Thoracic giant cell tumor after two total en bloc spondylectomies including one emergency surgery: A case report.

BACKGROUND: For patients with acute paraplegia caused by spinal giant cell tumor (GCT) who require emergency decompressive surgery, there is still a lack of relevant reports on surgical options. This study is the first to present the case of an acute paraplegic patient with a thoracic spinal GCT who underwent an emergency total en bloc spondylectomy (TES). Despite tumor recurrence, three-level TES was repeated after denosumab therapy. CASE SUMMARY: A 27-year-old female patient who underwent single-level TES in an emergency presented with sudden severe back pain and acute paraplegia due to a thoracic spinal tumor. After emergency TES, the patient's spinal cord function recovered, and permanent paralysis was avoided. The postoperative histopathological examination revealed that the excised neoplasm was a rare GCT. Unfortunately, the tumor recurred 9 months after the first surgery. After 12 months of denosumab therapy, the tumor size was reduced, and tumor calcification. To prevent recurrent tumor progression and provide a possible cure, a three-level TES was performed again. The patient returned to an active lifestyle 1 month after the second surgery, and no recurrence of GCT was found at the last follow-up. CONCLUSION: This patient with acute paraplegia underwent TES twice, including once in an emergency, and achieved good therapeutic results. TES in emergency surgery is feasible and safe when conditions permit; however, it may increase the risk of tumor recurrence.

Automated Breast Volume Scanner Is More Valuable Than Hand-Held Ultrasound in Diagnosis of Small Breast cancer: An Analysis of 725 Patients With 912 Lesions Evaluations.

ABSTRACT: This study aimed to evaluate the clinical value of automated breast volume scanner (ABVS) compared with hand-held ultrasound (HHUS). From January 2015 to May 2019, a total of 912 breast lesions in 725 consecutive patients were included in this study. κ statistics were calculated to identify interobserver agreement of ABVS and HHUS. The diagnostic performance for ABVS and HHUS was expressed as the area under the receiver operating characteristic curve, as well as the corresponding 95% confidence interval, sensitivity, and specificity. The sensitivities of ABVS and HHUS were 95.95% and 93.69%, and the specificities were 85.47% and 81.20%, respectively. A difference that nearly reached statistical significance was observed in sensitivities between ABVS and HHUS (P = 0.0525). The specificity of ABVS was significantly higher than that of HHUS (P = 0.006). When lesions were classified according to their maximum diameter, the sensitivity and specificity of ABVS were significantly higher than HHUS for lesions ≤20 mm, while they made no statistical significance between ABVS and HHUS for lesions >20 mm. The interobserver agreement for ABVS was better than that of HHUS. Automated breast volume scanner was more valuable than HHUS in diagnosing breast cancer, especially for lesions ≤20 mm, and it could be a valuable diagnostic tool for breast cancer.

Lineage tracing for multiple lung cancer by spatiotemporal heterogeneity using a multi-omics analysis method integrating genomic, transcriptomic, and immune-related features.

Introduction: The distinction between multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) holds clinical significance in staging, therapeutic intervention, and prognosis assessment for multiple lung cancer. Lineage tracing by clinicopathologic features alone remains a clinical challenge; thus, we aimed to develop a multi-omics analysis method delineating spatiotemporal heterogeneity based on tumor genomic profiling. Methods: Between 2012 and 2022, 11 specimens were collected from two patients diagnosed with multiple lung cancer (LU1 and LU2) with synchronous/metachronous tumors. A novel multi-omics analysis method based on whole-exome sequencing, transcriptome sequencing (RNA-Seq), and tumor neoantigen prediction was developed to define the lineage. Traditional clinicopathologic reviews and an imaging-based algorithm were performed to verify the results. Results: Seven tissue biopsies were collected from LU1. The multi-omics analysis method demonstrated that three synchronous tumors observed in 2018 (LU1B/C/D) had strong molecular heterogeneity, various RNA expression and immune microenvironment characteristics, and unique neoantigens. These results suggested that LU1B, LU1C, and LU1D were MPLC, consistent with traditional lineage tracing approaches. The high mutational landscape similarity score (75.1%), similar RNA expression features, and considerable shared neoantigens (n = 241) revealed the IPM relationship between LU1F and LU1G which were two samples detected simultaneously in 2021. Although the multi-omics analysis method aligned with the imaging-based algorithm, pathology and clinicopathologic approaches suggested MPLC owing to different histological types of LU1F/G. Moreover, controversial lineage or misclassification of LU2's synchronous/metachronous samples (LU2B/D and LU2C/E) traced by traditional approaches might be corrected by the multi-omics analysis method. Spatiotemporal heterogeneity profiled by the multi-omics analysis method suggested that LU2D possibly had the same lineage as LU2B (similarity score, 12.9%; shared neoantigens, n = 71); gefitinib treatment and EGFR, TP53, and RB1 mutations suggested the possibility that LU2E might result from histology transformation of LU2C despite the lack of LU2C biopsy and its histology. By contrast, histological interpretation was indeterminate for LU2D, and LU2E was defined as a primary or progression lesion of LU2C by histological, clinicopathologic, or imaging-based approaches. Conclusion: This novel multi-omics analysis method improves the accuracy of lineage tracing by tracking the spatiotemporal heterogeneity of serial samples. Further validation is required for its clinical application in accurate diagnosis, disease management, and improving prognosis.

TGFB2-AS1 inhibits triple-negative breast cancer progression via interaction with SMARCA4 and regulating its targets TGFB2 and SOX2.

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype for its high rates of relapse, great metastatic potential, and short overall survival. How cancer cells acquire metastatic potency through the conversion of noncancer stem-like cells into cancer cells with stem-cell properties is poorly understood. Here, we identified the long noncoding RNA (lncRNA) TGFB2-AS1 as an important regulator of the reversibility and plasticity of noncancer stem cell populations in TNBC. We revealed that TGFB2-AS1 impairs the breast cancer stem-like cell (BCSC) traits of TNBC cells in vitro and dramatically decreases tumorigenic frequency and lung metastasis in vivo. Mechanistically, TGFB2-AS1 interacts with SMARCA4, a core subunit of the SWI/SNF chromatin remodeling complex, and results in transcriptional repression of its target genes including TGFB2 and SOX2 in an in cis or in trans way, leading to inhibition of transforming growth factor ß (TGFß) signaling and BCSC characteristics. In line with this, TGFB2-AS1 overexpression in an orthotopic TNBC mouse model remarkably abrogates the enhancement of tumor growth and lung metastasis endowed by TGFß2. Furthermore, combined prognosis analysis of TGFB2-AS1 and TGFß2 in TNBC patients shows that high TGFB2-AS1 and low TGFß2 levels are correlated with better outcome. These findings demonstrate a key role of TGFB2-AS1 in inhibiting disease progression of TNBC based on switching the cancer cell fate of TNBC and also shed light on the treatment of TNBC patients.

LncRNA HABON promoted liver cancer cells survival under hypoxia by inhibiting mPTP opening.

Hypoxia is an important feature of the tumor microenvironment (TME). While targeting hypoxic TME is emerging as a potential strategy for treating solid tumors including liver cancer. Recent studies have shown that hypoxia can regulate tumor adaptation to hypoxic TME through long non-coding RNA (lncRNA). In the previous study, we identify a novel hypoxia-activated lncRNA and termed it as HABON. Here, we demonstrated that knockdown of HABON caused necroptosis of tumor tissue and inhibited the subcutaneous tumor growth of SMMC-7721 cells in nude mice. Moreover, knockdown of HABON increased RIPK1 and MLKL expression as well as their phosphorylation level in SMMC-7721 and Huh7 liver cancer cells. Meanwhile, Necrostatin-1 and GSK872 could restore cell death of liver cancer cells caused by knockdown of HABON under hypoxia. The above results suggested that HABON could inhibit hypoxia-induced necroptosis of liver cancer cells. Mechanically, knockdown of HABON in liver cancer cells aggravated mitochondrial dysfunction caused by hypoxia. Furthermore, the RNA pull-down combined with mass spectrometry analysis identified HABON can interact with mitochondria-related protein VDAC1 and the RNA immunoprecipitation (RIP) analysis proved the interaction. In addition, we proved that VDAC1 mediated the mitochondrial permeability transition pore (mPTP) opening, mitochondrial dysfunction, as well as necroptosis caused by knockdown of HABON. Overall, our work demonstrates HABON can reduce hypoxia-induced necroptosis of liver cancer cells and suggests that inhibition of HABON in the hypoxic TME is a potential therapeutic strategy for treating liver cancer.

CircFOXM1 acts as a ceRNA to upregulate SMAD2 and promote the progression of nasopharyngeal carcinoma.

BACKGROUND: In recent years, the development of high-throughput sequencing technology has promoted the rapid development of circRNA-related research. Studies have found that circRNA plays a key role in a variety of tumors, but few people study the role of circRNA in nasopharyngeal carcinoma. Under comprehensive treatments, the 5-year survival rate can reach about 70%, but some patients still have distant metastases or recurrences after treatment. Therefore, it is very important to study the molecular mechanisms of the proliferation and invasion of nasopharyngeal carcinoma. METHODS: QRT-PCR was applied to detect the relative expression level of circFOXM1 in NPC and nasopharyngeal epithelial cell lines. We knocked down circFOXM1 and studied the influence of circFOXM1 on NPC cells. Nuclear and cytoplasmic RNA isolation experiments, fluorescence in situ hybridization (FISH), bioinformatics analysis, the dual-luciferase reporter experiment, Western Blot, and other experiments were conducted to verify the relationships among circFOXM1, miR-136-5p, and SMAD2. We collected clinical NPC samples to prove the effect of circFOXM1 on the prognosis and treatment of NPC. RESULTS: In this study, we found that circFOXM1 is highly expressed in nasopharyngeal carcinoma tissue cells compared with adjacent normal tissues and is related to the staging of nasopharyngeal carcinoma. High expression of circFOXM1 indicates a poor prognosis for nasopharyngeal carcinoma. Knockdown of CircFOXM1 inhibited the proliferation and invasion of nasopharyngeal carcinoma cells. CONCLUSION: CircFOXM1 promotes the malignant proliferation of nasopharyngeal carcinoma cells by regulating the miR-136-5p-SMAD2 axis.

Combined LIM kinase 1 and p21-Activated kinase 4 inhibitor treatment exhibits potent preclinical antitumor efficacy in breast cancer.

LIM kinase 1 (LIMK1) and p21-activated kinase 4 (PAK4) are often over-expressed in breast tumors, which causes aggressive cancer phenotypes and unfavorable clinical outcomes. In addition to the well-defined role in regulating cell division, proliferation and invasion, the two kinases promote activation of the MAPK pathway and cause endocrine resistance through phosphorylating estrogen receptor alpha (ERα). PAK4 specifically phosphorylates LIMK1 and its functional partners, indicating possible value of suppressing both kinases in cancers that over-express PAK4 and/or LIMK1. Here, for the first time, we assessed the impact of combining LIMK1 inhibitor LIMKi 3 and PAK4 inhibitor PF-3758309 in preclinical breast cancer models. LIMK1 and PAK4 pharmacological inhibition synergistically reduced the survival of various cancer cell lines, exhibiting specific efficacy in luminal and HER2-enriched models, and suppressed development and ERα-driven signals in a BT474 xenograft model. In silico analysis demonstrated the cell lines with reliance on LIMK1 were the most prone to be susceptible to PAK4 inhibition. Double LIMK1 and PAK4 targeting therapy can be a successful therapeutic strategy for breast cancer, with a unique efficiency in the subtypes of luminal and HER2-enriched tumors.

Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRß-IL-6 axis in MUC1-positive cervical cancer.

Cancer stem cells (CSCs) are often enriched after chemotherapy and contribute to tumor relapse. While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of diverse types of cancer, whether EGFR-TKIs are effective against chemoresistant CSCs in cervical cancer is largely unknown. Here, we reveal that EGFR correlates with reduced disease-free survival in cervical cancer patients with chemotherapy. Erlotinib, an EGFR-TKI, effectively impedes CSCs enrichment in paclitaxel-resistant cells through inhibiting IL-6. In this context, MUC1 induces CSCs enrichment in paclitaxel-resistant cells via activation of EGFR, which directly enhances IL-6 transcription through cAMP response element-binding protein (CREB) and glucocorticoid receptor ß (GRß). Treatment with erlotinib sensitizes CSCs to paclitaxel therapy both in vitro and in vivo. More importantly, positive correlations between the expressions of MUC1, EGFR, and IL-6 were found in 20 cervical cancer patients after chemotherapy. Mining TCGA data sets also uncovered the expressions of MUC1-EGFR-IL-6 correlates with poor disease-free survival in chemo-treated cervical cancer patients. Collectively, our work has demonstrated that the MUC1-EGFR-CREB/GRß axis stimulates IL-6 expression to induce CSCs enrichment and importantly, this effect can be abrogated by erlotinib, uncovering a novel strategy to treat paclitaxel-resistant cervical cancer.

Malignant gastrointestinal neuroectodermal tumor, presenting as a second malignancy after gastric adenocarcinoma: a case report and literature review.

Malignant gastrointestinal neuroectodermal tumor (GNET), is a rare soft tissue sarcoma. Here we report a case of GNET arising in the intestine of a 33-year-old female, who had been treated for gastric adenocarcinoma with surgery and chemotherapy at the age of 19, in 2001. Since then, she underwent follow-up care annually and kept disease free. Nevertheless, in 2015 she presented with vomiting and was found to have a mass in the small intestine. Surgical excision was performed. Histologically, the tumor was characterized by polygonal cells with clear or eosinophilic cytoplasm, and variably scattered osteoclast-like multinucleated giant cells. Immunohistochemically, the tumor cells showed diffuse and strong expression for S100, but AE1/AE3 cytokeratin, HMB-45 and Melan-A were negative. Genetically, EWSR1 gene rearrangement was detected by fluorescence in situ hybridization (FISH). All these alterations were different from primary gastric adenocarcinoma. Moreover, the tumor gave metastases to ileal mesentery and lung in 1 and 4 years later, respectively. In summary, this is the first report of primary intestinal GNET with multiple metastases in a young woman who had a known history of chemotherapy for gastric adenocarcinoma. In consistence with previous literature, which reported a secondary GNET following chemotherapy for hepatoblastoma, we speculate that the chemotherapy might trigger the rearrangement of EWSR1 and then promote the tumorigenesis of GNET.

MiR-133b targets Sox9 to control pathogenesis and metastasis of breast cancer.

The miR-133b, a commonly recognized muscle-specific miRNA, was reported to be deregulated in many kinds of cancers. However, its potential roles in tumorigenesis remain greatly elusive. Herein, we demonstrate that miR-133b is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. Ectopic expression of miR-133b suppresses clonogenic ability and metastasis-relevant traits in vitro, as well as carcinogenesis and pulmonary metastasis in vivo. Further studies have identified Sox9, c-MET, and WAVE2 as direct targets of miR-133b, in which Sox9 contributes to all miR-133b-endowed effects including cell proliferation, colony formation, as well as cell migration and invasion in vitro. Moreover, re-expression of Sox9 reverses miR-133b-mediated metastasis suppression in vivo. Taken together, these findings highlight an important role for miR-133b in the regulation of tumorigenesis and metastatic potential of breast cancer and suggest a potential application of miR-133b in cancer treatment.

Reduced expression of BMP3 contributes to the development of pulmonary fibrosis and predicts the unfavorable prognosis in IIP patients.

Idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (INSIP) are two related diseases involving varying degrees of pulmonary fibrosis with no effective cure. Bone morphogenetic protein 3 (BMP3) is a member of the transforming growth factor-ß (TGF-ß) super-family, which has not been implicated in pulmonary fibrosis previously. In this study, we aimed to investigate the potential role of BMP3 playing in pulmonary fibrosis from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of BMP3 was evaluated in 83 cases of IPF and INSIP by immunohistochemistry. The function of BMP3 was investigated in both fibroblast cells and a bleomycin-induced murine pulmonary fibrosis model. The clinical relevance of BMP3 expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that BMP3 was significantly down-regulated in lung tissues of patients with IPF and INSIP. Consistently, lower expression of BMP3 also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of BMP3 prevented pulmonary fibrosis processing through inhibiting cellular proliferation of fibroblasts as well as TGF-ß1 signal transduction. Finally, the relatively higher expression of BMP3 in IPF patients was associated with less/worse mortality. Intravenous injection of recombinant BMP3. Taken together, our results suggested that the low expression level of BMP3 may indicate the unfavorable prognosis of IPF patients, targeting BMP3 may represent a novel potential therapeutic method for pulmonary fibrosis management.

MicroRNA-494 inhibits breast cancer progression by directly targeting PAK1.

MicroRNA (miRNA) is involved in the progression and metastasis of diverse human cancers, including breast cancer, as strong evidence has been found that miRNAs can act as oncogenes or tumor suppressor genes. Here, we show that miR-494 is decreased in human breast cancer specimens and breast cancer cell lines. Ectopic expression of miR-494 in basal-like breast cancer cell lines MDA-MB-231-LUC-D2H3LN and BT-549 inhibits clonogenic ability and metastasis-relevant traits in vitro. Moreover, ectopic expression of miR-494 suppresses neoplasm initiation as well as pulmonary metastasis in vivo. Further studies have identified PAK1, as a direct target gene of miR-494, contributes to the functions of miR-494. Remarkably, the expression of PAK1 is inversely correlated with the level of miR-494 in human breast cancer samples. Furthermore, re-expression of PAK1 partially reverses miR-494-mediated proliferative and clonogenic inhibition as well as migration and invasion suppression in breast cancer cells. Taken together, these findings highlight an important role for miR-494 in the regulation of progression and metastatic potential of breast cancer and suggest a potential application of miR-494 in breast cancer treatment.

MiR-630 suppresses breast cancer progression by targeting metadherin.

MicroRNAs have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. The miR-630 was reported to be deregulated and involved in tumor progression of several human malignancies. However, its expression regulation shows diversity in different kinds of cancers and its potential roles remain greatly elusive. Herein, we demonstrate that miR-630 is significantly suppressed in human breast cancer specimens, as well as in various breast cancer cell lines. In aggressive MDA-MB-231-luc and BT549 breast cancer cells, ectopic expression of miR-630 strongly inhibits cell motility and invasive capacity in vitro. Moreover, lentivirus delivered miR-630 bestows MDA-MB-231-luc cells with the ability to suppress cell colony formation in vitro and pulmonary metastasis in vivo. Further studies identify metadherin (MTDH) as a direct target gene of miR-630. Functional studies shows that MTDH contributes to miR-630-endowed effects including cell migration and invasion as well as colony formation in vitro. Taken together, these findings highlight an important role for miR-630 in the regulation of metastatic potential of breast cancer and suggest a potential application of miR-630 in breast cancer treatment.

ANGPTL2/LILRB2 signaling promotes the propagation of lung cancer cells.

Immune inhibitory receptors expressed on various types of immune cells deliver inhibitory signals that maintain the homeostasis of the immune system. Recently we demonstrated that leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) and its murine homolog, paired immunoglobulin-like receptor B (PIRB), are expressed on hematopoietic stem cells and acute myeloid leukemia stem cells and function in maintenance of stemness. Herein, we determined that both LILRB2 and its soluble ligand ANGPTL2 are highly expressed in non-small cell lung cancer (NSCLC) samples, and levels are adversely related to patient prognosis. Inhibition of LILRB2 expression in NSCLC cell lines, such as A549 cells, resulted in a dramatic decrease in proliferation, colony formation, and migration. Mechanistic analyses indicated that ANGPTL2 binds LILRB2 to support the growth of lung cancer cells and that the SHP2/CaMK1/CREB axis controls the proliferation of lung cancer cell lines. Our results suggest that signaling involving ANGPTL2 and LILRB2 is important for lung cancer development and represents a novel target for treatment of this type of cancer.