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Abstract Background The purpose of this study was to evaluate the efficacy and safety of fruquintinib‐based therapy as a salvage therapy for patients with advanced or metastatic sarcoma, including soft tissue sarcoma (STS) and bone sarcoma. Methods Patients with advanced or metastatic sarcoma were divided into two groups. One group received fruquintinib monotherapy, while the other received fruquintinib combined therapy. Safety and efficacy of fruquintinib‐based therapy were recorded and reviewed retrospectively, including progression‐free survival (PFS), overall response rate (ORR), and adverse events (AEs). Results Between August 2021 and December 2022, 38 sarcoma patients were retrospectively included. A total of 14 patients received fruquintinib alone (including 6 STS and 8 bone sarcoma), while 24 were treated with fruquintinib combined therapy (including 2 STS and 22 bone sarcoma). The median follow‐up was 10.2 months (95% CI, 6.4–11.5). For the entire population, the median PFS was 8.0 months (95% CI, 5.5–13.0). The ORR was 13.1%, while the disease control rate (DCR) was 86.8%. The univariate analysis showed that radiotherapy history (HR, 4.56; 95% CI, 1.70–12.24; p = 0.003), bone sarcoma (HR, 0.34; 95% CI, 0.14–0.87; p = 0.024), and treatment method of fruquintinib (HR, 0.36; 95% CI, 0.15–0.85; p = 0.021) were significantly associated with PFS. The multivariate analysis showed that patients without radiotherapy history were associated with a better PFS (HR, 3.71; 95% CI: 1.31–10.55; p = 0.014) than patients with radiotherapy history. Patients in combination group reported pneumothorax (8.3%), leukopenia (33.3%), thrombocytopenia (12.5%), diarrhea (4.2%), and anemia (4.2%) as the most frequent grade 3 or higher treatment‐emergent AEs (TEAEs), while there was no severe TEAEs occurred in the monotherapy group. Conclusions Fruquintinib‐based therapy displayed an optimal tumor control and an acceptable safety profile in patients with advanced or metastatic sarcoma.

Abstract Background Cell-based immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. Methods In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18–27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. Results From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. Conclusions Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. Trial registration ClinicalTrials.gov, NCT04074564.

Background: Observational studies suggest a potential association between atmospheric particulate matter 2.5 (PM2.5) and osteoporosis, but a causal association is unclear due to the presence of confounding factors.Methods: We utilized bone mineral density indices at four specific sites to represent osteoporosis: femoral neck (FN-BMD), lumbar spine (LS-BMD), forearm (FA-BMD), and heel (HE-BMD). The PM2.5 data was obtained from the UK Biobank database, while the datasets for FN-BMD, LS-BMD, and FA-BMD were obtained from the GEFOS database, and the dataset for HE-BMD was obtained from the EBI database. A two-sample Mendelian randomization analysis was conducted using mainly the inverse variance weighted method, horizontal pleiotropy and heterogeneity were also assessed.Results: The results indicated that PM2.5 was not correlated with a decrease in FN-BMD (β: −0.305, 95%CI: −0.762, 0.153), LS-BMD (β: 0.134, 95%CI: −0.396, 0.666), FA-BMD (β: -0.056, 95%CI: −1.172,1.060), and HE-BMD (β: −0.084, 95%CI: −0.261,0.093). Additionally, acceptable levels of horizontal pleiotropy and heterogeneity were observed.Conclusion: In contrast to most observational studies, our research did not discover a potential causal relationship between PM2.5 and the development of osteoporosis.

Abstract Purpose The human EGFR2 (HER2) signaling pathway is one of the most actively studied targets in cancer transformation research. Ttriplex-forming oligonucleotides (TFOs) activate DNA damage and induce apoptosis. We aim to encapsulate TFO-HER2 with nano-particle ZW-128 to suppress breast cell growth in vitro and in vivo. Experimental design We designed a set of TFO fragments targeting HER2 and verified their effectiveness. We encapsulated TFO-HER2 in ZW-128 to form nano-drug TFO@ZW-128. Cell counting kit 8, flow cytometry, and western blotting were used to evaluate the effect of TFO@ZW-128 on cell proliferation and the expressions of related proteins. The ant-itumor effect of TFO@ZW-128 was evaluated in vivo using nude mice breast cancer model. Results TFO@ZW-128 had efficient cellular uptake in amplified HER2 breast cancer cells. TFO@ZW-128 showed an 80-fold increase in TFO utilization compared with TFO-HER2 in the nude mouse breast cancer model. Meanwhile, TFO@ZW-128 dramatically inhibited the growth of HER2-overexpressing tumors compared with TFO-HER2 (P

Introduction: Cancer biomarkers are substances or processes highly associated with the presence and progression of cancer, which are applicable for cancer screening, progression surveillance, and prognosis prediction in clinical practice. In our previous studies, we discovered that cancer cells upregulate inositol 1,4,5-triphosphate receptor-interacting protein-like 1 (ITPRIPL1), a natural CD3 ligand, to evade immune surveillance and promote tumor growth. We also developed a monoclonal ITPRIPL1 antibody with high sensitivity and specificity. Here, we explored the application of anti-ITPRIPL1 antibody for auxiliary diagnosis of non-small cell lung cancer (NSCLC).Methods: NSCLC patient tissue samples (n = 75) were collected and stained by anti-ITPRIPL1 or anti-CD8 antibodies. After excluding the flaked samples (n = 15), we evaluated the expression by intensity (0-3) and extent (0-100%) of staining to generate an h-score for each sample. The expression status was classified into negative (h-score < 20), low-positive (20-99), and high-positive (≥ 100). We compared the h-scores between the solid cancer tissue and stroma and analyzed the correlation between the h-scores of the ITPRIPL1 and CD8 expression in situ in adjacent tissue slices.Results: The data suggested ITPRIPL1 is widely overexpressed in NSCLC and positively correlates with tumor stages. We also found that ITPRIPL1 expression is negatively correlated with CD8 staining, which demonstrates that ITPRIPL1 overexpression is indicative of poorer immune infiltration and clinical prognosis. Therefore, we set 50 as the cutoff point of ITPRIPL1 expression H scores to differentiate normal and lung cancer tissues, which is of an excellent sensitivity and specificity score (100% within our sample collection).Discussion: These results highlight the potential of ITPRIPL1 as a proteomic immunohistochemical NSCLC biomarker with possible advantages over the existing NSCLC biomarkers, and the ITPRIPL1 antibody can be applied for accurate diagnosis and prognosis prediction.

Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.

Abstract Radiotherapy and targeted therapy are essential treatments for patients with brain metastases from human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, the combination of radiotherapy and targeted therapy still needs to be investigated, and neurotoxicity induced by radiotherapy for brain metastases has also become an important issue of clinical concern. It remained unclear how to achieve the balance of efficacy and toxicity with the application of new radiotherapy techniques and new targeted therapy drugs. This article reviews the benefits and potential risk of combining radiotherapy and targeted therapy for HER2-positive breast cancer with brain metastases.

IntroductionTotally implanted ports (PORTs) have been widely used among patients with malignancy. Cardiac metastasis secondary to bone sarcoma and catheter-related right atrial thrombosis (CRAT) can be both present as cardiac masses. However, these two cardiac masses share very similar imaging characteristics.MethodsThe features, treatments, and outcomes of 5 bone sarcoma pediatric patients with PORTs who suffered from cardiac masses in the right atrium were analyzed. Clinical data and histological characteristics of cardiac masses were also recorded.ResultsAmong 928 patients with malignancy and PORTs, 5 bone sarcoma pediatric patients were found to have cardiac masses in the right atrium. The catheter tips were located in the right atrium of 4 patients and the superior vena cava-right atrium junction (CAJ) of 1 patient. Four patients with good response to anti-tumor treatment had received surgical lumpectomies for pathologic identification and mass excision, with cardiac metastases among 1 patient and thromboses among 3 patients. The median time from venous access port implantation to cardiac mass detection for CRAT was 6.3 months (range: 4.7–6.8 months) and to diagnosis of or possible cardiac metastasis was 13.3 months (range: 11.2–15.4 months).ConclusionThe placement of a catheter tip into the right atrium should be avoided. The time from PORTs implantation to cardiac mass detection might serve as a potential tool to differentiate cardiac metastasis from CRAT. Surgical management may be an effective treatment for bone sarcoma pediatric patients who had good response to anti-tumor treatment and suffered from cardiac masses in the right atrium.

Osteosarcomas are difficult to treat and have a limited response to immunotherapy. Here, the authors analyse osteosarcomas at the single-cell level, and identify both the transdifferentiation of malignant cells and an array of immune cells that could have implications for metastasis and immunotherapy.

Background: Melanoma is a highly malignant and aggressive tumor. The search for new and effective biomarkers facilitates early diagnosis and treatment, ultimately improving the prognosis of melanoma patients. Although the transmembrane protein TMEM176B has been linked to a number of cancers, its role in cancer immunity remains unknown.Methods: Expression levels of TMEM176B in normal tissues and several cancers, including Skin Cutaneous Melanoma (SKCM), were collected from TCGA and GTEx. We used Receiver operating characteristic and Kaplan–Meier survival curves and performed regression analysis to elucidate the link between TMEM176B and clinicopathological features of SKCM in order to determine the prognostic significance of TMEM176B in SKCM. We then used the GEPIA and STRING websites to search for proteins and associated top genes that may interact with TMEM176B and enriched them for analysis. The link between TMEM176B and immune cells infiltration was then investigated using TIMER, CIBERSORT algorithm and GSVA package of R (v3.6.3). Finally, animal tests were conducted to confirm the expression of Tmem176b and its influence on T-cell immune infiltration.Results:TMEM176B expression was considerably elevated in SKCM compared to normal tissues. Particularly, TMEM176B expression was also linked to pathological stage, tumor ulceration and radiation therapy. Patients with elevated TMEM176B expression had a better prognosis, according to the survival analysis. The majority of tumor infiltrating lymphocytes (TILs) especially T cells in SKCM was positively linked with TMEM176B expression. Our animal experiments also verified that the T-cell infiltration was significantly inhibited in local melanoma tissue of Tmem176b knockout mice. At the same time deleting Tmem176b accelerated tumor progress and impaired T cells effector function.Conclusion: Upregulated expression of TMEM176B in SKCM is associated with a better prognosis and it has the potential to serve as a diagnostic and prognostic marker for the disease. It may serve as a target for SKCM immunotherapy by regulating CD8+ T cells although it requires more evidence.

Osteosarcoma (OS) is the most common primary bone sarcoma, chemoresistance becomes an obstacle to its treatment. Metabolic reprogramming is a hallmark of malignancy, targeting the metabolic pathways might provide a reasonable therapeutic strategy for OS. Here we demonstrated that Ailanthone (AIL), a major component of the Chinese medicine Ailanthus altissima, significantly suppressed OS cell growth in vitro and in vivo. Furthermore, AIL dose-dependently inhibited cell migration and invasion, induced cell cycle arrest and apoptosis in OS cells. Combined transcriptomics, proteomics and metabolomics analyses revealed that AIL induced widespread changes in metabolic programs in OS cells, while the serine biosynthetic pathway (SSP) was the most significantly altered pathway. qRT-PCR and Western blot assay confirmed that the transcript and protein levels of the SSP genes (PHGDH, PSAT1 and PSPH) were downregulated dose-dependently by AIL. In addition, we found out that many downstream pathways of the SSP including the one-carbon pool by folate, purine metabolism, pyrimidine metabolism, DNA replication and sphingolipid metabolism were downregulated after AIL treatment. In the revere test, PHGDH overexpression but not exogenous serine supplementation clearly attenuated the effects of AIL on OS cells. Taken together, AIL exerts antitumor effects on OS through mediating metabolic reprogramming, at least in part, by suppressing the SSP. Our findings suggest that AIL could emerge as a potential therapeutic strategy in OS.

Abstract Background Tripartite motif-containing proteins (TRIM) play a crucial role in carcinogenesis. Little attention has been focused on the possible functions of TRIM6 on carcinogenesis. Methods The expression levels of TRIM6 were assessed in colorectal cancer (CRC) samples. TRIM6 expression was knocked down in CRC cell lines, and subjected to Cell counting kit-8 (CCK-8), bromodeoxyuridine (BrdU) incorporation and cell cycle assays. Immunoprecipitation and proteomics analysis was performed to identify potential associated proteins of TRIM6. Results TRIM6 expression was up-regulated in CRC samples and TRIM6 expression may be an independent prognostic marker for CRC. Knocking down TRIM6 expression suppressed CRC cell proliferation, induced cell cycle arrested at G2/M phase and increased sensitivity to 5-fluorouracil and oxaliplatin. TIS21, an anti-proliferative protein involved in the regulation of G2/M arrest, was identified as an interaction partner of TRIM6. Moreover, CRC cells with TRIM6 overexpression showed decreased TIS21 protein stability. TIS21 ubiquitination was increased in CRC cells overexpressing TRIM6, but not in those overexpressing TRIM6 E3 catalytic mutant (C15A). Further, Lys5 was essential for TRIM6 mediated TIS21 ubiquitination. TIS21 overexpression reversed the induced effects of TRIM6 overexpression on CRC cell proliferation, and the levels of forkhead box M1 (FoxM1), phosphorylated FoxM1, Cyclin B1 and c-Myc. Thiostrepton, a specific inhibitor for FoxM1, was less effective in anti-proliferative activity against CRC cells with lower level of TRIM6 in vitro and in vivo. Conclusions Our study suggests that TRIM6 promotes the progression of CRC via TIS21/FoxM1.

Abstract 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.

BackgroundImmunotherapy has provided an effective method for the treatment of many cancers. However, its efficacy in osteosarcoma is not satisfactory so far.Case PresentationHere, we presented a case of osteosarcoma treated with sequential chemotherapy and immunotherapy and showed promising therapeutic potential. The 29-year-old female patient presented 9th rib osteosarcoma with suspected right lung lower lobe metastasis. Surgery was performed to remove the primary lesion, and a series of chemotherapies were given afterward in consideration of the response and tolerance. The right lung lower lobe metastasis was under control first but progressed (PD) 9 months after the initiation of therapy. The lesion was surgically removed and subsequent chemotherapy was implemented. The patient had good tolerance with chemotherapy and maintained well for approximately 11 months before the discovery of 11th rib and right lung upper lobe metastases. Surgery was then performed on both lesions and achieved complete response. Post-surgical brief chemotherapy and subsequent long-term immunotherapy (pembrolizumab) maintained continuous remission for 33 months. The patient survived for 60 months with well-controlled disease from the time of confirmed diagnosis. Genetic alterations of all primary and metastatic lesions were investigated by whole-exome sequencing (WES). Substantial similarity in mutational landscape between the primary lesion and 11th rib metastasis and between the two lung metastases were revealed, while substantial heterogeneity was found between the rib lesions and lung metastases. The tumor mutational burden (TMB) for the 9th rib primary lesion, the metastatic 11th rib lesion, and the metastatic right upper and lower lobe nodule tissues was 8.02, 2.38, 4.61, and 0.14 mutations/Mb, respectively. The primary lesion exhibited the most diverse copy number variation (CNV) changes among all lesions. Furthermore, pathway enrichment analysis also suggested significant heterogeneity among the lesions.ConclusionsSurgery with sequential chemotherapy and maintenance immunotherapy was shown to have good response for the first time on osteosarcoma patient who had high TMB tumor lesions and good tolerance for chemotherapy and immunotherapy.

Pharmacists are health care professionals who are actively involved in identifying and solving drug-related problems (DRPs) in neoplasm patients. However, the effectiveness of pharmaceutical services at outpatient clinic for neoplasm patients have not been reported in China. This study aims to describe and investigate the impacts of pharmacists-managed oncology outpatient clinic on ambulatory neoplasm patients. We performed a descriptive, prospective study from June 6, 2018 to June 6, 2020. Firstly, we established a pharmacists-managed oncology outpatient clinic and a Pharmacists Work System of Medication Therapy Management (MTM) software with the cooperation of oncologists, pharmacists and software engineers in 2018. Subjects were neoplasm patients who visited the pharmacists-managed outpatient clinic. The pharmacists performed a comprehensive assessment of the patient’s medication and made planned interventions based on the DRPs identified. A total of 215 eligible patients with 707 visits were enrolled and recorded in the MTM software. A total of 316 DRPs (1.47 per patient) were identified. Adverse reactions, non-adherence, untreated indication, and drug interactions were the leading DRPs. 261 (82.6%) of the identified DRPs had been confirmed as resolved and 104 (78.2%) of adverse reactions were improved following pharmacist interventions and 2 to 3 course follow-up. Of the 382 planned interventions, 345 (90.3%) were accepted by patients or physicians. This is the first pharmacists-managed oncology outpatient clinic to describe the type of DRPs in neoplasm patients and evaluate the effectiveness of pharmacist interventions in China. Pharmacist interventions were efficacious in resolving DRPs and improving adverse reactions. We confirmed that pharmacists have an important role in ambulatory neoplasm patients care.

Background: Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive. Methods: Cell proliferation, invasion and migration were measured by CCK-8 and Transwell. Immunoprecipitation and mass spectrometry analysis were used to identify candidate proteins associated with TRIM7. Immunoprecipitation, immunofluorescence, pull down and ubiquitination assay were performed to examine the regulation between TRIM7 and its candidate protein. m6A modification of TRIM7 was measured by RNA immunoprecipitation. Findings: TRIM7 expression was upregulated in osteosarcoma tissues and was an independent risk factor in predicting poor prognosis. TRIM7 regulates osteosarcoma cell migration and invasion through ubiquitination of breast cancer metastasis suppressor 1 (BRMS1). Moreover, chemoresistance was readily observed in osteosarcoma cells and in patient-derived xenograft (PDX) mice with higher TRIM7 levels. Loss of TRIM7 m6A modification was observed in osteosarcoma tissues. METTL3 and YTHDF2 were the main factors involved in the aberrant m6A modification of TRIM7. Interpretation: Overall, our findings show that TRIM7 plays a key role in regulating metastasis and chemoresistance in osteosarcoma through ubiquitination of BRMS1. Funding: This work was financially supported by grants of NSFC (81001192, 81672658 and 81972521) and National Key Research Project of Science and Technology Ministry (2016YFC0106204).

Abstract Background Ubiquitin specific peptidase 39 (USP39), an essential factor in the assembly of the mature spliceosome complex, has an aberrant expression in several cancer. However, its function and the corresponding mechanism on human osteosarcoma has not been fully explored yet. Methods The mRNA and DNA copies of USP39 were increased in osteosarcoma cancer tissues compared with the one in human normal tissues according to datasets from the publicly available Oncomine database. A further western blot analysis also demonstrated an aberrant endogenous expression of USP39 in three different osteosarcoma cells. Then lentivirus-mediated short hairpin RNA (shRNA) was designed to silence USP39 in human osteosarcoma cell line U2OS, which is used to test the impact of USP39-silencing on cellular proliferation, colony formation, cell cycle distribution and apoptosis. Results Knockdown of USP39 expression in U2OS cell significantly decreased cell proliferation, impaired colony formation ability. A further analysis indicated suppression of USP39 arrested cell cycle progression at G2/M phase via p21 dependent way. In addition, the results of Annexin V/7-AAD staining suggested the knockdown of USP39 could promote U2OS cell apoptosis through PARP cleavage. Conclusions These results uncover the critical role of USP39 in regulating cancer cell mitosis and indicate USP39 is critical for osteosarcoma tumorigenesis.

Osteosarcoma (OS) is one of the most common primary bone tumors in children and young adults. The majority of osteosarcoma patients have limited alternative therapeutic options and metastatic patients generally have a poor prognosis. Thus, it is important to explore novel effective therapeutic targets in the treatment of osteosarcoma. Diacylglycerol kinase zeta (DGKZ) is a recently identified gene potentially associated with certain human carcinogenesis. However, the role of DGKZ in proliferation of osteosarcoma is still unclear. In this study, DGKZ's expression was firstly investigated in OS tumor samples and correlated with poor outcome in OS patients. Silence of DGKZ by shRNA hampered osteosarcoma cell growth and promoted cell apoptosis in vitro. In vivo, DGKZ's knockout also suppressed xenograft tumor proliferation as determined by bioluminescence imaging and weight/volume measurements. Meanwhile, Affymetrix GeneChip and Ingenuity Pathway Analysis (IPA) revealed that DGKZ knockdown resulted in a decreased activity of MYC pathway, and several target genes expression in MYC pathway were altered, including CCND1, CDKN2B, CDK6, PCNA, and EGR1. Furthermore, immunoprecipitation coupled with mass spectrometry (IP-MS) analysis was used to identify proteins that interacted with DGKZ in OS cells and revealed ERK1/2, a key MYC-interactor, to associate with DGKZ. Together, our study demonstrated that DGKZ might act as an oncogene in osteosarcoma via its possible interaction with ERK1/2 and MYC pathway.

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.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.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

The significance of ezrin immunoexpression and prognosis for osteosarcoma is still controversial. The aim was to provide a meta-analysis for ezrin immunoexpression and prognostic features of osteosarcoma patients.A detailed search was made in MEDLINE, EMBASE and the Web of Knowledge for relevant original articles published in English; methodological quality of the included studies was also assessed. Two reviewers extracted data independently. Studies were pooled and summary hazard ratios (HRs) and odds ratio (ORs) with corresponding confidence intervals (CIs) were calculated.Final analysis of 318 patients from 5 eligible studies was performed. Combined HR of ezrin immunohistochemical staining suggested that positive immunoexpression had an unfavorable impact on osteosarcoma patients' overall survival (n = 223 in 4 studies; HR = 4.79; 95% CI: 1.50-15.30; P = 0.008) but not on event-free survival (n = 202 in 3 studies; HR = 1.59; 95% CI: 0.61-4.15; P = 0. 0.342). Combined OR of ezrin immunohistochemical staining indicated that positive immunoexpression was associated with recurrence (n = 134 in 2 studies; OR = 3.79; 95% CI: 1.49-9.64; P = 0.005) but not with serum ALP level (n = 160 in 2 studies; OR = 2.16; 95% CI: 0.09-52.50; P = 0.637) and histological response to neoadjuvant chemotherapy(n = 260 in 4 studies; OR = 0.87; 95% CI: 0.37-2.03; P = 0.740).The results of this meta-analysis suggest that ezrin positive immunoexpression confers a higher risk of recurrence and a worse survival in osteosarcoma patients. Large prospective studies are needed to provide solid data to investigate the precise prognostic significance of ezrin.

BACKGROUND: Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined. METHODS: We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies. RESULTS: A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3-2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21-8.67, p = 0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed. CONCLUSION: With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

PURPOSE: Ezrin is a cytoskeletal protein involved in tumor growth and invasion. However its prognostic value for survival in patients with solid tumor remains controversial. METHODS: Several databases were searched, including Pubmed, Embase and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS). The pooled hazard ratio (HR) or odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: Twenty-seven eligible trials involving 4693 patients were ultimately identified. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive Ezrin expression had an impact on overall survival (OS) [1.95, 95% confidence interval (CI) 1.60-2.39; P

BACKGROUND: Combining targeted therapy has been extensively investigated in previously treated advanced non-small-cell lung cancer (NSCLC), but it is still unclear whether combining targeted therapy might offer any benefits against standard monotherapy with erlotinib. We thus performed a meta-analysis of randomized controlled trials to compare the efficacy and safety of combining targeted therapy versus erlotinib alone as second-line treatment for advanced NSCLC. METHODS: Several databases were searched, including Pubmed, Embase and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3 or 4 adverse event (AEs). The pooled hazard ratio (HR) or odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: Eight eligible trials involved 2417 patients were ultimately identified. The intention to treatment (ITT) analysis demonstrated that combining targeted therapy significantly improved OS (HR 0.90, 95% CI: 0.82-0.99, p = 0.024), PFS (HR 0.83, 95% CI: 0.72-0.97, p = 0.018), and ORR (OR 1.35, 95% CI 1.01-1.80, P = 0.04). Sub-group analysis based on phases of trials, EGFR-status and KRAS status also showed that there was a tendency to improve PFS and OS in combining targeted therapy, except that PFS for patients with EGFR-mutation or wild type KRAS favored erlotinib monotherapy. Additionally, more incidence of grade 3 or 4 rash, fatigue and hypertension were observed in combining targeted therapy. CONCLUSIONS: With the available evidence, combining targeted therapy seems superior over erlotinib monotherapy as second-line treatment for advanced NSCLC. More studies are still needed to identify patients who will most likely benefit from the appropriate combining targeted therapy.

Introduction: Cancer biomarkers are substances or processes highly associated with the presence and progression of cancer, which are applicable for cancer screening, progression surveillance, and prognosis prediction in clinical practice. In our previous studies, we discovered that cancer cells upregulate inositol 1,4,5-triphosphate receptor-interacting protein-like 1 (ITPRIPL1), a natural CD3 ligand, to evade immune surveillance and promote tumor growth. We also developed a monoclonal ITPRIPL1 antibody with high sensitivity and specificity. Here, we explored the application of anti-ITPRIPL1 antibody for auxiliary diagnosis of non-small cell lung cancer (NSCLC). Methods: NSCLC patient tissue samples (n = 75) were collected and stained by antiITPRIPL1 or anti-CD8 antibodies. After excluding the flaked samples (n = 15), we evaluated the expression by intensity (0-3) and extent (0-100%) of staining to generate an h-score for each sample. The expression status was classified into negative (h-score < 20), low-positive (20-99), and high-positive (≥ 100). We compared the hscores between the solid cancer tissue and stroma and analyzed the correlation between the h-scores of the ITPRIPL1 and CD8 expression in situ in adjacent tissue slices. Results: The data suggested ITPRIPL1 is widely overexpressed in NSCLC and positively correlates with tumor stages. We also found that ITPRIPL1 expression is negatively correlated with CD8 staining, which demonstrates that ITPRIPL1 overexpression is indicative of poorer immune infiltration and clinical prognosis. Therefore, we set 50 as the cutoff point of ITPRIPL1 expression H scores to differentiate normal and lung cancer tissues, which is of an excellent sensitivity and specificity score (100% within our sample collection). Discussion: These results highlight the potential of ITPRIPL1 as a proteomic immunohistochemical NSCLC biomarker with possible advantages over the existing NSCLC biomarkers, and the ITPRIPL1 antibody can be applied for accurate diagnosis and prognosis prediction. [ABSTRACT FROM AUTHOR]