX4 Axis to Promote the Progression of Non-Small Cell Lung Cancer

Objective: Explorations have been progressing in decoding the mechanism of non-small cell lung cancer (NSCLC). However, long noncoding RNA small nucleolar RNA host gene 5/microRNA-181c-5p/chromobox protein 4 (SNHG5/miR-181c-5p/CBX4) axis-oriented mechanisms in NSCLC is still in infancy. Therein, this study is proposed to probe this axis in NSCLC progression. Methods: Samples of 86 NSCLC patients were collected and SNHG5, miR-181c-5p and CBX4 expression was detected in NSCLC tissues and cells. NSCLC cells were transfected with plasmids to change SNHG5, miR-181c-5p or CBX4 expression, after which cell functions and phosphorylated (p)-nuclear factor (NF)-κB protein expression were evaluated. The relationships among SNHG5, miR-181c-5p and CBX4 were validated. Tumor xenografts were implemented to verify the roles of SNHG5, miR-181c-5p and CBX4 in tumor growth. Results: Low miR-181c-5p and high SNHG5 and CBX4 levels were found in NSCLC tissues and cells. Restoration of miR-181c-5p or knockdown of SNHG5 or CBX4 restrained NSCLC cell progression and inactivated the NF-κB pathway. Upregulated CBX4 abolished the effects of miR-181c-5p on reducing NSCLC cell progression. SNHG5 regulated the interaction between miR-181c-5p and CBX4. In vivo, restoration of miR-181c-5p or knockdown of SNHG5 or CBX4 retarded the tumor growth. Conclusion: This study has delineated that SNHG5 induces the NF-κB pathway by regulating the miR-181c-5p/CBX4 axis to promote NSCLC progression, which may pave a novel path for NSCLC treatment. (AU)

Long Noncoding RNA SNHG5 Induces the NF-κB Pathway by Regulating miR-181c-5p/CBX4 Axis to Promote the Progression of Non-Small Cell Lung Cancer.

OBJECTIVE: Explorations have been progressing in decoding the mechanism of non-small cell lung cancer (NSCLC). However, long noncoding RNA small nucleolar RNA host gene 5/microRNA-181c-5p/chromobox protein 4 (SNHG5/miR-181c-5p/CBX4) axis-oriented mechanisms in NSCLC is still in infancy. Therein, this study is proposed to probe this axis in NSCLC progression. METHODS: Samples of 86 NSCLC patients were collected and SNHG5, miR-181c-5p and CBX4 expression was detected in NSCLC tissues and cells. NSCLC cells were transfected with plasmids to change SNHG5, miR-181c-5p or CBX4 expression, after which cell functions and phosphorylated (p)-nuclear factor (NF)-κB protein expression were evaluated. The relationships among SNHG5, miR-181c-5p and CBX4 were validated. Tumor xenografts were implemented to verify the roles of SNHG5, miR-181c-5p and CBX4 in tumor growth. RESULTS: Low miR-181c-5p and high SNHG5 and CBX4 levels were found in NSCLC tissues and cells. Restoration of miR-181c-5p or knockdown of SNHG5 or CBX4 restrained NSCLC cell progression and inactivated the NF-κB pathway. Upregulated CBX4 abolished the effects of miR-181c-5p on reducing NSCLC cell progression. SNHG5 regulated the interaction between miR-181c-5p and CBX4. In vivo, restoration of miR-181c-5p or knockdown of SNHG5 or CBX4 retarded the tumor growth. CONCLUSION: This study has delineated that SNHG5 induces the NF-κB pathway by regulating the miR-181c-5p/CBX4 axis to promote NSCLC progression, which may pave a novel path for NSCLC treatment.

Clinical features and therapeutic outcomes of alveolar soft part sarcoma in children: A single-center, retrospective study.

Background: Alveolar soft part sarcoma (ASPS) is a rare sarcoma that has been shown to be highly effective to antiangiogenic agents and immune checkpoint inhibitors, but most reported studies about ASPS were concentrated on adult population. In this study, we aimed to describe the clinical features and therapeutic outcomes of ASPS in children. Methods: We retrospectively reviewed the records of patients with ASPS in our institution since Jan 2015. All patients included in this study were pathologically confirmed ASPS and aged under 12 years at the time of initial diagnosis. Demographic characteristics, tumor sizes, primary tumor sites, metastasis, treatments used, therapeutic responses and survivals were evaluated. Results: We identified a total of 56 patients to be initially diagnosed as ASPS since Jan 2015. A predisposition of high occurrence in head and neck (32.1%) was observed (versus 41.1% in limbs and 21.4% in trunk). 26 (46.4%) patients developed metastasis at the time of diagnosis or during follow-up. Tumors in tongue, pharynx and larynx had the least likelihood to metastasize (7.7%, P<0.05). Observation was recommended for 15 stage IV patients with only pulmonary metastasis. 7 (46.7%) patients remained stable until last follow up. The 1-year PFS rate was 83.3% and median progression-free survival time (PFS) was 29.4 months. 15 patients with progressive disease received mono or combined therapy. 11 patients received PD-1 monotherapy. 2 patients achieved partial response and 5 stable disease. The overall response rate was 18.2%. The median PFS of this group was 22.0 months, and the 1-year PFS rate was 70.0%. 4 patients received a combination therapy of PD-1 inhibitors plus tyrosine kinase inhibitors. All of them remained stable. No disease-related death occurred during follow-up. Conclusions: ASPS exhibits a higher occurrence in head and neck in children. ASPS originating from glossopharyngeal region tends to have a lower metastasis rate. ASPS displays a more indolent growth pattern in children, which makes observation a preferable choice for children with sole pulmonary metastasis. Pediatric ASPS appears to be less effective to targeted therapy and immunotherapy than adults. The treatment of progressive ASPS in children remains challenging.

Efficacy of PD-1 inhibitors combined with pegylated liposomal doxorubicin and dacarbazine compared with liposomal doxorubicin and dacarbazine in advanced leiomyosarcoma patients: a retrospective, single-institutional cohort study.

Background: PD-1 inhibitor monotherapy is ineffective for metastatic leiomyosarcoma (LMS), but it remains unclear whether PD-1 inhibitors demonstrate any efficacy when combined with chemotherapy. This study retrospectively evaluated pegylated liposomal doxorubicin (PLD) and dacarbazine (DTIC) with/without PD-1 inhibitors for advanced/metastatic LMS patients treated in our single institution. Methods: The inclusion criteria were a confirmed histological diagnosis of LMS, treatment between January 2020 and March 2022, measurable disease (evaluated by CT or MRI), an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and age ≥18 years. The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Results: A total of 41 patients were included in this study, among whom 21 received PLD and DTIC alone while 20 received PLD and DTIC with PD-1 inhibitors. There were no differences of clinical characteristics between the two groups. Although the chemo plus PD-1 group had a better ORR (30% vs. 4.8%, P=0.04), there were no benefits in terms of disease control rate (DCR) (80% vs. 66.7%, P=0.29), PFS (8.8 months, 95% CI: 4.57-13.0 vs. 6.1 months, 95% CI: 3.03-9.14, P=0.54), and OS (not reached in both groups, P=0.84) when compared to chemo alone. Multiple treatment lines and previous use of tyrosine kinase inhibitors (TKIs) seemed to be negative factors for PFS in the univariate analysis, but failed to be significant in the multivariate analysis. Conclusions: This retrospective, single-institutional study showed that PD-1 inhibitors combined with standard PLD and DTIC chemotherapy failed to exert benefits on survival for LMS patients. Considering the small sample size and retrospective clinical research design, further explorations are needed to verify the conclusion.

Intraoperative low-dose dopamine is associated with worse survival in patients with hepatocellular carcinoma: A propensity score matching analysis.

Background: Dopamine is widely used in patients during surgery. We evaluated the association between intraoperative low-dose dopamine administration and recurrence-free survival (RFS) and overall survival (OS) in patients with hepatocellular carcinoma (HCC). Methods: Consecutive patients with nonmetastatic HCC who underwent radical hepatectomy were enrolled between 2008 and 2010. Univariate and multivariate logistic regression analyses were used to evaluate the prognostic factors for RFS and OS. Survival outcomes were evaluated using Kaplan-Meier analyses with the log-rank test. A one-to-one propensity score matching (PSM) analysis was performed to reduce confounding bias. Results: A total of 805 HCC patients, including 699 patients who did not receive dopamine consumption and 106 patients who received low-dose dopamine during the operation, were retrospectively analyzed. The patients who were assigned low-dose dopamine had worse RFS (p = 0.009) and OS (p = 0.041) than those who did not receive dopamine. Multivariate regression analysis showed that the intraoperative administration of low-dose dopamine was an independent unfavorable predictor for RFS (p = 0.004) but not for OS (p = 0.059). After PSM, the low-dose dopamine-treated group still had significantly poorer RFS (p = 0.003) and OS (p = 0.002). When stratified by time of recurrence, patients with low-dose dopamine use had a significantly greater chance of recurrence within 2 years (p = 0.007) but not after 2 years (p = 0.186). Conclusions: Intraoperative low-dose dopamine use has a negative impact on RFS and OS in HCC patients who have undergone radical hepatectomy. Further prospective studies are required to assess the effects of low-dose dopamine on surgical outcomes in HCC patients.

Potential influence of anaesthesia techniques on the recurrence and progression after resection of non-muscle-invasive bladder cancer: a propensity score-matched analysis.

BACKGROUND: The non-muscle-invasive bladder cancer is a common malignancy of the urinary system. Many patients relapse after transurethral resection surgery. Different anaesthesia techniques may influence a patient's immune system during the perioperative time. In this study, we examined the effects of different anaesthesia techniques on the prognosis of primary non-muscle-invasive bladder cancer after transurethral resection surgery. METHODS: In the period 2008 to 2017, a total of 926 patients suffered primary non-muscle-invasive bladder and underwent transurethral resection of bladder tumour surgery for the first time. These patients were divided into two groups according to the techniques that were used. There were 662 patients in the general anaesthesia group, who received propofol, opioid drugs (fentanyl family), non-depolarizing muscle relaxants, and sevoflurane, and 264 patients in the epidural anaesthesia group, who had an epidural catheter placed in the L2-L3 or L3-L4 interspace with a combination of lidocaine and ropivacaine or bupivacaine. We analyzed the influence factors that might affect prognosis and compared the recurrence-free survival time and the progression between the two groups. RESULTS: The differences between the two groups in recurrence rate and progression rate were not statistically significant. Progression-free survival time of the epidural anaesthesia group was longer. Multivariate regression analysis showed that anaesthesia techniques were not independent influencing factors for recurrence and progression. CONCLUSIONS: It was not found that anaesthesia techniques affected the recurrence or progression of patients with primary non-muscle-invasive bladder cancer after transurethral resection of bladder tumour.

Phase II Study of TQB2450, a Novel PD-L1 Antibody, in Combination with Anlotinib in Patients with Locally Advanced or Metastatic Soft Tissue Sarcoma.

PURPOSE: To explore the efficacy and safety of TQB2450 combined with anlotinib in patients with locally advanced or metastatic soft-tissue sarcoma (LA/M STS). PATIENTS AND METHODS: This was a single arm phase II study (TQB2450-Ib-02 study) performed at two hospitals in China to assess the potency of TQB2450 combined with anlotinib in patients with LA/M STS. Patients were previously unresponsive to at least one chemotherapy regimen. Anlotinib (12 mg every day) was administered orally from day 1 to day 14 every 3 weeks. TQB2450 was administered by intravenous infusion at 1,200 mg on day 1 every 3 weeks. The primary endpoint was the objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. RESULTS: Between January 2019 and June 2020, 30 patients were enrolled. The ORR was 36.67% and the DCR was 76.67%. The median PFS was 7.85 months [95% confidence interval (CI), 2.89-23.06] and the median OS was not reached [95% CI, 10.58-not estimable (NE)]. Among the patients with alveolar soft part sarcoma (ASPS; 12/30, 40%), the ORR was 75% and the median PFS was 23.06 months (95% CI, 8.97-NE). The most common treatment related adverse events were hypothyroidism (76.67%), hypertriglyceridemia (63.33%), hypercholesterolemia (60.00%), and elevated blood lactate dehydrogenase (53.33%). CONCLUSIONS: The study showed the promising activity in patients with ASPS, also indicating the trend of treatment efficacy in other sarcomas. The toxicity was tolerable. More studies with larger sample size and controlled arm were warranted.

Effect of Dexmedetomidine-Assisted Intravenous Anesthesia on Gastrointestinal Motility in Colon Cancer Patients After Open Colectomy.

Background: To explore the effect of dexmedetomidine (Dex)-assisted intravenous anesthesia on gastrointestinal motility in patients with colon cancer (CC) after open colectomy. Methods: A total of 102 patients with CC, undergoing open colectomy in our hospital from January 2018 to January 2020, were selected and randomly divided into an observation group (n = 51) and a control group (n = 51). The patients in the control group received a routine combination of intravenous and inhalation anesthesia (CIIA), while those in the observation group received a Dex-assisted CIIA. The systolic blood pressure (SBP), the diastolic blood pressure (DBP), heart rate (HR), and the mean arterial pressure (MAP) were compared at different time points between the two groups. In addition, the intraoperative general conditions, the dosage of anesthetics, and the recovery of gastrointestinal functions were also compared between the two groups. Moreover, before operation and at 24 h after operation, the levels of serum gastrin (GAS) and plasma motilin (MTL) were detected by radioimmunoassay, and the level of plasma cholecystokinin (CCK) was detected by an enzyme-linked immunosorbent assay. The incidence of gastrointestinal complications was recorded in both groups. Results: At T1-T3, the HR, SBP, DBP, and MAP levels were lower in both groups than those at T0. In addition, they were also lower in the observation group than those in the control group, showing significant differences (p < 0.05). The dosage of propofol and remifentanil in the observation group was lower than that in the control group, and there was a significant difference (p < 0.05). In the observation group, the postoperative first exhaust time, first defecation time, first ambulation time, and first feeding time were all earlier than those in the control group with significant differences (p < 0.05). After the operation, the observation group had higher levels of GAS and MTL but a lower level of CCK than the control group, and the differences were significant (p < 0.05). The incidence rate of gastrointestinal complications in the observation group (7.04%) was lower than that in the control group (19.61%), and there was a significant difference (χ2 = 4.346, p < 0.05). Conclusions: Dex-assisted intravenous anesthesia can facilitate the recovery of gastrointestinal motility, can regulate the levels of gastrointestinal hormones, and can stabilize the levels of hemodynamic indexes in patients with CC after open colectomy.

The efficacy of 99mTc-rituximab as a tracer for sentinel lymph node biopsy in cutaneous melanoma patients.

Background: The sentinel lymph node (SLN) status is a vital prognostic factor for malignant melanoma (MM) patients. There is increasing evidence that a radioactive agent, rather than its combination with blue dye, is sufficient for a SLN biopsy (SLNB). Thus, we discussed the efficacy of 99mTc-rituximab as a tracer in MM patients. Methods: A total of 502 consecutive patients with MM who underwent SLNB were enrolled in this study. All participants were peritumorally injected with 99mTc-rituximab before imaging, and scanned with single-photon emission computed tomography-computed tomography (SPECT-CT) to detect the number and location of the SLN. A gamma detection probe was employed to detect radioactive SLNs in operation. Follow up was conducted to observe whether nodal or distant recurrence occurred. Results: The SLNs were successfully imaged via SPECT-CT and harvested from all 502 participants. No drainage tube was indwelled and 32 (6.3%) participants experienced the following complications: seroma (n=26, 5.2%), wound infections or lymphangitis (n=6, 1.2%), sensory nerve injuries (n=4, 0.8%). There were 380 patients who were diagnosed as SLN-negative and 122 (24.2%) were SLN-positive. A total of 85 SLN-positive patients received complete lymph node dissection, and 28 (32.9%) had additional positive lymph nodes. During a median follow-up of 24 months, 28 participants were found to have a false negative (FN) SLN. The FN rate was 18.7%. A higher T stage was a predictive factor for FN [odds ratio (OR) 1.77; P<0.05]. There was no significant difference in the positive or FN rate between the acral and cutaneous groups. Conclusions: The radiopharmaceutical 99mTc-rituximab could be employed as a simple and safe tracer in acral and cutaneous melanoma SLN biopsies.

Real-world experience with pembrolizumab in patients with advanced soft tissue sarcoma.

BACKGROUND: The goal of this study was to retrospectively analyze the efficacy and safety of pembrolizumab in the real-world treatment of soft tissue sarcoma (STS). METHODS: We analyzed 38 patients who suffered from STS and received pembrolizumab treatment from July 2017 to December 2018 in our hospital. We investigated the influence of clinical characteristics, treatment timing, and treatment protocol on objective response rate (ORR). We also investigated the factors affecting overall survival (OS) and progression-free survival (PFS), as well as the occurrence of severe adverse events (SAEs). RESULTS: The overall ORR was 19.4% (7/36). The ORRs of patients who received pembrolizumab treatment as first-line, second-line, and third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). Four patients (11.1%) maintained a complete response (CR) or partial response (PR) for at least 6 months with pembrolizumab monotherapy, or after withdrawal of chemotherapy or targeted therapy regimens. The median PFS was 2.9 months [95% confidence interval (CI): 2.4-3.4 months] and the median OS was 12.0 months (95% CI: 10.2-13.8 months). Cox regression analysis showed that treatment time was an independent factor affecting PFS (P=0.041), while Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was the only independent factor affecting OS (P=0.028). CONCLUSIONS: In the real world, the effectiveness of pembrolizumab in the treatment of STS was low. Some subtypes showed a limited response to pembrolizumab, including alveolar soft part sarcoma (ASPS), undifferentiated pleomorphic sarcoma (UPS), exoskeletal chondrosarcoma (ESCS), and angiosarcoma (AS), while the response in leiomyosarcoma (LMS) was low. Combination therapy may increase the risk of SAEs, especially when combined with pazopanib.

Elevated HMGB1 expression induced by hepatitis B virus X protein promotes epithelial-mesenchymal transition and angiogenesis through STAT3/miR-34a/NF-κB in primary liver cancer.

HBV infection plays a crucial role in primary liver cancer development. Also, HBV related liver cancer has higher invasiveness and earlier discovered distant metastasis. HBV-encoded X protein (HBx) exerts various biological functions on liver cancer progression, including proliferation, invasion, and venous metastasis. There is evidence that High-mobility group box 1 (HMGB1) promotes epithelial-mesenchymal transition (EMT) and angiogenesis of tumors, including liver cancer. Therefore, this study investigates whether HMGB1 mediates HBx-induced EMT and angiogenesis in HBV related liver cancer. We collected 76 tumor samples of primary liver cancer patients to analyze the relationship between HMGB1 and portal vein tumor thrombus (PVTT) in HBV related liver cancer. To test the influence of HMGB1 on EMT and angiogenesis, we constructed HBx lentivirus transfected HepG2/Huh7 cell lines and performed invasion assays, tube formation and in vivo metastatic experiments. We evaluated HMGB1 and STAT3/miR-34a/NF-κB pathway in vivo and in vitro by immunoblot, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence and immunohistochemistry analysis. Subsequent RNA interference (RNAi) and luciferase reporter assay were conducted to detect the functional correlation between HMGB1 and STAT3/miR-34a/NF-κB pathway. Our results showed enhanced expression of HMGB1 in HBV related liver cancer, especially with PVTT, while HMGB1 expression was associated with tumor invasion and metastasis. Further experiments indicated that the activation of STAT3 mediated HBx-induced HMGB1, which is involved in EMT and tumor angiogenesis. Besides, HMGB1 expression stimulated by HBx was dependent on the activation of the NF-κB signaling pathway, which was inhibited by miR-34a, while STAT3 suppressed the expression of miR-34a. Moreover, extracellular HMGB1 induced the IL-6/STAT3/miR-34a axis activation, which indicated a reciprocal relationship between HMGB1 and miR-34a. Collectively, our study provided evidence to reveal that HBx-mediated high expression of HMGB1 accounted for EMT and tumor angiogenesis in HBV related liver cancer, and HMGB1 may be a potential target for predicting venous metastasis.

Target therapy for metastatic alveolar soft part sarcoma: a retrospective study with 47 cases.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a translocation-associated soft-tissue tumor resistant to conventional cytotoxic agents. This report aims to compare the efficacy of anlotinib versus pazopanib as targeted monotherapy in metastatic ASPS and to determine the impact of drug dosage reduction on disease control. METHODS: Sixteen and 31 patients with metastatic ASPS were respectively treated with anlotinib and pazopanib monotherapy at a single institution. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were retrieved and compared between both therapeutic arms. Adverse events (AEs) within each group were recorded. Kaplan-Meier survivorship curves computed the impact of drug dosage reduction on PFS. RESULTS: The anlotinib group showed an ORR of 31.2%, compared to 35.5% in the pazopanib arm (P=0.772). Median PFS was 23.6 months [95% confidence interval (CI), 16.2-31.0 months] in patients treated with anlotinib, but dropped to 13.7 months (95% CI, 10.8-16.7 months) in those managed with pazopanib (P=0.023). One (6.3%) patient on anlotinib and 11 (35.5%) on pazopanib developed AEs requiring drug dosage reduction (P=0.029), which significantly reduced patients' PFS in the latter setting (10.5 vs. 15.8 months, P=0.012). In patients without dosage reduction, anlotinib showed a bordering advantage than pazopanib on median PFS (24.5 vs. 15.8 months, P=0.112). CONCLUSIONS: Compared to pazopanib, anlotinib yielded longer PFS and lower incidence of AEs in ASPS patients. Drug dosage reduction was more frequently encountered with the former agent and affected the disease control.

KIF18B promotes tumor progression in osteosarcoma by activating ß-catenin.

Objective: Osteosarcoma is a common primary highly malignant bone tumor. Kinesin family member 18B (KIF18B) has been identified as a potential oncogene involved in the development and metastasis of several cancer types. While KIF18B overexpression in osteosarcoma tissue is clearly detected, its specific function in the disease process remains to be established. Methods:KIF18B expression was assessed in osteosarcoma tissues and cells. We additionally evaluated the effects of KIF18B on proliferation, migration, and invasion of osteosarcoma cells, both in vitro and in vivo. Results: Our results showed overexpression of KIF18B in osteosarcoma tissues and cells. Knockdown of KIF18B induced G1/S phase arrest and significantly inhibited proliferation, migration, and invasion of osteosarcoma cells, both in vitro and in vivo. KIF18B regulated ß-catenin expression at the transcriptional level by controlling nuclear aggregation of ATF2 and at the post-transcriptional level by interacting with the adenomatous polyposis coli (APC) tumor suppressor gene in osteosarcoma cells. Conclusions: KIF18B plays a carcinogenic role in osteosarcoma by regulating expression of ß-catenin transcriptionally via decreasing nuclear aggregation of ATF2 or post-transcriptionally through interactions with APC. Our collective findings support the potential utility of KIF18B as a novel prognostic biomarker for osteosarcoma.

Puerarin inhibits hepatocellular carcinoma invasion and metastasis through miR-21-mediated PTEN/AKT signaling to suppress the epithelial-mesenchymal transition.

Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumors of the liver worldwide. Liver resection and transplantation are currently the only effective treatments; however, recurrence and metastasis rates are still high. Previous studies have shown that the epithelial-mesenchymal transition (EMT) is a key step in HCC invasion and metastasis. Inhibition of EMT has become a new therapeutic strategy for tumors. Recently, puerarin, a well-characterized component of traditional Chinese medicine, has been isolated from Pueraria radix and exerts positive effects on many diseases, particularly cancers. In this study, CCK-8, EdU immunofluorescence, colony formation, wound healing, and migration assays were used to detect the effects of puerarin on HCC cells. We further analyzed the relationship between puerarin and miR-21/PTEN/EMT markers in HCC cell lines. Our results showed that HCC cell proliferation, migration, invasion, tumor formation, and metastasis were reduced by puerarin in vitro and in vivo. Additionally, puerarin inhibited the EMT process of HCC by affecting the expression of Slug and Snail. Moreover, oncogenic miR-21 was inhibited by puerarin, coupled with an increase in the tumor suppressor gene PTEN. Increasing miR-21 expression or decreasing PTEN expression reversed the inhibition effects of puerarin in HCC. These data confirmed that puerarin affects HCC through the miR-21/PTEN/EMT regulatory axis. Overall, puerarin may represent a chemopreventive and/or chemotherapeutic agent for HCC treatment.

Puerarin inhibits hepatocellular carcinoma invasion and metastasis through miR-21-mediated PTEN/AKT signaling to suppress the epithelial-mesenchymal transition

Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumors of the liver worldwide. Liver resection and transplantation are currently the only effective treatments; however, recurrence and metastasis rates are still high. Previous studies have shown that the epithelial-mesenchymal transition (EMT) is a key step in HCC invasion and metastasis. Inhibition of EMT has become a new therapeutic strategy for tumors. Recently, puerarin, a well-characterized component of traditional Chinese medicine, has been isolated from Pueraria radix and exerts positive effects on many diseases, particularly cancers. In this study, CCK-8, EdU immunofluorescence, colony formation, wound healing, and migration assays were used to detect the effects of puerarin on HCC cells. We further analyzed the relationship between puerarin and miR-21/PTEN/EMT markers in HCC cell lines. Our results showed that HCC cell proliferation, migration, invasion, tumor formation, and metastasis were reduced by puerarin in vitro and in vivo. Additionally, puerarin inhibited the EMT process of HCC by affecting the expression of Slug and Snail. Moreover, oncogenic miR-21 was inhibited by puerarin, coupled with an increase in the tumor suppressor gene PTEN. Increasing miR-21 expression or decreasing PTEN expression reversed the inhibition effects of puerarin in HCC. These data confirmed that puerarin affects HCC through the miR-21/PTEN/EMT regulatory axis. Overall, puerarin may represent a chemopreventive and/or chemotherapeutic agent for HCC treatment.

Local recurrence of Ewing sarcoma: Is wide excision an acceptable treatment?

BACKGROUND AND OBJECTIVES: Local recurrence in Ewing sarcoma (ES) is associated with poor prognosis. The purpose of the study is to determine what factors affect overall survival after local recurrence and whether wide excision constitutes appropriate treatment. METHODS: From 1992 to 2017, 26 patients were treated for local recurrence of ES. Sixteen patients presented with local recurrence only while 10 had metastasis. The median follow-up was 23 months (range, 3-255 months). Overall survival was assessed with Kaplan-Meier analysis. RESULTS: At the last follow-up, seven of 26 (27%) patients were alive. Overall survival after local recurrence was 28% at 5 years. Later onset of local recurrence (P = .041), surgical treatment (P < .001), and complete eradication of all recurrent disease (P < .001) predicted better survival. Metastasis was associated with worse survival (P = .014). All three patients who survived more than 10 years were treated with wide local excision. A second local recurrence developed in seven patients (28%) but did not predict worse overall survival. CONCLUSIONS: Overall survival after local recurrence is better for patients with nonmetastatic disease treated surgically. Wide excision can be compatible with long survival. We do not advocate amputation on a routine basis for local recurrence. Complete eradication of all diseases is associated with better survival.

Efficacy of vinorelbine combined with low-dose methotrexate for treatment of inoperable desmoid tumor and prognostic factor analysis.

OBJECTIVE: To assess the efficacy of conservative chemotherapy for inoperable desmoid tumor (DT) and analyze the prognostic factors. METHODS: From November 2008 to April 2016, 71 patients of inoperable DT were treated with vinorelbine and low-dose methotrexate in the Department of Bone and Soft Tissue Tumors, Peking University Cancer Hospital & Institute, and enrolled in this retrospective study. The chemotherapy duration is one year. The efficacy of chemotherapy and the prognosis were observed. RESULTS: Of the 71 patients, 55% were female. Age of onset varied from 1 to 47 years, and the median age was 14 years. Only 11 (15.5%) cases suffered primary tumor. The distribution of the site of tumors was: 31 (43.7%) in the trunk, 36 (50.7%) in the limbs, and 4 (5.6%) in the peritoneal and pelvic cavity. The size of tumor (the maximum diameter) differed from 2 to 37 cm with a mean of 9.3 cm. The median follow-up duration was 28 (range, 6-87) months. Common side effects included: nausea and vomiting, liver injury, bone marrow suppression and oral ulcers. When the chemotherapy finished, 1 (1.4%) case achieved complete response, 24 (33.8%) achieved partial response, 37 (52.1%) achieved stable disease and 9 (12.7%) had progressive disease. The overall response rate was 87.3%. The progression-free survival (PFS) of the participants were from 6 to 87 months, and the 2-, 3- and 5-year PFS was 79.9%, 68.4% and 36.3%, respectively. No significant difference was identified in PFS in subgroups of gender, age of onset, age of chemotherapy, tumor site and tumor size. CONCLUSIONS: For recurrent, inoperable and progressive DT, enough course of chemotherapy with vinorelbine combined with low-dose methotrexate was an optional choice for local control.