Background Chondrosarcoma (CS) most commonly involves the pelvis. This study aimed to analyze differences in clinical characteristics and prognostic factors between primary and secondary conventional pelvic CS, and provide reference for clinical diagnosis and treatment. Methods Eighty patients (54 primary cases and 26 secondary cases) with pelvic CS were included in this retrospective study. The tumor site, Enneking stage, soft tissue mass, margin, initial tumor grade, incidence of local recurrence and distant metastasis were evaluated. Kaplan-Meier method was used to calculate the overall survival rate. X-2 test and log-rank test were used for univariate analysis, and Cox test was used in multivariate analysis. Results The average age of patients with secondary CS was significantly younger than that of patients with primary CS (P < 0.001). The soft tissue mass of patients with secondary CS was significantly larger than that of patients with primary CS (P = 0.002). There was a significant difference in initial tumor pathologic grade between the two groups (P = 0.002). No statistically significant difference was observed in the local recurrence rate between the two groups. The median recurrence time of patients with primary CS after the first treatment was significantly shorter than that of patients with secondary CS (P < 0.001). The overall survival rate of patients with secondary CS was much higher than that of patients with primary CS (P = 0.003). Cox regression analysis showed that the initial tumor grade was an independent factor in the overall survival rate of patients with CS. Conclusion There were significant differences in age, soft tissue mass, initial tumor grade, and overall survival rate between the two groups. The overall survival rate of pelvic CS was related to the initial tumor grade of CS.
Background: Triple-Negative Breast Cancer (TNBC) is an aggressive and complex subtype of breast cancer. The current biomarkers used in the context of breast cancer treatment are highly dependent on the targeting of oestrogen receptor, progesterone receptor, or HER2, resulting in treatment failure and disease recurrence and creating clinical challenges. Thus, there is still a crucial need for the improvement of TNBC treatment; the discovery of effective biomarkers that can be easily translated to the clinics is essential. Methods: We report an approach for the discovery of biomarkers that can predict tumour relapse and pathologic complete response (pCR) in TNBC on the basis of mRNA expression quantified using the NanoString nCounter Immunology Panel. To overcome the limited sample size, prediction models based on random Forest were constructed using the differentially expressed genes (DEGs) as selected features. We also evaluated the differences between pre- and post-treatment groups aiming for the combinatorial assessment of pCR and relapse using additive models in edgeR. Results: We identify nine and 13 DEGs strongly associated with pCR and relapse, respectively, from 579 immune genes in a small number of samples (n = 55) using edgeR. An additive model for the comparison of pre- and post-treatment groups via the adjustment of the independent subject in the relapse group revealed associations for 41 genes. Comprehensive analysis indicated that our prediction models outperformed those constructed using features extracted from the existing feature selection model Elastic Net in terms of accuracy. The prediction models were assessed using a randomization test to validate the robustness (empirical P for the model of pCR = 0.015 and empirical P for the model of relapse = 0.018). Furthermore, three DEGs (FCER1A, EDNRB, and TGFBI) in the model of relapse showed prognostic significance for predicting the survival of patients with cancer through Cox proportional hazards regression model-based survival analysis. Conclusion: Gene expression quantified via the NanoString nCounter Immunology Panel can be seamlessly analysed using edgeR, even considering small sample sizes. Our approach provides a scalable framework that can easily be applied for the discovery of biomarkers based on the NanoString nCounter Immunology Panel. Data availability The source code will be available from github at .
Zoledronic acid (ZA) is one of the most important and effective class of anti-resorptive drug available among bisphosphonate (BP), which could effectively reduce the risk of skeletal-related events, and lead to a treatment paradigm for patients with skeletal involvement from advanced cancers. However, the exact molecular mechanisms of its anticancer effects have only recently been identified. In this review, we elaborate the detail mechanisms of ZA through inhibiting osteoclasts and cancer cells, which include the inhibition of differentiation of osteoclasts via suppressing receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK) pathway, non-canonical Wnt/Ca2+/calmodulin dependent protein kinase II (CaMKII) pathway, and preventing of macrophage differentiation into osteoclasts, in addition, induction of apoptosis of osteoclasts through inhibiting farnesyl pyrophosphate synthase (FPPS)-mediated mevalonate pathway, and activation of reactive oxygen species (ROS)-induced pathway. Furthermore, ZA also inhibits cancer cells proliferation, viability, motility, invasion and angiogenesis; induces cancer cell apoptosis; reverts chemoresistance and stimulates immune response; and acts in synergy with other anti-cancer drugs. In addition, some new ways for delivering ZA against cancer is introduced. We hope this review will provide more information in support of future studies of ZA in the treatment of cancers and bone cancer metastasis.
BackgroundThe aim of this study was to develop and validate a visual nomogram for predicting the risk of bone metastasis (BM) in newly diagnosed thyroid carcinoma (TC) patients.MethodsThe demographics and clinicopathologic variables of TC patients from 2010 to 2015 in the Surveillance, Epidemiology and End Results (SEER) database were retrospectively reviewed. Chi-squared (chi 2) test and logistic regression analysis were performed to identify independent risk factors. Based on that, a predictive nomogram was developed and validated for predicting the risk of BM in TC patients. The C-index was used to compute the predictive performance of the nomogram. Calibration curves and decision curve analysis (DCA) were furthermore used to evaluate the clinical value of the nomogram.ResultsAccording to the inclusion and exclusion criteria, the data of 14,772 patients were used to analyze in our study. After statistical analysis, TC patients with older age, higher T stage, higher N stage, poorly differentiated, follicular thyroid carcinoma (FTC) and black people had a higher risk of BM. We further developed a nomogram with a C-index of 0.925 (95%CI,0.895-0.948) in the training set and 0.842 (95%CI,0.777-0.907) in the validation set. The calibration curves and decision curve analysis (DCA) also demonstrated the reliability and accuracy of the clinical prediction model.ConclusionsThe present study developed a visual nomogram to accurately identify TC patients with high risk of BM, which might help to further provide more individualized clinical decision guidelines.
BackgroundDiffuse large B cell lymphoma (DLBCL) is the commonest lymphoma that is highly aggressive where one-third of the patients relapse despite effective treatment. Interaction between the lymphoma cells and the non-clonal immune cells within the bone marrow microenvironment is thought to play a critical role in the pathogenesis of DLBCL.MethodsWe used flow cytometry to characterize the proportion of B cell subpopulations in the bone marrow (N=47) and peripheral blood (N=54) of 75 DLBCL patients at diagnosis and study their impact on survival.ResultsAnergic B cells in the bone marrow (BM), characterized as having CD21(-/low)/CD38- expression, influenced survival with high numbers (defined as >13.9%) being associated with significantly shorter overall survival (59.7months vs 113.6months, p=0.0038). Interestingly, low numbers of anergic B cells in the BM (defined as <= 13.9%) was associated with germinal center B cell type of DLBCL (p=0.0354) that is known to have superior rates of survival when compared to activated B cell type. Finally, Cox regression analysis in our cohort of patients established that the inferior prognosis of having high numbers of anergic B cells in the bone marrow was independent of the established Revised International Prognostic Index (R-IPI) score.ConclusionsHigh proportion of anergic B cells in the BM characterized by CD21(-/low)/CD38- expression predicts poor survival outcomes in DLBCL.
BackgroundIn general, human papillomavirus (HPV) vaccines have demonstrated efficacy in young women worldwide, but there is limited evidence on the efficacy of the quadrivalent HPV6/11/16/18 vaccine in adult women and no evidence of its effectiveness in Japanese adult women in particular. This study aims to evaluate the efficacy of the quadrivalent HPV6/11/16/18 vaccine for persistent HPV16/18 infection in Japanese women aged 27-45years.MethodsThis is an interventional, nonrandomized, non-double-blind prospective cohort study designed to compare the rates of persistent HPV16/18 infection between the vaccinated arm and unvaccinated arm. The subjects will consist of all women aged 27-45years who have normal cytology results confirmed by cervical cancer screening from May 2019 to March 2021. The follow-up time is two years. The subjects will be divided into two groups: the vaccinated group and the unvaccinated group. The study will need to enroll 600 vaccinated participants (experimental arm) and 2200 unvaccinated participants (control arm).DiscussionThe findings of this trial (HAKUOH study) might provide the first local evidence on the subject and be significantly useful not only to medical academia but also to the Japanese Ministry of Health, Labour and Welfare. The findings could contribute to public health improvement by providing local supportive knowledge on the prevention of HPV infection through HPV vaccination in young adult women in Japan, where active recommendations have been suspended for a long time due to adverse effects.Trial registrationTrial registration number: NCT04022148.Registration began on December 1, 2019.
Background: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small cell lung cancer (NSCLC) patients. CKD-516, a novel vascular disrupting agent (VDA), mainly affects blood vessels in the central area of the tumor and blocks tubulin polymerization, thereby destroying the aberrant tumor vasculature with a rapid decrease in blood, resulting in rapid tumor cell death. Therefore, we evaluated the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examined tumor necrosis, delayed tumor growth, and expression of proteins involved in hypoxia and angiogenesis in this study. Methods: A xenograft mouse model of lung squamous cell carcinoma was established, and the tumor was exposed to IR 5days per week. CKD-516 was administered with two treatment schedules (day 1 or days 1 and 5) 1h after IR. After treatment, tumor tissues were stained with hematoxylin and eosin, and pimonidazole. HIF-1 alpha, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated using immunohistochemical staining. Results: Short-term treatment with IR alone and CKD-516+IR (d1) significantly reduced tumor volume (p=0.006 and p=0.048, respectively). Treatment with CKD-516+IR (d1 and d1, 5) resulted in a marked reduction in the number of blood vessels (p < 0.005). More specifically, CKD-516+IR (d1) caused the most extensive tumor necrosis, which resulted in a significantly large hypoxic area (p=0.02) and decreased HIF-1 alpha, Glut-1, VEGF, and Ki-67 expression. Long-term administration of CKD-516+IR reduced tumor volume and delayed tumor growth. This combination also greatly reduced the number of blood vessels (p=0.0006) and significantly enhanced tumor necrosis (p=0.004). CKD-516+IR significantly increased HIF-1 alpha expression (p=0.0047), but significantly reduced VEGF expression (p=0.0046). Conclusions: Taken together, our data show that when used in combination, CKD-516 and IR can significantly enhance anti-tumor efficacy compared to monotherapy in lung cancer xenograft mice.
BackgroundCell lines are extremely useful for both basic and clinical research. Thus, establishing endometrial cancer cell lines with malignant histology is important. This study aimed to extensively characterize an endometrial clear cell carcinoma cell line.MethodsThis cell line, named 150,057, was derived from the endometrial clear cell cancer of a 63-year-old woman. The morphology, chromosomes, chemosensitivity, tumor markers, xenotransplantation characteristics, and cancer-related genes of the cell line were characterized.ResultsThis cell line exhibited adequate growth, being passaged more than 70 times. The morphology of the cells was polygonal with a cobblestone-like appearance. Karyotyping of the cell line revealed a hypodiploid chromosomal number. 150057 cells expressed CA19-9 and CA125. The cell line was sensitive to doxorubicin, paclitaxel, carboplatin, and cisplatin. After the cells were transplanted into the subcutaneous region of non-obese diabetic-severe combined immunodeficiency mice, they generated xenograft tumors with similar histology as the original tumor. A total of 59 somatic nucleotide mutations were identified in 25 of the 53 examined tumor suppressor genes and oncogenes. Two novel mutations were found in FGFR3 and ARID1A.ConclusionWe established and characterized an endometrial clear cell carcinoma cell line that may be useful in carcinogenesis and treatment research for endometrial cancer.
BackgroundIntraventricular neuroepithelial tumors (IVT) are rare lesions and comprise different pathological entities such as ependymomas, subependymomas and central neurocytomas. The treatment of choice is neurosurgical resection, which can be challenging due to their intraventricular location. Different surgical approaches to the ventricles are described. Here we report a large series of IVTs, its postoperative outcome at a single tertiary center and discuss suitable surgical approaches.MethodsWe performed a retrospective chart review at a single tertiary neurosurgical center between 03/2009-05/2019. We included patients that underwent resection of an IVT emphasizing on surgical approach, extent of resection, clinical outcome and postoperative complications.ResultsForty five IVTs were resected from 03/2009 to 05/2019, 13 ependymomas, 21 subependymomas, 10 central neurocytomas and one glioependymal cyst. Median age was 52,5years with 55.6% (25) male and 44.4% (20) female patients. Gross total resection was achieved in 93.3% (42/45). 84.6% (11/13) of ependymomas, 100% (12/21) of subependymomas, 90% (9/10) of central neurocytomas and one glioependymal cyst were completely removed. Postoperative rate of new neurological deficits was 26.6% (12/45). Postoperative new permanent cranial nerve deficits occurred in one case with 4th ventricle subependymoma and one in 4th ventricle ependymoma. Postoperative KPSS was 90% (IR 80-100). 31.1% of the patients improved in KPSS, 48.9% remained unchanged and 20% declined. Postoperative adverse events rate was 20.0%. Surgery-related mortality was 2.2%. The rate of shunt/cisternostomy-dependent hydrocephalus was 13.3% (6/45). 15.4% of resected ependymomas underwent adjuvant radiotherapy. Mean follow-up was 26,9 (30.1) months.Conclusion Our surgical findings emphasize satisfactory complete resection throughout all entities. Surgical treatment can remain feasible, if institutional experience is given. Satisfying long-term survival and cure is possible by complete removal. Gross total resection should always be performed under function-remaining aspects due to mostly benign or slow growing nature of IVTs. Further data is needed to evaluate standard of care and alternative therapy options in rare cases of tumor recurrence or in case of patient collective not suitable for operative resection.
BackgroundHeterogeneity of metastatic renal cell carcinoma (RCC) constraints accurate prognosis prediction of the tumor. We therefore aimed at developing a novel nomogram for accurate prediction of overall survival (OS) of patients with metastatic RCC.MethodsWe extracted 2010 to 2016 data for metastatic RCC patients in the Surveillance, Epidemiology, and End Results (SEER) database, and randomly stratified them equally into training and validation sets. Prognostic factors for OS were analyzed using Cox regression models, and thereafter integrated into a 1, 3 and 5-year OS predictive nomogram. The nomogram was validated using the training and validation sets. The performance of this model was evaluated by the Harrell's concordance index (C-index), calibration curve, integrated discrimination improvement (IDI), category-free net reclassification improvement (NRI), index of prediction accuracy (IPA), and decision curve analysis (DCA).ResultsOverall, 2315 metastatic RCC patients in the SEER database who fulfilled our inclusion criteria were utilized in constructing a nomogram for predicting OS of newly diagnosed metastatic RCC patients. The nomogram incorporated eight clinical factors: Fuhrman grade, lymph node status, sarcomatoid feature, cancer-directed surgery and bone, brain, liver, and lung metastases, all significantly associated with OS. The model was superior to the American Joint Committee on Cancer (AJCC) staging system (7th edition) both in training (C-indices, 0.701 vs. 0.612, P<0.001) and validation sets (C-indices, 0.676 vs. 0.600, P<0.001). The calibration plots of the nomogram corresponded well between predicted and observed values. NRI, IDI, and IPA further validated the superior predictive capability of the nomogram relative to the AJCC staging system. The DCA plots revealed reliable clinical application of our model in prognosis prediction of metastatic RCC patients.ConclusionsWe developed and validated an accurate nomogram for individual OS prediction of metastatic RCC patients. This nomogram can be applied in design of clinical trials, patient counseling, and rationalizing therapeutic modalities.
BackgroundExtensive research has revealed that genes play a pivotal role in tumor development and growth. However, the underlying involvement of gene expression in gastric carcinoma (GC) remains to be investigated further.MethodsIn this study, we identified overlapping differentially expressed genes (DEGs) by comparing tumor tissue with adjacent normal tissue using the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) database.ResultsOur analysis identified 79 up-regulated and ten down-regulated genes. Functional enrichment analysis and prognosis analysis were conducted on the identified genes, and the fatty aldehyde dehydrogenase (FALDH) gene, ALDH3A2, was chosen for more detailed analysis. We performed Gene Set Enrichment Analysis (GSEA) and immunocorrelation analysis (infiltration, copy number alterations, and checkpoints) to elucidate the mechanisms of action of ALDH3A2 in depth. The immunohistochemical (IHC) result based on 140 paraffin-embedded human GC samples indicated that ALDH3A2 was over-expressed in low-grade GC cases and the OS of patients with low expression of ALDH3A2 was significantly shorter than those with high ALDH3A2 expression. In vitro results indicated that the expression of ALDH3A2 was negatively correlated with PDCD1, PDCD1LG2, and CTLA-4.ConclusionWe conclude that ALDH3A2 might be useful as a potential reference value for the relief and immunotherapy of GC, and also as an independent predictive marker for the prognosis of GC.
BackgroundImmunomodulatory activities of human mesenchymal stromal /stem cells (hMSCs) has been widely recognized as the most critical function of hMSCs for exerting its therapeutic effects. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previous studies revealed that the Notch1 protein exerted a pro-immunomodulatory function probably through interacting with the protein(s) subjective to proteasome-mediated protein degradation. The DLC-1 protein represents a well characterized tumor suppressor subjective to proteasome-mediated degradation. However, the detailed signaling pathway of Notch1 and the involvement of DLC-1 in regulating the immunomodulation of hMSCs have not been studied before.MethodsThe transfection with cDNA or siRNA into hMSCs assisted by co-culture of hMSCs with peripheral blood mononuclear cells and small molecule inhibitors of signaling proteins, followed by immunoprecipitation, Western blotting, RT-PCR, and flowcytometry, were employed to characterize the Notch1 signaling, to identify DLC-1 as a candidate proteasome-targeted protein, and to characterize DLC-1 signaling pathway and its interaction with the Notch1 signaling, in the regulation of immunomodulation of hMSCs, specifically, the inhibition of pro-inflammatory CD4(+)-Th1 lymphocytes, and the release of immunomodulatory molecule IDO1.Statistical analysisOne-way ANOVA was utilized as a statistical tool to analyze the data presented as means SEM of at least three separate experiments.ResultsThe present study revealed that the Notch1-Hey1 axis, but not the Notch1-Hes1 axis, was likely responsible for mediating the pro-immunomodulatory function of the Notch1 signaling. The DLC-1 protein was found subjective to proteasome-mediated protein degradation mediated by the DDB1 and FBXW5 E3 ligases and served as an inhibitor of the immunomodulation of hMSCs through inhibiting Rock1, but not Rock2, downstream the DLC-1 signaling. The Notch1 signaling in the Notch1-Hey1 pathway and the DLC-1 signaling in the DLC-1-Rock1-FBXW5 pathway exhibited a mutual exclusion interaction in the regulation of immunomodulation of hMSCs.Conclusions The present study uncovers a novel function of DLC-1 tumor suppressor in regulating the immunomodulation of hMSCs. It also proposes a novel mutual exclusion mechanism between the DLC-1 signaling and the Notch1 signaling that is possibly responsible for fine-tuning the immunomodulation of hMSCs with different clinical implications in hMSCs therapy.
Background Estimating the risk of lymph node metastasis (LNM) is crucial for determining subsequent treatments following curative resection of early colorectal cancer (ECC). This multicenter study analyzed the risk factors of LNM and the effectiveness of postoperative chemotherapy in patients with ECC. Methods We retrospectively analyzed the data of 473 patients with ECC who underwent general surgery in five hospitals between January 2007 and October 2018. The correlations between LNM and sex, age, tumor size, tumor location, endoscopic morphology, pathology, depth of invasion and tumor budding (TB) were directly estimated based on postoperative pathological analysis. We also observed the overall survival (OS) and recurrence in ECC patients with and without LNM after matching according to baseline measures. Results In total, 473 ECC patients were observed, 288 patients were enrolled, and 17 patients had LNM (5.90%). The univariate analysis revealed that tumor size, pathology, and lymphovascular invasion were associated with LNM in ECC (P = 0.026, 0.000, and 0.000, respectively), and the multivariate logistic regression confirmed that tumor size, pathology, and lymphovascular invasion were risk factors for LNM (P = 0.021, 0.023, and 0.001, respectively). There were no significant differences in OS and recurrence between the ECC patients with and without LNM after matching based on baseline measures (P = 0.158 and 0.346, respectively), and no significant difference was observed between chemotherapy and no chemotherapy in ECC patients without LNM after surgery (P = 0.729 and 0.052). Conclusion Tumor size, pathology, and lymphovascular invasion are risk factors for predicting LNM in ECC patients. Adjuvant chemotherapy could improve OS and recurrence in patients with LNM but not always in ECC patients without LNM.
Background S-1 and cyclophosphamide (CPA) can be given orally, and their combination may have great potential for treating metastatic breast cancer (MBC). A phase I study of sequential S-1 and CPA therapy was conducted in patients with MBC; the recommended doses that were determined for this regimen were 80 mg/m(2)/day for S-1 and 100 mg/m(2)/day for CPA. We then conducted a phase II study of this oral S-1 and CPA regimen. Methods This was a single-arm, open-label, single-center prospective phase II study to evaluate the efficacy of a sequential S-1 and CPA regimen for MBC. S-1 was administered orally 2x/day for 14 consecutive days, and then CPA was administered orally 2x/day for 14 consecutive days in a repeating 4-week cycle (S-1 for 2 weeks, CPA for 2 weeks). The primary endpoint was the overall response rate (ORR). Secondary endpoints included the overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety. Results Thirty-six patients were enrolled in this study. The overall response was complete response in 0 (0%), partial response in 12 (33.3%), stable disease in 12 (33.3%), and progressive disease in 11 (30.1%) patients. The ORR was 33.3% (12/36). The CBR was 66.7% (24/36). The median PFS was 9.5 months (95%CI: 7.8-12.6 months). The median OS was 20.2 months (95%CI: 15.0-25.4 months) Grade 3/4 adverse events included leukopenia in seven patients (19.4%). Dose reductions because of adverse events occurred in 12 patients (33.3%). There was no treatment-related mortality. Conclusion The combination of sequential therapy with S-1 and CPA was tolerable and had efficacy with good disease control. Sequential therapy with S-1 and CPA may be a feasible new treatment option for patients with MBC; however, further study is warranted to explore the efficacy of this therapy.
BackgroundThe nuclear transport system has been proposed to be indispensable for cell proliferation and invasion in cancers. Prognostic biomarkers and molecular targets in nuclear transport systems have been developed. However, no systematic analysis of genes related to nuclear transport in gliomas has been performed. An integrated prognostic classification involving mutation and nuclear transport gene signatures has not yet been explored.MethodsIn the present study, we analyzed gliomas from a training cohort (TCGA dataset, n=660) and validation cohort (CGGA dataset, n=668) to develop a prognostic nuclear transport gene signature and generate an integrated classification system. Gene set enrichment analysis (GSEA) showed that glioblastoma (GBM) was mainly enriched in nuclear transport progress compared to lower-grade glioma (LGG). Then, we developed a nuclear transport risk score (NTRS) for gliomas with a training cohort. NTRS was significantly correlated with clinical and genetic characteristics, including grade, age, histology, IDH status and 1p/19q codeletion, in the training and validation cohorts.ResultsSurvival analysis revealed that patients with a higher NTRS exhibited shorter overall survival. NTRS showed better prognostic value compared to classical molecular markers, including IDH status and 1p/19q codeletion. Furthermore, univariate and multivariate analyses indicated that NTRS was an independent prognostic factor for gliomas. Enrichment map and Gene Ontology analysis demonstrated that signaling pathways related to the cell cycle were enriched in the NTRSHigh group. Subgroup survival analysis revealed that NTRS could differentiate the outcomes of low- and high-risk patients with wild-type IDH or mutant IDH and 1p/19q non-codeletion.ConclusionsNTRS is associated with poor outcomes and could be an independent prognostic marker in diffuse gliomas. Prognostic classification combined with IDH mutation, 1p/19q codeletion and NTRS could better predict the survival of glioma patients.