Advanced esophageal cancer with bone metastases: Prognostic biomarkers and palliative treatment.

Esophageal cancer (EC) is a common and devastating tumor of the upper digestive tract. Unfortunately, by the time any symptoms have manifested, the disease has often progressed to an advanced stage and is accompanied by macro- and micrometastases, including in the bones. The treatment of esophageal cancer with bone metastases remains clinically challenging, given the poor prognosis associated with this condition. Effective prognostic biomarkers can help medical staff choose the appropriate operation and treatment plan, that is for most beneficial for making patients. Current treatments for esophageal cancer with bone metastases include pain-relieving drugs, surgical therapy, radiotherapy (RT), chemotherapy (CT, including molecular-targeted drug therapy), endocrine therapy (ET), bisphosphonates (BPs) and interventional therapy. Of these robust measures, radiotherapy has emerged as a particularly promising therapy for bone metastases from esophageal cancer. Substantial progress has been made in radiation therapy techniques since the discovery of X-rays by Roentgen in 1895. In its palliative capacity, the key goals of radiotherapy are to relieve the patients' bone pain and debilitate effects, including relieving spinal cord compression, correcting the spinal deformity and restoring spinal stability. However, it is worth mentioning that RT for esophageal cancer has various side effects. Currently, the available studies focused exclusively on radiotherapy for ECBM are too small to draw any definitive conclusions, and each of these studies has significant limitations. In this review, in addition to the epidemiology described at the beginning, we will explore the current prognostic biomarkers and radiotherapy for esophageal cancer, with a particular focus on those with bone metastases.

Spine MRI image segmentation method based on ASPP and U-Net network.

The spine is one of the most important structures in the human body, serving to support the body, organs, protect nerves, etc. Medical image segmentation for the spine can help doctors in their clinical practice for rapid decision making, surgery planning, skeletal health diagnosis, etc. The current difficulty is mainly the poor segmentation accuracy of skeletal Magnetic Resonance Imaging (MRI) images. To address the problem, we propose a spine MRI image segmentation method, Atrous Spatial Pyramid Pooling (ASPP)-U-shaped network (UNet), which combines an ASPP structure with a U-Net network. This approach improved the network feature extraction by introducing an ASPP structure into the U-Net network down-sampling structure. The medical image segmentation models are trained and tested on publicly available datasets and obtained the Dice coefficient and Mean Intersection over Union coefficients with 0.866 and 0.755, respectively. The experimental results show that ASPP-UNet has higher accuracy for spine MRI image segmentation compared with other mainstream networks.

Emerging Perspectives of Bone Metastasis in Hepatocellular Carcinoma.

Recent evidence suggests the global incidence and mortality of hepatocellular carcinoma (HCC) are increasing. Although the highest incidence of HCC remains entrenched in WHO regions with high levels of HBV-HCV infection, the etiology of this disease is rapidly changing to include other lifestyle risk factors. Extrahepatic metastasis is a frequent feature of advanced HCC and most commonly locates in the lungs and bone. Bone metastasis in HCC (HCC-BM) signals a more aggressive stage of disease and a poorer prognosis, simultaneously HCC-BM compromises the function and integrity of bone tissue. HCC induced osteolysis is a prominent feature of metastasis that complicates treatment needed for pathologic fractures, bone pain and other skeletal events like hypercalcemia and nerve compression. Early detection of bone metastases facilitates the treatment strategy for avoiding and relieving complications. Although recent therapeutic advances in HCC like targeting agents and immunotherapy have improved survival, the prognosis for patients with HCC-BM remains problematic. The identification of critical HCC-BM pathways in the bone microenvironment could provide important insights to guide future detection and therapy. This review presents an overview of the clinical development of bone metastases in HCC, identifying key clinical features and identifying potential molecular targets that can be deployed as diagnostic tools or therapeutic agents.

Primary leiomyosarcoma of cervical spine invading the vertebra without obvious osteoclasia: Case report and literature review.

Context: Primary leiomyosarcomas are malignant tumors of smooth muscles, with few reported cases occurring in the cervical spine. The authors report a case involving a 29-year-old man with primary leiomyosarcoma in the spinal canal posterior to the C3-C5 vertebrae.Findings: No obvious osteolytic lesions could be found in neither X-ray nor computed tomography scan. Because of the confusion of nontypical imaging findings, a decompressive surgery of anterior cervical corpectomy of C4 and reconstruction with a mesh cage filled with allogenic bone grafts were performed. The patient refused a second operation and then was advised to receive the radiotherapy. No recurrence of the symptoms was evident 6 months after surgery.Conclusion: When a patient suffers from upper cervical tumor, the leiomyosarcoma should be kept in mind as possible diagnoses despite its low occurring ratio. Early detection, early diagnosis, and early treatment must be the goal of the strategy.

Fusion of CNN1 and CNN2-based magnetic resonance image diagnosis of knee meniscus injury and a comparative analysis with computed tomography.

PURPOSE: We used convolutional neural network (CNN) technology to improve the accuracy of diagnosis of knee meniscus injury and shorten the diagnosis time. METHOD: We propose a meniscus detection method based on Fusion of CNN1 and CNN2 (CNNf), which uses Magnetic Resonance Imaging (MRI) and Computer tomography (CT) to compare the diagnosis results, verifies the proposed method through 2460 images collected from 205 patients in the hospital. We used accuracy, sensitivity, specificity, receiver operating characteristics (ROC), and damage total rate to evaluate performance. RESULTS: The accuracy of our model was 93.86%, the sensitivity was 91.35%, the specificity was 94.65%, and the area under the receiver operating characteristic curve was 96.78%. The total damage rate of MRI is 91.57%, which is far greater than the total damage rate of CT diagnosis of 80.13%. CONCLUSION: CNNf-based MRI technology of knee meniscus injury has high practical value in clinical practice. It can effectively improve the accuracy of diagnosis and reduce the rate of misdiagnosis.

Nanocomposite coating of albumin/Li-containing bioactive glass nanospheres promotes osteogenic activity of PEEK.

Polyetheretherketone (PEEK) is an important material applied in orthopedic applications, as it posses favorable properties for orthopedic implants, e.g., radiolucency and suitable elastic modulus. However, PEEK exhibits insufficient osteogenesis and osteointegration that limits its clinical applications. In this study, we aimed to enhance the osteogenisis of PEEK by using a surface coating approach. Nanocomposite coating composed of albumin/lithium containing bioactive glass nanospheres was fabricated on PEEK through dip-coating method. The presence of nanocomposite coating on PEEK was confirmed by SEM, FTIR, and XRD techniques. Nanocomposite coatings significantly enhanced hydrophilicity and roughness of PEEK. The nanocomposite coatings also enhanced adhesion, proliferation, and osteogenic differentiation of bone mesenchymal stem cells due to the presence of bioactive glass nanospheres and the BSA substrate film. The results indicate the great potential of the nanocomposite coating in enhancing osteogenesis and osteointegration of PEEK implants.

RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs.

BACKGROUND: Low back pain has become a serious social and economic burden and the leading cause of disability worldwide. Among a variety of pathophysiological triggers, intervertebral disc (IVD) degeneration plays a primary underlying role in causing such pain. Specifically, multiple independent endplate changes have been implicated in the initiation and progression of IVD degeneration. METHODS: In this study, we built a signaling network comprising both well-characterized IVD pathology-associated proteins as well as some potentially correlated proteins that have been associated with one or more of the currently known pathology-associated proteins. We then screened for the potential IVD degeneration-associated proteins using patients' normal and degenerative endplate specimens. Short hairpin RNAs for receptor interacting serine/threonine kinase 1 (RIPK1) were constructed to examine the effects of RIPK1 knockdown in primary chondrocyte cells and in animal models of caudal vertebra intervertebral disc degeneration in vivo. RESULTS: RIPK1 was identified as a potential IVD degeneration-associated protein based on IVD pathology-associated signaling networks and the patients' degenerated endplate specimens. Construction of the short hairpin RNAs was successful, with short-term RIPK1 knockdown triggering inflammation in the primary chondrocytes, while long-term knockdown triggered apoptosis through cleavage of the caspase 3 pathway, down-regulated NF-κB and mitogen-activating protein kinase (MAPK)s cascades, and decreased cell survival and inflammation. Animal models of caudal vertebra intervertebral disc degeneration further demonstrated that apoptosis was induced by up-regulation of tumor necrosis factor (TNF) accompanied by down-regulation of NF-κB and MAPKs cascades that are dependent on caspase and RIPK1. CONCLUSIONS: These results provide proof-of-concept for developing novel therapies to combat IVD degeneration through interfering with RIPK1-mediated apoptosis signaling pathways especially in patients with RIPK1 abnormality.

Histone methyltransferase SUV39H2 serves oncogenic roles in osteosarcoma.

Suppressor of variegation 3­9 homologue 2 (SUV39H2), a SET domain­containing histone methyl-transferase, trimethylates histone H3 at lysine 9 and serves crucial roles in heterochromatin organization and genome stability. SUV39H2 is overexpressed in various types of human cancer, whereas it is almost undetectable in normal adult tissues, except testis. The aim of this study was to investigate a potential role of SUV39H2 in osteosarcoma. In the present study, increased SUV39H2 expression levels were observed in osteosarcoma, the most common primary bone cancer in children and adolescents, and the knockdown of SUV39H2 expression by specific small interfering RNAs in osteosarcoma cells markedly suppressed cancer cell growth and led to a notable reduction in cell viability. Furthermore, overexpression of SUV39H2 promoted cell proliferation, which indicated that SUV39H2 may possess oncogenic activity in human osteosarcoma. Notably, depletion of SUV39H2 expression caused an increase in the population of G1 phase and induced apoptosis, which implied that SUV39H2 may have biological significance in the process of cell cycle. These results indicated that SUV39H2 may be an ideal target for osteosarcoma therapeutics.

Long Noncoding RNA SNHG16 Promotes Cell Proliferation by Sponging MicroRNA-205 and Upregulating ZEB1 Expression in Osteosarcoma.

BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) have been a research hotspot, as they play important roles in tumor development. However, their expression pattern and biological function in osteosarcoma have not yet been clarified. METHODS: Differentially expressed lncRNAs in osteosarcoma and paracarcinoma tissues were identified by screening an lncRNA microarray, and candidate lncRNAs were verified by quantitative real-time PCR (qRT-PCR). A series of bioinformatics and molecular biological methods were adopted to investigate the interaction among lncRNA, microRNA (miRNA), and miRNA target genes during the development and occurrence of osteosarcoma. Cell viability was measured using a Cell Counting Kit-8 assay. RESULTS: Chip microarray screening combined with the validation of differentially expressed candidate lncRNAs showed that the lncRNA small nucleolar RNA host gene 16 (SNHG16) had the largest fold change. SNHG16 was highly expressed in osteosarcoma tissues and cell lines, and its downregulation led to the suppressed proliferation of osteosarcoma cells. Further investigations revealed that SNHG16 could upregulate zinc finger E-box-binding homeobox 1 (ZEB1) expression by acting as an endogenous sponge of miR-205. Moreover, rescue assays proved that the effects of SNHG16 on the proliferation of osteosarcoma cells were dependent on miR-205. CONCLUSION: SNHG16 can significantly enhance the proliferation of osteosarcoma cells. In addition, SNHG16, miR-205, and ZEB1 interact in a common pathway during the development and occurrence of osteosarcoma, providing novel targets for intervention in the treatment of osteosarcoma.

MicroRNA-524 promotes cell proliferation by down-regulating PTEN expression in osteosarcoma.

BACKGROUND: Increasing numbers of studies have examined the correlation between specific miRNAs and tumours to enable their diagnosis and treatment. However, there are few reports regarding the concrete role and mechanism of miRNA in osteosarcoma. METHODS: The expression of miR-524 in osteosarcoma tissues and cell lines was examined by qRT-PCR. The cell proliferation was examined using CCK-8 in vitro. A series of bioinformatics and molecular biology techniques were adopted to investigate the regulatory relationship between miR-524 and target genes in osteosarcoma. RESULTS: The results showed that the miRNA with the most significant differential expression in osteosarcoma was miR-524, which was significantly up-regulated in both osteosarcoma tissues and cell lines. MiR-524 knockdown inhibited proliferation and promoted apoptosis of osteosarcoma cells, while overexpression of miR-524 induced their proliferation. Bioinformatics analysis and luciferase assay confirmed that PTEN was a direct target gene of miR-524 and that miR-524 induced proliferation of osteosarcoma cells through activation of the PI3K/AKT pathway via inhibition of PTEN. CONCLUSIONS: MiR-524 induces the proliferation of osteosarcoma cells through activation of the PI3K/AKT pathway via inhibition of the target gene PTEN, which provides a theoretical basis for selecting a new therapeutic target for osteosarcoma.

Surgical Outcomes of Single-Level Transforaminal Lumbar Interbody Fusion for Degenerative Spondylolisthesis With and Without Kyphotic Alignment.

OBJECTIVE: We sought to investigate the impact of single-level transforaminal lumbar interbody fusion (TLIF) on lumbar sagittal profile in degenerative spondylosis (DS) patients with or without kyphotic alignment, as well as compare radiologic and clinical outcomes based on preoperative sagittal alignment. BACKGROUND: DS with a kyphotic alignment at an involved segment constitutes a distinct subgroup. However, previous studies concerning surgical outcomes often lump all patients together without focusing on this distinct subgroup. METHODS: This study reviewed a consecutive series of patients who received single-level TLIF for DS between 2009 and 2016. They were assigned to Groups K and L. All patients were followed up for >2 years. Then demographics and radiographic and clinical outcomes were compared between the groups. RESULTS: There were 19 and 115 patients in Group K and Group L, respectively. Compared with Group L, Group K was characterized by loss of lumbar lordosis and anterior shifting of L1 axis S1 distance. After surgery, lumbar lordosis and L1 axis S1 distance was significantly improved in Group K, while no significant change occurred in group L. The mean reduction rate was significantly higher in Group K, which had less slippage after surgery, but the differences in slip angle, anterior disk height, and posterior disk height were not significant. The preoperative Oswestry Disability Index and visual analog scale for back pain scores were significantly higher in Group K, while no differences were found in postoperative evaluation. CONCLUSIONS: Despite effective changes radiographic parameters and clinical outcomes, our findings suggest that the 2 groups behave differently in response to single-level TLIF procedure. Reconstruction of lumbar sagittal profile can be achieved in DS with a kyphotic alignment after surgery.

Development and validation of nomogram based on miR-203 and clinicopathological characteristics predicting survival after neoadjuvant chemotherapy and surgery for patients with non-metastatic osteosarcoma.

BACKGROUND: Recently, nomograms have been used as models for risk prediction in malignant tumor because they can predict the outcome of interest for a certain individual based on many variables. This study aimed to establish an effective prognostic nomogram for osteosarcoma based on the clinicopathological factors and microRNA-203. RESULTS: The results showed that miR-203 expression was significantly lower in osteosarcoma tissues compared with the corresponding adjacent tissues (P < 0.001). Patients with low miR-203 expression had poor overall survival (OS) in osteosarcoma. The histological type, tumor size, AJCC stage and miR-203 expression were integrated in the nomogram. The nomogram showed significantly better prediction of OS than for patients with non-metastatic osteosarcoma. The ROC curve also showed higher specificity and sensitivity for predicting 3- and 5-year osteosarcoma patients' survival compared with AJCC stage. The decision curve analysis also indicated more potential of clinical application of the nomogram compared with AJCC staging system. Moreover, our findings were supported by the validation cohort. MATERIALS AND METHODS: We retrospectively investigated 301 patients with non-metastatic osteosarcoma. Data from primary cohort (n = 198) were used to develop multivariate nomograms. This nomogram was internally validated for discrimination and calibration with bootstrap samples and was externally validated with an independent patient cohort (n = 103). CONCLUSIONS: Our proposed nomogram showed more accurate prognostic prediction for patients with non-metastatic osteosarcoma.

MicroRNAs with prognostic significance in osteosarcoma: a systemic review and meta-analysis.

INTRODUCTION: This study aimed to elucidate the prognostic value of microRNAs (miRNAs) in patients with osteosarcoma. MATERIALS AND METHODS: Studies were recruited by searching PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang data-bases (final search update conducted January 2017). Eligible studies were identified and the quality was assessed using multiple search strategies. RESULTS: A total of 55 articles that investigated the correlation between miRNA expression and either patient survival or disease recurrence in osteosarcoma was initially identified. Among these, 30 studies were included in the meta-analysis. The results of our meta-analysis revealed that elevated levels of miR-21, miR-214, miR-29, miR-9 and miR-148a were associated with poor prognosis in osteosarcoma. Additionally, downregulated miR-382, miR26a, miR-126, miR-195 and miR-124 expression indicated poor prognosis in osteosarcoma. CONCLUSIONS: miRNAs may act as independent prognostic factors in patients with osteosarcoma and are useful in stratifying risk.

Silencing of histone methyltransferase NSD3 reduces cell viability in osteosarcoma with induction of apoptosis.

NSD3 is a histone lysine methyltransferase that methylates histone H3 at lysine 36. NSD3 is located at chromosome 8p11.23, the locus that exhibits strong cancer relevance. Thus, NSD3 is likely involved in multiple human cancers. Nevertheless, its roles in human carcinogenesis remain unknown. In the present study, we demonstrated that silencing of NSD3 in osteosarcoma, the most common primary bone cancer in children and adolescents, results in a marked decrease in the number of viable cancer cells, accompanied by increases in the cell population at the G2/M phase and the number of apoptotic cells. In addition, 549 NSD3­regulated genes were identified and a set of selected candidate genes were validated. Bioinformatic analysis revealed that NSD3 negatively regulates a number of genes that are involved in the process of negative regulation of signal transduction as well as negative regulation of signaling and cell communication. Our results indicate the oncogenic roles of NSD3 in the development and progression of human osteosarcoma, and implicate NSD3 as a potential molecular target for selective therapy for human osteosarcoma.

Bay11-7082 attenuates neuropathic pain via inhibition of nuclear factor-kappa B and nucleotide-binding domain-like receptor protein 3 inflammasome activation in dorsal root ganglions in a rat model of lumbar disc herniation.

Lumbar disc herniation (LDH) is an important cause of radiculopathy, but the underlying mechanisms are incompletely understood. Many studies suggested that local inflammation, rather than mechanical compression, results in radiculopathy induced by LDH. On the molecular and cellular level, nuclear factor-kappa B (NF-κB) and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome have been implicated in the regulation of neuroinflammation formation and progression. In this study, the autologous nucleus pulposus (NP) was implanted in the left L5 dorsal root ganglion (DRG) to mimic LDH in rats. We investigated the expression of NF-κB and the components of NLRP3 inflammasome in the DRG neurons in rats. Western blotting and immunofluorescence for the related molecules, including NLRP3, apoptosis-associated speck-like protein containing caspase-1 activator domain (ASC), caspase-1, interleukin (IL)-1ß, IL-18, IκBα, p-IκBα, p65, p-p65, and calcitonin gene-related peptide (CGRP) were examined. In the NP-treated group, the activations of NLRP3, ASC, caspase-1, IL-1ß, IL-18, p-IκBα, and p-p65 in DRG neurons in rats were elevated at 1 day after surgery, and the peak occurred at 7 days. Treatment with Bay11-7082, an inhibitor of the actions of IKK-ß, was able to inhibit expression and activation of the molecules (NLRP3, ASC, caspase-1, IL-1ß, IL-18, p-IκBα, and p-p65) and relieve the pain in rats. Our study shows that NF-κB and NLRP3 inflammasome are involved in the maintenance of NP-induced pain, and that Bay11-7082 could alleviate mechanical allodynia and thermal hyperalgesia by inhibiting NF-κB and NLRP3 inflammasome activation.

[Effect of interleukin 17 on invasion of human colon cancer cells].

OBJECTIVE: To investigate the effect and its possible mechanism of interleukin-17 (IL-17) on invasion and metastasis of human colon cancer cells. METHODS: IL-17 was added into the culture media of human colon cancer cells SW480 and LOVO. Cells were divided into 4 groups: SW480 control group (SW480 cells), LOVO control group (LOVO cells), SW480 experiment group (50 µg/L IL-17+SW480 cells), and LOVO experiment group (50 µg/L IL-17+LOVO cells). Cell growth was measured by CCK-8 assay. The proliferation rate(%)=[(Aexperiment group-Ablank)/(Acontrol group-Ablank)]×100%). The ability of cell invasion and migration was measured by transwell assay. Real time-PCR was used to detect mRNA expression of VEGF and MMP-9. Western blot was performed to detect protein expression of STAT3, p-STAT3, VEGF and MMP-9. Enzyme-linked immunosorbent assay (ELISA) was applied to measure the protein content of VEGF and MMP-9 in the supernatant. RESULTS: After cultivation for 24, 48 and 72 hours, CCK-8 assay revealed that the proliferation rate of SW480 was 1.18%±0.07%, 1.42%±0.09%, and 1.62%±0.08%; the proliferation rate of LOVO was 1.13%±0.02%, 1.32%±0.05% and 1.73%±0.02% in experiment group. Transwell experiments showed that after cultivation with IL-17 for 24 hours, number of invasion cell in experimental groups (SW480: 34.00±0.45, LOVO: 41.60±0.51) was higher as compared to corresponding control groups (SW480: 4.53±0.14; LOVO: 3.67±0.33) with significant differences (SW480: t=-76.026, P=0.001; LOVO: t=-81.580, P=0.005). The number of migration cell in experimental groups (SW480: 36.40±0.51, LOVO: 46.40±0.68) was higher as compared to corresponding control groups (SW480: 7.83±0.69; LOVO: 6.67±0.48) with significant differences (SW480: t=-51.542, P=0.003; LOVO: t=-49.265, P=0.005). Real-time PCR results revealed that after cultivation with IL-17 for 24 hours, VEGF and MMP-9 mRNA relative expression levels in experimental groups (SW480: VEGF:1.53±0.12, MMP-9: 2.44±0.23; LOVO: VEGF: 2.96±0.35, MMP-9: 3.38±0.55) were higher than those in control groups (both 1) with significant differences (VEGF: t=3.799, P=0.043; MMP-9: t=5.254, P=0.039). Western blot illustrated that after cultivation with IL-17 for 24 hours, STAT3, p-STAT3, VEGF and MMP-9 proteins relative expression levels in experimental groups were significantly higher that those in control groups (SW480:STAT3: t=3.233, P=0.023; p-STAT3: t=3.954, P=0.032; VEGF: t=3.201, P=0.025; MMP-9: t=3.154, P=0.029; LOVO: STAT3: t=3.788, P=0.012; p-STAT3: t=2.662, P=0.040; VEGF: t=4.118, P=0.035; MMP-9: t=4.268, P=0.030). ELISA indicated that content of VEGF and MMP-9 in the supernatant of experimental groups (SW480: VEGF 5 491.41±63.22, MMP-9: 21.43±1.35. LOVO: VEGF: 8 631.46±129.59, MMP-9: 178.32±3.20) were higher than those in control groups (SW480: VEGF:4 456.32±87.56, MMP-9:18.57±2.44. LOVO: VEGF: 8 122.38±108.66, MMP-9: 163.22±6.89) with significant differences (SW480: VEGF: t=6.993, P=0.037; MMP-9: t=5.587, P=0.040. LOVO: VEGF: t=7.013, P=0.044; MMP-9: t=6.762, P=0.043). CONCLUSION: IL-17 may be able to activate STAT3 signal transduction pathway in vitro through up-regulation of VEGF and MMP-9 expression, thereby enhancing the invasion and migration of colon cancer SW480 and LOVO cells.

[Analysis of long-time construct failure of spinal surgery in patients with Parkinson's disease].

OBJECTIVE: To assess the rate of complications of spine surgery and the therapeutic efficacy in the patients with Parkinson's disease (PD) and characterize the special needs of this unique population. METHODS: The data of 25 PD patients undergoing the spinal surgery from January 1998 to December 2006 were analyzed. The patients not followed on a regular basis by their spine surgeons were invited for a follow-up review. The points of analysis were complications, revisions and reasons of surgery failure. RESULTS: The mean follow-up period was 56.3 months. Of 25 patients, 20 (80%) required additional surgery for a total of 25 reoperations. Three patients in need of additional surgery underwent another operation at a remote spinal segment. And 17 patients had the reoperations because of segmental instability at the operated or adjacent levels. CONCLUSION: The PD patients undergoing spine surgery have a high reoperation rate associated with technical complications. They should be appropriately counseled regarding an increased risk of operative complications. A closely follow-up is essential.