Impact of chemotherapy cycles and intervals on outcomes of nonspinal Ewing sarcoma in adults: a real-world experience.

BACKGROUND: Adult Ewing sarcoma (ES) is a rare disease, the optimal treatment model is unknown. This study aimed to retrospectively analyze treatment-related prognostic factors of nonspinal ES in Chinese adults. METHODS: Eighty-one patients treated between January 2005 and December 2017 were included in the present study. Thirty-three (40.7%) presented with metastatic disease at diagnosis. Eight patients were submitted to primary surgery followed by chemotherapy, while 73 patients received chemotherapy before and after surgery and/or local radiotherapy. The chemotherapy regimen included 8-17 cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) every 3 weeks. Clinical outcomes and safety were analyzed. RESULTS: VDC/IE chemotherapy was well tolerated in adult patients with ES. Multivariate Cox regression analyses revealed that chemotherapy of at least 12 cycles was a favorable independent prognostic factor of event-free survival (hazard ratio, 0.558; 95% confidence interval, 0.323-0.965; P = 0.037) and overall survival (hazard ratio, 0.424; 95% confidence interval, 0.240-0.748; P = 0.003). Similarly, a low frequency of chemotherapy delays was an independent prognostic factor of improved OS (hazard ratio, 0.438; 95% confidence interval, 0.217-0.887; P = 0.022). CONCLUSION: Our study suggests that adults with ES should be treated with an aggressive multidisciplinary approach, intensive chemotherapy with adequate cycles and appropriate intervals can be recommended in this group.

Safety and efficacy of multilevel vertebroplasty for painful osteolytic spinal metastases: a single-centre experience.

OBJECTIVE: To retrospectively assess the safety and efficacy of percutaneous vertebroplasty (PVP) for painful osteolytic spinal metastases when treating more than three vertebrae per session. METHODS: A total of 153 patients with painful osteolytic spinal metastases underwent PVP. Group A patients (n = 93) underwent PVP at up to three vertebral levels per session. Group B patients (n = 60) underwent PVP at more than three levels in one session. Pain, quality of life (QoL), and mobility were assessed before and after PVP. Minor and major complications were systematically assessed. RESULTS: Both groups experienced significant pain relief and QoL improvement after the intervention (p < 0.001). Mobility improvement was observed in both groups, despite worse mobility status before PVP in group B compared with group A. There was no significant difference between the two groups throughout the follow-up period in overall pain relief and improvement in QoL and mobility. There was also no significant difference between groups in minor and major complications. CONCLUSIONS: Multilevel vertebroplasty is safe and effective for the treatment of multiple osteolytic spinal metastases. Multilevel PVP relieves pain and improves QoL and mobility. KEY POINTS: • Percutaneous vertebroplasty is safe and effective for painful osteolytic spinal metastases. • Multilevel vertebroplasty does not cause more complications than single-level vertebroplasty. • Multiple spinal metastases patients may regain functional independence after multilevel vertebroplasty.

Vastatin, an Endogenous Antiangiogenesis Polypeptide That Is Lost in Hepatocellular Carcinoma, Effectively Inhibits Tumor Metastasis.

Hepatocellular carcinoma (HCC) is a hypervascular cancer without effective treatment. Here we report that polypeptide of NC1 domain of type VIII collagen (Vastatin) is an endogenous polypeptide expressed in normal liver tissue but lost in the liver of most HCC patients (73.1%). Its expression level is negatively associated with tumor size (P = 0.035) and metastasis (P = 0.016) in HCC patients. To evaluate its potential use as a therapeutic, we constructed a recombinant adeno-associated virus carrying Vastatin (rAAV-Vastatin) to treat HCC in an orthotopic Buffalo rat model. rAAV-Vastatin treatment significantly prolonged the median survival, inhibited tumor growth, and completely prevented metastasis in HCC-bearing rats by decreasing microvessel density and increasing tumor necrosis. No detectable toxicity in nontumor-bearing mice was observed. To investigate its molecular mechanisms, we performed DNA microarray, western blotting assays, and bioinformatic analysis to determine its effect on global gene expression patterns and signal transduction pathways. Our results indicated that rAAV-Vastatin significantly reduced the expressions of Pck1, JAG2, and c-Fos, thus inhibiting the cellular metabolism, Notch and AP-1 signaling pathways, respectively. Hence, we demonstrated for the first time that Vastatin is a novel, safe, and effective antiangiogenic therapeutic and a potential biomarker for HCC.

CD133(+) CD44(+) Cells Mediate in the Lung Metastasis of Osteosarcoma.

CD133 and CD44 are commonly used markers of cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical value and significance of CD133 and CD44 in lung metastasis of osteosarcoma (OS) remains controversial. The purpose of this study was to investigate whether CD133(+) CD44(+) cells mediates the metastasis of OS. We identified the CD133(+) CD44(+) cells in lung metastatic lesions and OS cell lines, and next demonstrated CD133(+) CD44(+) cells were more aggressive in sphere formation, migration and invasiveness compared with CD133(+) CD44(-) , CD133(-) CD44(+) , or CD133(-) CD44(-) cells. We finally sorted the CD133(+) CD44(+) and CD133(-) CD44(-) cells from Saos-2 cell lines, after intratibial xenograft in nude mice, these cells developed primary tumors, and CD133(+) CD44(+) cells are more potential to form lung metastatic tumors. Thus we concluded that CD133(+) CD44(+) cells may mediate in the lung metastasis of OS.

Overall survival benefits for irinotecan-containing regimens as first-line treatment for advanced gastric cancer: an updated meta-analysis of ten randomized controlled trials.

The standard treatment for patients with advanced gastric cancer (AGC) is still debated, and the available data on the benefit of irinotecan-containing regimen as first-line treatment for those patients are controversial. We performed a systematic review and meta-analysis of randomized controlled trials to determine the survival benefits of irinotecan-containing regimens in this setting. A total of 1,837 patients from ten trials were included in the analysis. Our results showed that irinotecan-containing regimens significantly improved overall survival [OS: hazard ratio (HR) 0.86, 95% CI = 0.78-0.94, p = 0.002] and progression-free survival [HR = 0.82, 95% CI = 0.69-0.97, p = 0.026); however, the improvement of time to failure (HR = 0.90; 95% CI = 0.77-1.04, p = 0.15), 1-year survival rate [1-year SR: relative risk (RR) 1.10, 95% CI = 0.97-1.24, p = 0.13] and overall response rate (RR = 1.16, 95% CI = 0.91-1.49, p = 0.24] were nonsignificant. Equivalent frequencies of toxicities were found between the two groups excluding more Grade 3 or 4 fatigue (p = 0.001) in irinotecan-containing regimens. This updated meta-analysis provided strong evidence for a survival benefit of irinotecan-containing regimen as first-line treatment for AGC. A clear advantage of irinotecan-containing over nonirinotecan-containing regimen had not been established. These results should help to inform decisions about patient management and design of future trials.

Risk of venous thromboembolic events associated with VEGFR-TKIs: a systematic review and meta-analysis.

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been widely used in advanced cancers. Concerns have arisen regarding the risk of venous thromboembolism with the use of these drugs. Currently, the contribution of VEGFR-TKIs to venous thromboembolism is still unknown. We performed a meta-analysis to determine the incidence and relative risk (RR) of venous thromboembolism events (VTEs) associated with these agents. Eligible studies included phase II and III prospective trials evaluating US Food and Drug Administration approved VEGFR-TKIs (pazopanib, sunitinib, sorafenib and vandetanib), and data on VTEs were available. Overall incidence rates, RR and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of included trials. A total of 14 studies (4,430 patients) were selected for this meta-analysis. The incidence of VTEs related to VEGFR-TKIs was 3% (95%CI: 1.7-5.1%), and there was no statistically significant increase in the risk of VTEs for VEGFR-TKIs versus controls in overall population (RR0.912, 95%CI: 0.617-1.348, p = 0.643). On subgroup analysis, no significant increase in the risk of VTEs was found among different VEGFR-TKIs or tumor types. No evidence of publication bias was observed. The use of VEGFR-TKIs does not significantly increase the risk of VTEs, the risk of VTEs in patients with cancer is driven predominantly by tumor types, host factors and concomitant usage of anticancer agents. These results would provide important information for clinicians who use VEGFR-TKIs to treat patients with solid cancer.

Risk of venous and arterial thromboembolic events in cancer patients treated with gemcitabine: a systematic review and meta-analysis.

AIMS: Gemcitabine has been associated with an increased risk of arterial and venous thromboembolic events (ATEs and VTEs), although the overall risk remains unclear. As indications for its use in oncology are expanding, a comprehensive characterization of these complications becomes imperative. METHODS: Pubmed was searched for articles published from 1 January 1990 to 31 December 2012. Eligible studies included prospective randomized controlled phase II and III trials evaluating gemcitabine based vs. non-gemcitabine based chemotherapy in patients with solid tumours. Data on VTEs and ATEs were extracted. Overall incidence rates, odds ratio (OR), and 95% confidence intervals (CIs) were calculated employing fixed or random effects models depending on the heterogeneity of included trials. RESULTS: A total of 4845 patients from 19 trials were included. Among patients treated with gemcitabine based chemotherapy, the overall incidence of VTEs (13 studies comprising 3823 patients) and ATEs (eight studies consisting of 2431 patients) was 2.1% (95% CI 1.2%, 3.8%) and 2.2% (95% CI 1.4%, 3.2%). The associated ORs of VTEs and ATEs were 1.56 (95% CI 0.86, 2.83, P = 0.15) and 1.82 (95% CI 0.89, 3.75, P = 0.10) compared with non-gemcitabine based therapy. A tendency to increase the risk of ATE and VTEs was also detected in any prespecified subgroup. CONCLUSION: The use of gemcitabine does not significantly increase the risk of VTEs and ATEs in patients with solid tumours when compared with non-gemcitabine based chemotherapy.

Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials.

AIM: To perform a systematic review and meta-analysis of published clinical trials to determine incidence rate and overall risk of hypertension with vandetanib in cancer patients. METHODS: A comprehensive literature search for studies published up to March 2012 was performed. Summary incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: A total of 11 trials with 3154 patients were included for the meta-analysis. The summary incidences of all-grade and high-grade hypertension in patients with cancer were 24.2% [95% confidence interval (CI), 18.1-30.2%] and 6.4% (95% CI, 3.3-9.5%), respectively. Subgroup analysis demonstrated that the pooled incidences of all-grade and high-grade hypertension were 21.8% [95% CI, 15-30.5%] and 7.6% (95% CI, 2.8-18.8%), respectively, among non-small-cell lung cancer (NSCLC) patients, and 32.1% (95% CI: 27.3-37.3%) and 8.8% (5.9%-12.9%), respectively, among MTC patients, and 15.4 (95% CI: 3.2-33.7%) and 3.4% (95% CI: 1%-11.1%) respectively, among non-MTC/NSCLC tumors patients. Furthermore, vandetanib was associated with a significant increased risk of all-grade hypertension (RR 5.1, 95% CI: 3.76-6.92, P = 0.000) and high-grade hypertension (RR 8.06, 95% CI: 3.41-19.04, P = 0.000) in comparison with controls. CONCLUSIONS: There is a significant risk of developing hypertension in cancer patients receiving vandetanib. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.

Percutaneous vertebroplasty combined with zoledronic acid for the treatment of painful osteolytic spinal metastases in patients with breast cancer.

PURPOSE: To assess retrospectively the efficacy and safety of percutaneous vertebroplasty (PVP) combined with zoledronic acid (ZA) for the treatment of painful osteolytic spinal metastases from breast cancer. MATERIALS AND METHODS: PVP was performed in 43 patients with breast cancer and painful osteolytic spinal metastases; 126 vertebrae were treated. The patients subsequently received 4 mg ZA via a 15-minute intravenous infusion every 4 weeks for 12 months. Pain and quality of life (QoL) were assessed using a visual analog scale (VAS) and Karnofsky performance scale (KPS), respectively, 24 hours before PVP and 24 hours, 1 month, 3 months, 6 months, and 12 months after PVP. Skeletal-related events (SREs) were assessed for 12 months following the intervention. RESULTS: The mean VAS scores decreased significantly from 7.6 ± 1.9 at 24 hours before PVP to 3.6 ± 1.4 at 24 hours, 2.0 ± 1.5 at 1 month, 2.8 ± 1.6 at 3 months, 3.1 ± 0.8 at 6 months, and 2.5 ± 0.9 at 12 months after the intervention (P < .05). KPS scores increased significantly after the combination treatment (P < .05). Compared with previous studies without PVP or ZA treatment, this patient group had a lower incidence of SREs. No major complications were observed. CONCLUSIONS: PVP combined with ZA was shown to be a highly effective and safe combination therapy to relieve pain and improve QoL in patients with osteolytic spinal metastases from breast cancer. The combination therapy also prevented the occurrence of SREs.

The prognostic value of survivin expression in patients with colorectal carcinoma: a meta-analysis.

OBJECTIVE: The prognostic role of survivin in colorectal carcinoma remains controversial. This meta-analysis aimed to explore the association between survivin expression and survival outcomes in patients with colorectal carcinoma. METHODS: A comprehensive literature search for relevant studies published up to April 2013 was performed using PubMed, MEDLINE and ISI Web of Science. Only articles in which survivin was detected by immunohistochemical staining were included. This meta-analysis was done using STATA and Review Manager. RESULTS: A total of 1784 patients from 14 studies were included in the analysis. Our results showed that survivin overexpression in patients with colorectal carcinoma was significantly associated with poor overall survival (hazard ratio, 1.505; 95% confidence interval, 1.197-1.893; P = 0.000) and disease-free survival (hazard ratio, 2.323; 95% confidence interval, 1.687-3.199; P = 0.000). The results indicated that a significant relationship between survivin expression and overall survival was also exhibited in studies with an Asian country (hazard ratio, 1.684; 95% confidence interval, 1.477-1.921), patient number >100 (hazard ratio, 1.604; 95% confidence interval, 1.371-1.877), the cut-off level <50% (hazard ratio, 1.449; 95% confidence interval, 1.045-2.010), the percentage of survivin overexpression >50% (hazard ratio, 1.528; 95% confidence interval, 1.056-2.211) and the hazard ratio estimated (hazard ratio, 1.643; 95% confidence interval, 1.262-2.139). Moreover, upregulation of survivin was associated with stages (III/IV vs. I/II: odds ratio, 1.08; 95% confidence interval, 0.80-1.46), the depth of invasion (T3/T4 vs. T1/T2: odds ratio, 1.79; 95% confidence interval 0.67-4.74), lymph node metastasis (positive vs. negative: odds ratio, 1.49; 95% confidence interval, 0.99-2.26), distant metastasis (positive vs. negative: odds ratio, 2.37; 95% confidence interval, 0.99-5.72) and grade of differentiation (well/moderate vs. poor: odds ratio, 1.02; 95% confidence interval, 0.43-2.41), but without significance. CONCLUSION: The present meta-analysis indicated that upregulation of survivin was associated with poor prognosis in patients with colorectal carcinoma.

Comparison of pirarubicin-based versus gemcitabine-docetaxel chemotherapy for relapsed and refractory osteosarcoma: a single institution experience.

BACKGROUND: The prognoses for patients with relapsed and refractory osteosarcoma are poor and the optimal treatment strategy is still to be defined. We conducted this retrospective study to compare the feasibility and efficacy of pirarubicin-based chemotherapy with gemcitabine-docetaxel combination regimens for the salvage of these patients. METHODS: The clinical data of 75 patients who received pirarubicin-based (n = 52) or gemcitabine-docetaxel (n = 23) chemotherapy as a second-line treatment for relapsed and refractory osteosarcoma between January 2005 and September 2011were reviewed retrospectively. Tumor response was evaluated every two chemotherapy cycles by computed tomography/magnetic resonance imaging (CT/MRI) scans using the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival (OS) were evaluated by Kaplan-Meier analysis. Toxicity was examined according to the National Cancer Institute Toxicity Criteria grading system. RESULTS: Patient characteristics were well balanced in the two groups. The response rate was 25.0 % in patients who received pirarubicin-based chemotherapy, while it was 13.0 % in the gemcitabine-docetaxel group. Moreover, the median OS was longer in the pirarubicin-based chemotherapy group (14.0 vs. 9.0 months, P < 0.05), especially in the pirarubicin-ifosfamide (14.0 months) and pirarubicin-cisplatin (15.0 months) subgroups. The incidence of grade 3-4 neutropenia was higher in the gemcitabine-docetaxel group (5.8 vs. 43.5 %, P < 0.05); other grade 3-4 toxicities were comparable in the two groups. CONCLUSIONS: In our experience, pirarubicin-based chemotherapy was comparable with gemcitabine-docetaxel as a second-line treatment for relapsed and refractory osteosarcoma, and it even seemed to show greater efficacy, with milder toxicity. Further studies, especially prospective clinical trials, focusing on pirarubicin-based treatments for relapsed and refractory osteosarcoma patients should be strongly considered.

Clinical significance of adjuvant therapy after radical surgery for primary osteosarcoma of the jaws.

BACKGROUND: Osteosarcoma of the jaw is one of the rare malignancies and the role of postoperative adjuvant therapy is unclear. This study explored the efficacy of adjuvant therapy after radical surgery for primary osteosarcoma of the jaw. METHODS: The data were retrospectively analyzed from May 2012 to June 2021. The recurrence rate, disease-free survival (DFS) and 5­year overall survival (OS) rate were calculated by Kaplan-Meier method. Intergroup rates were examined by chi-square test. RESULTS: 125 post-radical surgery patients were included. The median follow-up time was 66 months. Forty five cases suffered recurrence. The recurrence rate was 36.0%, and the 5­year OS rate was 68.8%. In the adjuvant treatment group, twenty eight of 99 patients experienced disease progression. In the surgical treatment alone group, seventeen of 26 patients experienced disease progression. The recurrence rates in the two groups were 28.3 and 65.4%, respectively (χ2 = 12.303, p < 0.001). The 5­year OS rate was 75.8 and 42.3%, respectively (χ2 = 10.734, p = 0.001). The median DFS of the relapse patients was 15.1 months (95% CI:13.00-17.20 months), and the 5­year OS rate was 40.0%. Among them, 28 patients received adjuvant therapy while 17 received surgical treatment alone. The median DFS was 15.7 and 11.5 months, respectively, p = 0.024. The median OS was 69.6 months (95% CI 55.69 ~ 83.51 months) and 62.4 months (95% CI 49.06 ~ 75.74 months), respectively(p = 0.034). CONCLUSION: Adjuvant therapy is one of the effective measures to reduce the relapse rate and improve OS after radical surgery for primary osteosarcoma of the jaw.

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma.

Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4+ macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3+ T cells with high proportion of TIGIT+ cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.

The expression of CRM1 is associated with prognosis in human osteosarcoma.

The nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 (CRM1) is involved in the nuclear export of proteins and messenger RNAs and, thus, mediates the subcellular distribution of important molecules. Osteosarcoma is a ubiquitous and highly aggressive malignant bone tumor. The expression of CRM1 protein in human osteosarcoma has not been reported to date. We investigated the expression of CRM1 in 57 human osteosarcoma and 5 normal cartilage tissues. Western blot investigation revealed expression of CRM1 was significantly increased in osteosarcoma compared with normal tissues. High expression of CRM1 was significantly associated with increased serum level of alkaline phosphatase (ALP, P=0.001) but did not associate with that of lactate dehydrogenase (LDH, P=0.06). In univariate analysis, a significant association between CRM1 expression and tumor size (P=0.014) as well as histological grade (P=0.003) was observed, while high CRM1 expression was not correlated with the other clinicopathological parameters. In Kaplan-Meier survival analysis, high CRM1 expression was a significant prognostic indicator for progression-free survival (P=0.016) as well as overall survival (P=0.008). Multivariate analysis demonstrated that expression of CRM1 was an independent prognostic parameter for longer overall survival (95% CI, 1.27-5.39). Additional prospective studies are required to investigate the prognostic role of high expression of CRM1.

Prognostic value of CRM1 in pancreas cancer.

PURPOSE: Pancreatic cancer is a highly aggressive malignant tumour with poor prognosis. The median survival is only 6 months. This study investigated the prognostic value of nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 (CRM1) expression in pancreas cancer. METHODS: CRM1 expression was detected, by Western blot, in pancreatic tissue from 69 cancer patients and 10 normal subjects. RESULTS: CRM1 showed increased expression in pancreatic cancer tissue (P = 0.007). The high expression of CRM1 was associated with increased serum levels of CEA (P = 0.002) and CA19-9 (P = 0.005). There was an association between CRM1 expression and tumour size (P = 0.01), lymphadenopathy (P = 0.004) and liver metastasis (P = 0.003). High CRM1 expression was not correlated with the other clinicopathological parameters. High CRM1 expression was a prognostic indicator for progression-free survival (PFS) (P = 0.006) as well as overall survival (OS) (P = 0.001). Expression of CRM1 was an independent prognostic parameter for poorer PFS and OS (95% CI, 1.27-5.39). CONCLUSIONS: CRM1 expression demonstrated prognostic value in pancreatic cancer. Prospective studies are required to determine the prognostic role of high expression of CRM1 in pancreatic cancer.

Curcumin inhibits the proliferation and invasion of MG-63 cells through inactivation of the p-JAK2/p-STAT3 pathway.

PURPOSE: The aims of this study were to determine the effect of curcumin on osteosarcoma (OS) cells due to inactivation of the p-JAK2/p-STAT3 pathway and evaluate the prognostic value of this pathway in OS. MATERIALS AND METHODS: We exposed a human OS cell line (MG-63) to different concentrations of curcumin. Then, we characterized the effects on MG-63 cells using assays (cell viability, colony formation, cell cycle, wound healing, invasion), flow cytometry, Western blot, immunohistochemical analyses, and tumor xenograft. RESULTS: The half-maximal inhibitory of curcumin for MG-63 cells at 24 hours was 27.6 µM. The number of colonies of MG-63 cells was decreased obviously upon curcumin (10 and 20 µM) treatment. We also found increased accumulation of MG-63 cells in the G2/M phase upon curcumin (10 and 20 µM) treatment. Apoptosis was increased in 10 and 20 µM curcumin-treated MG-63 cells. After incubation of physically wounded cells for 24 hours, the percentage wound width increased upon curcumin exposure. Curcumin obviously decreased the expression of pJAK-2 and pSTAT-3 in MG-63 cells in a dose-dependent manner. Curcumin dose-dependently inhibited the proliferation, migration, and invasion of MG-63 cells and induced arrest of the G0/G1 phase and apoptosis by inhibiting the p-JAK2/p-STAT3 pathway. The linear correlativity between expression of p-JAK2 and STAT3 was very prominent, and both were closely associated with lung metastasis. In vivo study suggested that curcumin suppressed tumor growth through JAK2/STAT3 signaling. CONCLUSION: Curcumin-mediated inhibition of the proliferation and migration of MG-63 cells was associated with inactivation of JAK/STAT signaling.

Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1.

Osteosarcoma (OS), which is the most common primary malignant bone tumor, has a high incidence of pulmonary metastasis. CCL18 (C-C motif chemokine ligand 18), which is secreted by tumor-associated macrophages (TAMs), has been found to be increased in various tumors and is associated with tumor metastasis. However, the role of CCL18 in OS remains unclear. Here, we evaluated the effect of CCL18 on the OS cell lines MG63 and 143B and explored its potential mechanisms. We found that CCL18 enhanced the proliferation and migration of OS cells and upregulated UCA1 through transcription factor EP300. Subsequently, we further revealed that the downstream Wnt/ß-catenin signaling pathway participated in this process. In addition, the high expression of CCL18 in both tissue and serum from patients was closely related to pulmonary metastasis and poor survival in OS patients. The tumor xenograft models also showed that CCL18 promoted the metastasis of OS cells. Collectively, our study indicated that macrophage-derived CCL18 promotes OS proliferation and metastasis via the EP300/UCA1/Wnt/ß-catenin pathway and that CCL18 may be used as a prognostic marker and therapeutic target of OS. KEY MESSAGES: CCL18 promotes proliferation and migration of osteosarcoma cells by EP300/ UCA1/ Wnt/ß-catenin pathway. CCL18+ TAMs are significantly correlated with pulmonary metastasis and poor survival in osteosarcoma patients. CCL18 may be used as a prognostic marker and therapeutic target for osteosarcoma.

Impact of first-line treatment on outcomes of Ewing sarcoma of the spine.

The optimal first-line treatment for primary Ewing sarcoma (ES) of the spine is unclear, especially when the patients present with acute neurological deficits. This study aimed to retrospectively analyze the effect of first-line treatment with surgery or chemotherapy on neurological and survival outcomes of ES of the spine. 39 patients treated between January 2005 and December 2016 were included in the present analysis. 29 (74.4%) presented with symptomatic spinal cord compression at diagnosis. 21 patients were submitted to primary surgery followed by chemotherapy and local radiotherapy, while 18 patients received induction chemotherapy before surgery and/or local radiotherapy. Neurological deficit before and after treatment, event-free survival and overall survival were analyzed. The results indicated that chemotherapy as the first-line treatment could achieve similar results as primary surgery in preserving neurological function, even in case of major neurological deficits. Compared with primary surgery, induction chemotherapy contributed to a higher rate of en bloc resection with a microscopic negative margin (R0) of primary tumor (72.7% vs. 28.6%, P < 0.05). Multivariate Cox regression analyses revealed that initial chemotherapy was a favorable independent prognostic factor of event-free survival (hazard ratio, 0.215; 95% confidence interval, 0.077-0.596; P = 0.003) and overall survival (hazard ratio, 0.288, 95% confidence interval, 0.098-0.852; P = 0.024). In conclusion, our study suggests that first-line treatment of ES of the spine should be induction chemotherapy, even in case of major neurological deficits.

Lack of association between platelet indices and disease stage in osteosarcoma at diagnosis.

PURPOSE: The purpose of this study was to investigate the relationship between platelet indices [mean platelet volume (MPV), platelet count (PLT), platelet distribution width (PDW) and plateletcrit (PCT)] at diagnosis in osteosarcoma. METHODS: The information of 233 patients with osteosarcoma at diagnosis between 2007 and 2015 was retrospectively reviewed. Clinical parameters such as gender, age, size and site of tumor, and tumor necrosis rate after neoadjuvant chemotherapy were analyzed. RESULTS: No significant difference was noted in the mean values of MPV, PLT, PDW and PCT among stage I, II and III patients. In localized patients, the median disease-free survival (DFS) values were 42 and 22 months in the PLT<300×109/L and ≥300×109/L groups, respectively, but the difference was not statistically significant (P = 0.2611). No difference in the DFS among the three different levels of MPV was observed. CONCLUSION: No significantly different platelet indices were noted among the different stages. Although a shorter median DFS was found in localized patients with PLT≥300×109/L, there was still a lack of strong evidence to demonstrate the association between platelet indices and osteosarcoma.

The prognostic value of D-dimer levels in metastatic osteosarcoma patients treated with second-line chemotherapy.

We performed a retrospective analysis of 32 metastatic osteosarcoma cases to examine the prognostic value of the plasma D-dimer level. We assessed the D-dimer level before second-line chemotherapy (D1) and the D-dimer level after two cycles of second-line chemotherapy (D2). The change in D-dimer level (ΔD) was defined as D2 minus D1. The overall survival (OS) of patients with a high D1 was significantly shorter than those with a low D1 (median OS, 4.7 vs. 16.2 months, P=0.001). Similar results were observed for the D2 (median OS, 4.7 vs. 8.6 months, P=0.033). Multivariable analysis demonstrated that a high D1 (hazard ratio, 3.375; 95% confidence interval, 1.133-10.053; P=0.029) was an unfavorable independent prognostic factor. The mean D2 of 11 patients with stable disease decreased by 0.69 mg/mL compared to the D1 (P = 0.016). The mean D2 increased by 1.47 mg/mL compared to the D1 in 21 patients with progressive disease (P = 0.004). The data suggest that D-dimer may serve as a prognostic biomarker for metastatic osteosarcoma patients treated with second-line chemotherapy.