Background: Endometrial cancer (EC) is a prevalent gynecological malignancy with limited therapeutic options due to drug resistance and systemic toxicity. Exosomes have emerged as promising targeted drug delivery vehicles, but their application in EC remains underexplored. Thrombospondin-1 (THBS1), a key regulator of extracellular matrix remodeling and transforming growth factor β (TGF-β) signaling, may offer a novel therapeutic strategy for EC. Methods: Differentially expressed genes were identified from the public transcriptomic datasets and subjected to GO and KEGG enrichment analyses. Exosomes derived from Human embryonic kidney 293 (HEK293) cells overexpressing THBS1 were isolated and characterized by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis. Their effects on EC cells were assessed using Cell Counting Kit-8, 5-ethynyl-2’-deoxyuridine incorporation, colony formation, wound healing, and cell invasion assays. TGF-β pathway involvement was assessed using the agonist SRI-011381. In vivo experiments were conducted to evaluate tumor growth, epithelial–mesenchymal transition (EMT) marker expression, and treatment safety. Results: THBS1 expression was downregulated in the EC cells. The restoration of THBS1 expression through exosome delivery inhibited cell proliferation, migration, and invasion. THBS1-overexpressing exosomes attenuated the activation of the TGF-β/Smad pathway and modulated EMT-related markers. The inhibitory effects of THBS1-exosomes were reversed by SRI-011381. In vivo, THBS1-exosome treatment markedly suppressed tumor growth, enhanced E-cadherin expression, reduced vimentin levels, and exhibited no observable toxicity. Conclusions: Exosomes overexpressing THBS1 effectively suppressed EC progression by targeting the TGF-β/Smad signaling axis and EMT. These findings support the potential of THBS1-enriched exosomes as a novel, safe, and targeted therapeutic modality for future EC.

To evaluate the efficacy of 18F-AIF-NOTA-FAPI-04 PET/CT in improving the accuracy of target volume delineation in nasopharyngeal carcinoma (NPC). Automatic delineation of the primary tumor target volume was conducted for 21 newly diagnosed NPC patients using 18F-AIF-NOTA-FAPI-04 PET/CT images, which applied a threshold-based segmentation with 5

Patients with ALK-rearranged non-small cell lung cancer (NSCLC) who are treated with ALK tyrosine kinase inhibitors (ALK TKIs) have better prognoses. In this case report, we provide evidence of a novel ALK fusion, XPO1-ALK (intergenic), identified by next-generation DNA sequencing in a patient with advanced lung cancer. After 5 months of brigatinib targeted therapy, the patient clearly experienced tumor disintegration, and this treatment resulted in partial remission. To date, this patient has experienced 5 months of progression-free survival after brigatinib treatment. In addition to reporting the identification of a novel ALK fusion, XPO1-ALK (intergenic), and the sensitivity and safety of brigatinib treatment for lung cancer, this study increased the list of known ALK fusion partners in ALK-positive NSCLC. This case report has a significant clinical reference.

Lung cancer is the leading cause of cancer death, accounting for one-third of all cancer deaths worldwide. The MET (c-MET) gene, as one of the therapeutic target spots of NSCLC, has become increasingly more important. MET amplification/overexpression was divided into primary (intrinsic) and secondary (acquired). Studies indicated that the combination of Osimertinib and Savolitinib was safe and showed promising antitumor effect in NSCLC patients with secondary MET amplification after EGFR mutations. However, NSCLC patients with primary MET amplification/overexpression and EGFR mutations are rare in clinics, and the efficacy of dual-target therapy combined with EGFR-TKI and Savolitinib for them has not been studied yet. Here, we reported two NSCLC patients with primary MET amplification/overexpression and EGFR mutation, who benefited from T+S therapy (the dual-target therapy of EGFR-TKI plus Savolitinib) and achieved a progression-free survival (PFS) of approximately 5 months. The two cases indicated that T+S therapy has an acceptable safety profile and encouraging antitumor efficacy in NSCLC patients harboring concurrent primary MET amplification/overexpression and EGFR mutation. Meanwhile, the observation stresses the importance of genetic testing, and the MET gene needs to be detected at first diagnosis for the best choice of targeted therapies.

expression pattern of miR-627-5p, miR-128-3p, miR-101-3p, miR-129-5p (A), miR-1246 and miR-155-5p (C) in AC and health controls or miR-150-5p, miR-4459, miR-6873-3p, miR-9-3p (B), miR-149-5p and miR-1246 (D) in SCC and health controls comparison by evaluating threshold cycle number difference (A, B) or calculating 2ÃÆ'Ã,Æ'ÂÃ,â¢ÃƒÆ'Ã,‚-ÃÆ'Ã,‚ÂÃ,â³Ct(C, D).

Strategy for the evaluation of the early diagnostic accuracy of AC- and SCC-specific tumor-derived exosomal miRNAs in a symptomatic set

PURPOSE:Radiotherapy is an indispensable treatment for esophageal cancer (EC), but radioresistance is not uncommon. Curcumol, as an active extract from traditional Chinese medicines, has been reported to have antitumor activity in various types of human tumor cells. However, its reversal of radioresistance has been rarely reported.MATERIALS AND METHODS:In the present study, curcumol was prepared as an inclusion complex with β-cyclodextrin. EC cell lines were treated with radiation and curcumol β-cyclodextrin inclusion complex (CβC), and the effect of radiosensitization of CβC was investigated in vitro and in vivo. The in vitro experiments included cell proliferation assay, clonogenic survival assay, apoptosis assay, cell cycle assay, and western blot assay.RESULTS:The in vitro data revealed that CβC and irradiation synergistically inhibited the proliferation, reduced the colony formation, promoted the apoptosis, increased the G2/M phase, inhibited DNA damage repair, and reversed the hypoxia-mediated radioresistance of EC cells to a greater extent than did CβC alone or irradiation alone. The sensitization enhancement ratios (SERs) were 1.39 for TE-1 and 1.48 for ECA109 under hypoxia. The SERs were 1.25 for TE-1 and 1.32 for ECA109 under normoxia. The in vivo data demonstrated that the combination of CβC and irradiation could inhibit tumor growth to the greatest extent compared with either monotherapy alone. The enhancement factor was 2.45.CONCLUSION:This study demonstrated that CβC could enhance radiosensitivity of EC cells under hypoxic and normoxic condition. Thus, CβC can be used as an effective radiosensitizer for EC.

enrichment of selected miRNAs potential target genes in oncogenesis-related pathway

mappable miRNA was chosen for further analysis based on differentially expressed gene (DEG) analysis

Rectal cancer is a life‑threatening disease worldwide. Chemotherapy resistance is common in rectal adenocarcinoma patients and has unfavorable survival outcomes; however, its related molecular mechanisms remain unknown. To identify genes related to the initiation and progression of rectal adenocarcinoma, three datasets were obtained from the Gene Expression Omnibus database. In total, differentially expressed genes were analyzed from 294 tumor and 277 para-carcinoma samples from patients with rectal cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functions were investigated. Cytoscape software and MicroRNA Enrichment Turned Network were applied to construct a protein-protein interaction network of the dependent hub genes and related microRNAs. The Oncomine database was used to identify hub genes. Additionally, Gene Expression Profiling Interactive Analysis was applied to determine the RNA expression level. Tumor immune infiltration was assessed using the Tumor Immune Estimation Resource database. The expression profiles of hub genes between stages, and their prognostic value, were also evaluated. During this study, data from The Cancer Genome Atlas were utilized. In rectal adenocarcinoma, four hub genes including CXCL1, CXCL2, CXCL3, and GNG4 were highly expressed at the gene and RNA levels. The expression of CXCL1, CXCL2, and CXCL3 was regulated by has-miR-1-3p and had a strong positive correlation with macrophage and neutrophil. CXCL2 and CXCL3 were differentially expressed at different tumor stages. High expression levels of CXCL1 and CXCL3 predicted poor survival. In conclusion, the CXCL1 and CXCL3 genes may have potential for prognosis and molecular targeted therapy of rectal adenocarcinoma.

Abstract Background The development of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has dramatically improved the prognosis of patients with EGFR-mutant non-small-cell lung cancer (NSCLC). The purpose of this study is to investigate the clinical outcome with or without EGFR-TKI resistance before WBRT and the sequence between EGFT-TKIs and whole brain radiotherapy (WBRT) of EGFR-mutant NSCLC patients who developed multiple brain metastases (BMs). Patients and methods Three hundred forty-four EGFR-mutant NSCLC patients with multiple BMs were reviewed. Enrolled patients were divided into TKI-naïve group and TKI-resistant group. The intracranial progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan-Meier method. Results For patients with multiple BMs treated by WBRT, the median intracranial PFS and OS were longer in the TKI-naïve group than those in the TKI-resistant group, but there were no statistically significant between two groups (Intracranial PFS: 7.7 vs. 5.4 months, p = 0.052; OS: 11.2 vs. 9.2 months, p = 0.106). For patients with Lung-molGPA 0–2, no significant differences in median intracranial PFS (6.2 vs. 5.2 months, p = 0.123) and OS (7.8 vs. 6.7 months, p = 0.514) between TKI-naïve and TKI-resistant groups. For patients with Lung-molGPA 2.5–4, intracranial PFS: 12.8 vs. 10.1 months; OS: 23.3 vs. 15.3 months. Conclusions Our study found that there were no difference in intracranial PFS and OS in all patients between the two groups of TKI-naïve and TKI-resistant. But for patients in subgroup of Lung-molGPA 2.5–4, there were a better intracranial PFS and OS in TKI-naïve group.

PURPOSE:Apatinib is effective and safe for several advanced or metastatic cancers, but its therapeutic value in cervical cancer is still unknown. The aim of the study was to assess the therapeutic value of apatinib in patients with chemo-refractory advanced cervical cancer. PATIENTS AND METHODS:This was a retrospective study of patients with advanced cervical cancer treated with apatinib between April 2015 and December 2018 at the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Patients had to have failed at least 2 lines of chemotherapy prior to receiving apatinib. The clinical tumor response was evaluated after 4 weeks of apatinib treatment, and then every 8 weeks (two cycles). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were evaluated. RESULTS:Twenty-five patients were included in this study. The median PFS was 5.8 months (95% CI, 4.65-6.95), and the median OS was 12.2 months (95% CI, 8.99-15.41). ORR was 48% and DCR was 96%. Complete response was not observed. The most common adverse events in this study (all grades) were hand-foot syndrome (48%), hypertension (20%), and mouth mucositis (20%). CONCLUSION:Apatinib monotherapy showed good therapeutic value with tolerable adverse events for patients with chemo-refractory advanced cervical cancer.

INTRODUCTION:Sparing of the organs at risk (OARs) is a crucial task in daily radiotherapy practice. Irradiation of the optic chiasm (OC) results in radiation-induced optic neuropathy (RION). The structure of the OC is complex, and OC morphology can vary in axial images. Therefore, a standard atlas can result in inaccurate descriptions of OC morphology in different patients. The aim of our study was to provide a guide based on computed tomography (CT) for the delineation of different types of OC.METHODS:Thirty-six patients were selected to participate in our study. These patients underwent CT analysis of the brain, head and neck regions in a supine position. Axial images 3 mm in thickness were obtained at 3-mm intervals. A magnetic resonance imaging (MRI) study was also performed using the same set-up. The OC was then delineated. The contours were revised by three neuroradiologists and nine radiation oncologists with > 5 years of expertise.RESULTS:Three types of OC were distinguished by magnetic resonance (MR). The location and boundaries of normal, prefixed and postfixed chiasms were developed with a CT-based atlas. Discrepancies were observed in the delineation of the prefixed and postfixed OC.CONCLUSIONS:Our guide allows improved definitions of the anatomical boundaries for different types of OC. Our experience could provide useful information for radiation oncologists in daily practice.

Background and objectives The survival rate of patients with advanced oesophageal cancer is very low and can vary significantly, even among patients with the same TNM stage. It is important to look for indicators that are economical and readily available to predict overall survival. The aim of this study was to determine whether lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR) could be potential predictors of survival in patients with advanced oesophageal squamous cell carcinoma (ESCC) undergoing concurrent chemoradiotherapy. Methods Differences in survival among 204 patients with advanced oesophageal cancer who underwent concurrent chemoradiotherapy were collected and analysed. Univariate and multivariate COX regression analyses were used to investigate the association between blood inflammatory markers and patient survival before treatment. Results Univariate COX regression analyses showed that a history of alcohol use, neutrophil count, LMR, NLR, tumour length, and N stage were significantly associated with the survival of tumour patients receiving concurrent chemoradiotherapy. Multivariate COX regression analysis showed that NLR and LMR were predictors of outcome in tumour patients receiving chemoradiotherapy. According to receiver operating characteristic (ROC) curve analysis, the AUC of LMR and NLR was 0.734 and 0.749, and the best cutoff point for LMR and NLR was 3.03 and 2.64, respectively. Conclusions LMR and NLR can be used to predict the survival of patients with advanced oesophageal cancer receiving concurrent chemoradiotherapy, thereby providing clinicians with suggestions for further treatment options.

Abstract Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non–small cell lung cancer (NSCLC). Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals. Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively. Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311–9. ©2017 AACR.

Objective: A Phase II study was designed to test the safety and efficacy of concurrent chemoradiotherapy with a modified target volumes delineation method for inoperable oesophageal cancer patients. Methods: All eligible patients were treated with concurrent chemoradiotherapy. The method of delineating target volume is as follows: Planning gross target volume (PGTV) was defined as the primary gross tumour volume (GTV-t) plus a 3 cm margin longitudinally and a 0.5 cm margin circumferentially, and positive lymph nodes (GTV-n) plus a 0.5 cm margin in all directions. Clinical target volume (CTV) was defined as PGTV plus a 0.5 cm margin in all directions and elective nodal region. Planning target volume (PTV) was defined as CTV plus a 0.5 cm margin in all directions. The dose of PGTV is 54-60 Gy in 27-30 fractions (2 Gy per fraction). The dose of PTV is 48.6-54 Gy in 27-30 fractions (1.8 Gy per fraction). The regimen consists of paclitaxel 135 mg m(-2) on 1 day and DDP 25 mg m(-2) on 3 days per 3 weeks. The patients received 2 cycles of chemotherapy during radiotherapy and 2-4 cycles of chemotherapy after radiotherapy. Results: 34 patients were enrolled in this study. The median follow-up time was 20.9 months (range: 3.7-28.4 months) for all patients. The 1-and 2-year survival rates for all patients were 70.5 and 44.1%, respectively. Clinical complete response was observed in 21 patients (61.8%), cPR was observed in 9 patients (26.5%) and cSD was observed in 4 patients (11.7%). Conclusion: This modified method with concurrent chemotherapy could achieve better locoregional control rate. The 1-and 2-year survival rates of this method were close to the survival rates of the current methods widely adopted. Advances in knowledge: The modified target volumes delineation method can enhance locoregional control rate of concurrent chemoradiotherapy.

Background: The aim of this study was to evaluate toxicity, compliance, recurrence and the survival of weekly and triweekly cisplatin-based concomitant chemoradiation in treatment of cervical cancer.Materials and Methods: The databases were searched from 1995 until 2015 to identify eligible studies on weekly versus triweekly cisplatin chemoradiotherapy. The data were analyzed by RevMan 5.3 software.Results: A total of 5 randomized controlled trials were included in this review. Weekly cisplatin regimen significantly reduced the incidence of Hematologic toxicity. However, there was no significantly different between the 2 arms in compliance, recurrence and the survival rate (all P > 0.05).Conclusions: Weekly cisplatin regimen had the similar therapeutic effect as the triweekly cisplatin regimen but with less hematologic toxicity. Therefore, we recommend the weekly cisplatin 30 to 40 mg/m(2) chemoradiotherapy as the strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer.

Background: The rates of locoregional and distant recurrence for esophageal squamous cell carcinoma (ESCC) patients underwent radical esophagectomy remain high. The purpose of this study is to explore an optimal postoperative therapeutic modality by investigating the efficacy of various adjuvant therapies in the treatment of ESCC. Methods: We retrospectively reviewed 408 ESCC patients underwent thoracic esophagectomy and 3-field lymph node dissection from 2010 to 2015. Patients were classified into surgery alone (Group S), adjuvant chemotherapy (Group CT) and postoperative chemotherapy plus radiotherapy (Group CRT), respectively. Univariate and multivariate Cox regression analyses were used to analyze prognostic factors and survival. Results: The overall survival (OS) and disease-free survival (DFS) were similar among groups. Postoperative CT and CRT both were beneficial for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment compared with surgery alone. The 3-year OS and DFS for patients with 3 or more lymph nodes involvement were 30.8%, 53.7%, 50.5% and 19.9%, 41.6%, 34.0% for Group S, CT, and CRT, respectively (p=0.04; p=0.004, respectively). There was no notable difference in OS and DFS between the adjuvant Group CT and CRT (p=0.42; p=0.49, respectively). Postoperative CRT significantly reduced the rates of distant metastasis and overall recurrence for patients with positive lymph nodes (p=0.042; p=0.01, respectively). Number of metastatic lymph nodes, extent of resection, and AJCC stage were independent predictors of survival. Grade 1-2 myelosuppression was experienced significantly more frequently by patients in Group CRT than those in Group CT (P=0.03). Late toxicities were rare and manageable overall. Conclusions: Postoperative CT and CRT both were associated with better survival for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment. Postoperative CRT was significantly more effective at reducing the rates of distant metastasis and overall recurrence for patients with positive lymph nodes.

Background: Breast cancer coexisting with primary thyroid lymphoma is a very rare combination of multiple primary malignant neoplasms. We present an unusual case of primary thyroid extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma) occurring in a patient with breast cancer. Case presentation: A 76-year-old female was admitted to our hospital with bilateral thyroid nodules, which were detected two years and eight months ago. In May 2006, she underwent modified radical mastectomy for invasive ductal carcinoma of the left breast. The patient was treated with total left thyroid lobectomy, isthmusectomy and subtotal right lobectomy. Histopathological and immunohistochemical (IHC) examination of surgical specimen confirmed the diagnosis of primary thyroid MALT lymphoma. She received chemotherapy and levothyroxine substitution therapy postoperatively. At the time of last follow-up (seven years and ten months after thyroid surgery), she was found to have a good prognosis (there was no recurrence). Conclusion: Clinical awareness of primary thyroid lymphoma in patients with malignant thyroid nodules should be increased. Surgery should be recommended for suspected malignant thyroid nodules in patients with a history of breast cancer. Post-operative histopathological and IHC examination of surgical specimen confirms the diagnosis. Early treatment is associated with a good prognosis.

The survival time of non-small cell lung cancer (NSCLC) patients with brain metastases has been previously reported to be 6.5-10.0 months, even with systematic treatment. Patients that possess a certain epidermal growth factor receptor (EGFR) mutation alongside NSCLC with brain metastases also have a short survival rate, and a reliable prognostic model for these patients demonstrates a strong correlation between the outcome and treatment recommendations. The Cox proportional hazards regression and classification tree models were used to explore the prognostic factors in EGFR mutation-positive NSCLC patients with brain metastases following whole-brain radiation therapy (WBRT) and EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment. A total of 66 EGFR mutation-positive NSCLC patients with brain metastases were retrospectively reviewed. Univariate and multivariate analyses by Cox proportional hazards regression were then performed. The classification tree model was applied in order to identify prognostic groups of the patients. In the survival analysis, age, carcinoembryonic antigen (CEA) and status of the primary tumor were prognostic factors for progression free survival (P=0.006, 0.014 and 0.005, respectively) and overall survival (P=0.009, 0.013 and 0.009, respectively). The classification tree model was subsequently applied, which revealed 3 patient groups with significantly different survival times: Group I, age <65 years and CEA ≤10 µg/ml; Group II, age <65 years and CEA >10 µg/ml or age ≥65 years and CEA ≤10 µg/ml; and Group III, age ≥65 years and CEA >10 µg/ml. The major prognostic predictors for EGFR mutation-positive NSCLC patients with brain metastases following WBRT and EGFR-TKI were age and CEA. In addition, primary tumor control may be important for predicting survival.