Microvessel barrier dysfunction in sinonasal inverted papilloma-associated squamous cell carcinoma and its manifestation in dynamic contrast-enhanced MRI.

BACKGROUND: To date, an effective means to preoperatively predict the malignant transformation of sinonasal inverted papilloma (SIP) remains lacking due to similarities in clinical appearance. This study aimed to retrospectively evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and microvessel structure in tumors with histologically confirmed SIP and inverted papilloma-associated squamous cell carcinoma (IP-SCC), as well as correlate DCE-MRI findings with angiogenesis biomarkers. METHODS: Absolute quantitative DCE-MRI parameters (Ktrans , Kep , Ve ) based on the Tofts model and model-free semi-quantitative indices (Tpeak , WR, MaxSlope) of SIP (n = 22) and IP-SCC (n = 20) were investigated. Regions of interest (ROIs) were oriented according to the tumor subsites in the surgical records. Micro-vessel density (MVD) counts and tight junction protein (claudin-5) expression were evaluated in tumor specimens obtained during surgery. Differences in the above data were compared between the two groups. Correlations between DCE-MRI parameters and angiogenic biomarkers were analyzed. RESULTS: Compared with SIP specimens, IP-SCC specimens were characterized by a significantly higher MVD and a leakier microvessel barrier. The values of Tpeak and Ve were significantly higher for SIP than those for IP-SCC, whereas WR, MaxSlope, and Kep were significantly lower, indicating early enhancement and a faster dispersion model in IP-SCC. MVD was positively correlated with WR and Kep and negatively correlated with Tpeak . Tpeak was slightly positively correlated to claudin-5 expression. CONCLUSION: DCE-MRI can serve as a noninvasive biomarker of angiogenesis in the malignant transformation from SIP to IP-SCC. DCE-MRI may assist in the differentiation of malignancies and treatment selection.

The role of insulinoma-associated protein 1 in predicting the progression and prognosis of human olfactory neuroblastoma in China.

OBJECTIVE: Recent studies have suggested that insulinoma-associated protein 1 (INSM1) is a useful marker for pathological diagnosis of neuroendocrine tumors. In the present study, we investigated the association between INSM1 expression and prognosis in patients with olfactory neuroblastoma (ONB) and assessed the usefulness of INSM1 as a prognostic biomarker in these patients. METHOD: Immunohistochemistry was performed on 109 ONB patients who underwent endoscopic surgery at Beijing Tong Ren Hospital (Beijing, China) between June 2006 and November 2021 Patient age at the time of surgery ranged from 10 months to 72 years (mean age, 43.55 ± 13.47 years). In total, 63 (57.8%) and 46 (42.2%) tumors occurred in male and female patients, respectively. The percentages of grade I-IV cases were 13.8% (15/109), 36.7% (40/109), 29.4% (32/109) and 20.2% (22/109), respectively. RESULTS: The expression rate (moderately/strongly positive) of INSM1 was significantly higher in high-grade (Ⅲ/Ⅳ; 83%; 45/54) than low-grade (Ⅰ/Ⅱ; 27%; 15/55) ONB cases. High expression levels of INSM1 were significantly positively associated with high pathological stage (p < 0.001), local recurrence, and death. Kaplan­Meier analysis revealed that patients with high INSM1 expression had significantly shorter disease­free survival (DFS) and mean survival (75.01 ± 10.71 vs. 158.56 ± 10.32) times, and shorter overall survival (OS). Multivariate Cox regression analysis revealed that INSM1 was an independent prognostic factor for DFS (HR: 4.963, 95%CI [2.11-10.84] p < 0.001) and OS (HR: 4.791, 95%CI [2.117-10.485], p < 0.001) after adjusting for sex, age, and tumor grade. In addition, INSM1 was an independent prognostic factor for DFS in patients treated with surgery (HR: 3.714, 95%CI [1.267-10.889], p = 0.017) and chemotherapy (HR: 5.574, 95%CI [1.584-19.612], p = 0.007). CONCLUSION: INSM1 expression had a positive association with the prognosis of patients with ONB and could serve as a prognostic biomarker in these patients.

IgE directly affects eosinophil migration in chronic rhinosinusitis with nasal polyps through CCR3 and predicts the efficacy of omalizumab.

BACKGROUND: Whether IgE affects eosinophil migration in chronic rhinosinusitis with nasal polyps (CRSwNP) remains largely unclear. Moreover, our understanding of local IgE, eosinophils, and omalizumab efficacy in CRSwNP remains limited. OBJECTIVE: We investigated whether IgE acts directly on eosinophils and determined its role in omalizumab therapy. METHODS: Eosinophils and their surface receptors were detected by hematoxylin and eosin staining and flow cytometry. IgE and its receptors, eosinophil peroxidase (EPX), eosinophilic cationic protein, and CCR3 were detected by immunohistochemistry and immunofluorescence. Functional analyses were performed on blood eosinophils and polyp tissues. Logistic regression was performed to screen for risk factors. Receiver operating characteristic curve was generated to evaluate the accuracy. RESULTS: Both FcεRI and CD23 were expressed on eosinophils. The expression of FcεRI and CD23 on eosinophil in nasal polyp tissue was higher than in peripheral blood (both P < .001). IgE and EPX colocalized in CRSwNP. IgE directly promoted eosinophil migration by upregulating CCR3 in CRSwNP but not in healthy controls. Omalizumab and lumiliximab were found to be effective in restraining this migration, indicating CD23 was involved in IgE-induced eosinophil migration. Both IgE+ and EPX+ cells were significantly reduced after omalizumab treatment in those who experienced response (IgE+ cells, P = .001; EPX+ cells, P = .016) but not in those with no response (IgE+ cells, P = .060; EPX+ cells, P = .151). Baseline IgE+ cell levels were higher in those with response compared to those without response (P = .024). The baseline local IgE+ cell count predicted omalizumab efficacy with an accuracy of 0.811. CONCLUSIONS: IgE directly promotes eosinophil migration, and baseline local IgE+ cell counts are predictive of omalizumab efficacy in CRSwNP.

Genomic profiling and immune landscape of olfactory neuroblastoma in China.

Background: Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the olfactory mucosa. The paucity of genomic data has prevented the development of individualized ONB treatments. Here, we investigated the genomic and immune landscape of ONB in Chinese patients. Methods: Whole exome sequencing (WES) and multiplex immunofluorescence (MIF) analysis were performed on tissue samples from 19 Chinese ONB patients. Patients were divided into low- and high-grade groups. Results: Overall, 929 nonsynonymous alterations were identified in 18 (94.74%) ONB cases. The most prevalent altered cancer-related genes were CTNNB1 (16%) and ZNRF3 (16%). The most mutated oncogenic pathways were the WNT and RAS pathways. The median tumor mutation burden (TMB) was 0.45, ranging from 0 to 3.25. Only one case expressed PD-L1 (> 1%) in the tumor region. The percentage of CD8+ tumor-infiltrating lymphocytes (TILs) in the tumor region ranged from 0.03% to 84.9%, with a median of 1.08%. No significant differences were observed between the low- and high-grade groups for clinicopathological features, mutant genes, mutant pathways, TMB, tumor neoantigen burden (TNB), mutant-allele tumor heterogeneity (MATH), PD-L1 expression levels, or CD8+ TIL percentage. However, the low-grade group showed significantly more CD68+ macrophages in both the tumor and total region than the high-grade group. Notably, CD68+CD163- macrophages accounted for an average of 80.5% of CD68+ macrophages. Conclusion: This study presents data on the genomic and immune landscape of ONB cases in China. CTNNB1 and ZNRF3 were the most prevalent altered cancer-related genes. The results of TMB, PD-L1, and CD8+ Tils suggest that ONB may be insensitive to immunotherapy. M1 macrophages may be positively associated with the prognosis of ONB. Implications for Practice: In this study, the most prevalent altered cancer-related genes were CTNNB1 (16%) and ZNRF3 (16%). The most mutated oncogenic pathways were the WNT and RAS pathways. The median tumor mutation burden (TMB) was 0.45, ranging from 0 to 3.25. Only one (1/15) case expressed PD-L1 (> 1%) in the tumor region. However, the low-grade group showed significantly more CD68+ macrophages in both the tumor and total region than the high-grade group. The higher level of CD68-related macrophages indicates that M1 macrophages potentially play an important role in ONB development that is possibly associated with prognosis.

Angiectatic nasal polyps with pleomorphism ‒ a diagnostic pitfall.

OBJECTIVE: To generalise the features of PANP in case of potential clinical and pathological pitfall of diagnosis. METHODS: Thirteen patients diagnosed as PANP were retrospectively analyzed in the Pathology Department of Capital Medical University from August 2014 to December 2019. Immunohistochemical staining with CD34, CK, Vim, Calponin, Ki67, Bcl-2, and STAT-6 was performed with envision-two steps method. RESULTS: PANP is a benign tumor presenting with gross variegated tan to gray soft fleshy tissue with foci of obvious hemorrhage and necrosis. The imaging shows internal heterogeneous hyperintensity with a peripheral hypointense rim while postcontrast images display a strong nodular and patchy enhancement. Vimentin (Vim) stain was consistently positive, while negative for CD34, STAT-6 and Bcl-2 (focal positive in two cases). Calponin and CK stain was positive in nine cases, respectively. CONCLUSION: PANP is a clinically rare tumor which may simulate malignancy lesion. Recognizing of characteristic features in these thirteen patients would be beneficial to avoid misdiagnosis and unnecessary aggressive treatment. LEVEL OF EVIDENCE: This work was Level 2 of evidence according to the Guide for Authors.

Machine learning method for the cellular phenotyping of nasal polyps from multicentre tissue scans.

BACKGROUND: This study aimed to establish a convenient and accurate chronic rhinosinusitis evaluation platform CRSAI 1.0 according to four phenotypes of nasal polyps. RESEARCH DESIGN AND METHODS: Tissue sections of a training (n = 54) and test cohort (n = 13) were sourced from the Tongren Hospital, and those for a validation cohort (n = 55) from external hospitals. Redundant tissues were automatically removed by the semantic segmentation algorithm of Unet++ with Efficientnet-B4 as backbone. After independent analysis by two pathologists, four types of inflammatory cells were detected and used to train the CRSAI 1.0. Dataset from Tongren Hospital were used for training and testing, and validation tests used the multicentre dataset. RESULTS: The mean average precision (mAP) in the training and test cohorts for tissue eosinophil%, neutrophil%, lymphocyte%, and plasma cell% was 0.924, 0.743, 0.854, 0.911 and 0.94, 0.74, 0.839, and 0.881, respectively. The mAP in the validation dataset was consistent with that of the test cohort. The four phenotypes of nasal polyps varied significantly according to the occurrence of asthma or recurrence. CONCLUSIONS: CRSAI 1.0 can accurately identify various types of inflammatory cells in CRSwNP from multicentre data, which could enable rapid diagnosis and personalized treatment.

A novel prognostic model based on ferritin and nomogram-revised risk index could better stratify patients with extranodal natural killer/T-cell lymphoma.

BACKGROUND: Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) is an aggressive lymphoma with marked heterogeneity, resulting in a distinct prognosis even in patients with the same disease stage. The nomogram-revised risk index (NRI) has been proposed to stratify patients with ENKTCL. Numerous reports have revealed the prognostic role of serum ferritin in various cancers. PURPOSE: We aimed to evaluate the role of NRI in our single cohort of patients with ENKTCL treated uniformly, explore the prognostic value of ferritin, and establish a new prognostic model to better stratify patients with ENKTCL. METHODS: We included 326 patients with ENKTCL with detailed data regarding clinical characteristics and survival outcomes. All patients were treated with asparaginase-based chemotherapy with or without radiotherapy. Multiple R packages were used to analyze the prognostic factors and derive a novel prognostic model. RESULTS: In the training cohort comprising 236 patients with ENKTCL, NRI significantly correlated with progression-free survival (PFS) and overall survival (p < 0.0001). Using a ferritin level of 400 µg/L as the cutoff value, patients with high ferritin levels had significantly inferior PFS (p = 0.00028). Integrating the NRI score and four easily accessible clinical parameters, namely ferritin, hemoglobin, albumin, and D-dimer, a new prognostic model was constructed, stratifying patients with ENKTCL into three risk groups. This new prognostic model was independent of disease stage and NRI and performed better than NRI. Furthermore, this model helped to stratify patients within the same NRI risk groups. Finally, the role of this novel prognostic model was validated in the external validation cohort comprising 90 patients with ENKTCL. CONCLUSIONS: Serum ferritin level could be a novel prognostic factor in patients with ENKTCL. The new prognostic model combining NRI and clinical parameters could better predict the prognosis of ENKTCL, thereby warranting further validation and potentially guiding individualized treatment in future prospective clinical trials.

Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution.

BACKGROUND: To compare the efficacy and safety of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL) at a single institution. METHODS: This retrospective study included 115 newly diagnosed patients with WR-DLBCL, of whom 68 patients received R-CHOP, and 47 patients received DA-EPOCH-R as their first-line treatment. The baseline features of the two groups were well balanced using a 1:1 propensity score matching method, and a total of 84 cases were obtained, including respective 42 cases in the R-CHOP and DA-EPOCH-R groups, for further survival and prognosis analysis. The primary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: During a median follow-up of 45 months, there were nine (21.4%) deaths in the R-CHOP group and two (4.8%) in the DA-EPOCH-R group. Kaplan-Meier analysis showed statistically significant improvements in PFS and OS in patients with DA-EPOCH-R compared with those treated with R-CHOP (log-rank test, P  = 0.025 and P  = 0.035, respectively). The 2-year PFS and OS rates in the DA-EPOCH-R group were 90.1% (95% confidence interval [CI]: 81.4-99.8%) and 95.2% (95% CI: 89.0-100.0%), respectively, and 80.5% (95% CI: 69.3-93.6%) and 90.5% (95% CI: 52.8-99.8%) in the R-CHOP group. Patients without B symptoms and elevated lactate dehydrogenase levels had a higher PFS in the DA-EPOCH-R group, with P values of 0.038 (hazard ratio [HR]: 0.11; 95% CI: 0.01-0.88) and 0.042 (HR: 0.19; 95% CI: 0.04-0.94), respectively. There were no statistically significant differences in clinical responses and treatment-related toxicities between the two groups. CONCLUSION: Compared with patients received R-CHOP, those treated by DA-EPOCH-R had superior PFS, OS, and controlled toxicity in patients with WR-DLBCL.

Investigation of the Value of T 2 Mapping in the Prediction of Eosinophilic Chronic Rhinosinusitis With Nasal Polyps.

OBJECTIVES: Patients with eosinophilic chronic rhinosinusitis with nasal polyps (eosCRSwNP) usually have more extensive sinus disease, severe symptoms, and poorer disease control compared with patients with non-eosCRSwNP. Separating these entities will be crucial for patient management. The purpose of this study is to investigate T 1, T 2 , and apparent diffusion coefficient (ADC) values of the nasal polyps in patients with CRSwNP and evaluate the usefulness of these parameters for differentiating these diseases. METHODS: Sinonasal magnetic resonance imaging was performed in 36 patients with eosCRSwNP and 20 patients with non-eosCRSwNP (including T 1 mapping, T 2 mapping, and diffusion-weighted imaging) before surgery. The T 1 , T 2 , and ADC values were calculated and correlated with pathologically assessed inflammatory cells of nasal polyps. RESULTS: Significant higher T 2 value, higher eosinophil count, and lower lymphocyte count of the nasal polyps were observed in eosCRSwNP than those in non-eosCRSwNP. There was no significant difference in T 1 or ADC values between the 2 groups. T 2 value was correlated with eosinophil count and lymphocyte count in CRSwNP. The area under the curve of T 2 value for predicting eosCRSwNP was 0.78 with 89.9% sensitivity and 60.0% specificity. CONCLUSION: T 2 value is a promising imaging biomarker for predicting eosCRSwNP. It can help to distinguish eosCRSwNP from non-eosCRSwNP.

Endotypes of chronic rhinosinusitis based on inflammatory and remodeling factors.

BACKGROUND: Previous studies on the endotyping of chronic rhinosinusitis (CRS) that were based on inflammatory factors have broadened our understanding of the disease. However, the endotype of CRS combined with inflammatory and remodeling features has not yet been clearly elucidated. OBJECTIVE: We sought to identify the endotypes of patients with CRS according to inflammatory and remodeling factors. METHODS: Forty-eight inflammatory and remodeling factors in the nasal mucosal tissues of 128 CRS patients and 24 control subjects from northern China were analyzed by Luminex, ELISA, and ImmunoCAP. Sixteen factors were used to perform the cluster analysis. The characteristics of each cluster were analyzed using correlation analysis and validated by immunofluorescence staining. RESULTS: Patients were classified into 5 clusters. Clusters 1 and 2 showed non-type 2 signatures with low biomarker concentrations, except for IL-19 and IL-27. Cluster 3 involved a low type 2 endotype with the highest expression of neutrophil factors, such as granulocyte colony-stimulating factor, IL-8, and myeloperoxidase, and remodeling factors, such as matrix metalloproteinases and fibronectin. Cluster 4 exhibited moderate type 2 inflammation. Cluster 5 exhibited high type 2 inflammation, which was associated with relatively higher levels of neutrophil and remodeling factors. The proportion of CRS with nasal polyps, asthma, allergies, anosmia, aspirin sensitivity, and the recurrence of CRS increased from clusters 1 to 5. CONCLUSION: Diverse inflammatory mechanisms result in distinct CRS endotypes and remodeling profiles. The explicit differentiation and accurate description of these endotypes will guide targeted treatment decisions.

High expression of AP2M1 correlates with worse prognosis by regulating immune microenvironment and drug resistance to R-CHOP in diffuse large B cell lymphoma.

BACKGROUND: First-line treatment with R-CHOP has cured 50%-60% patients of diffuse large B cell lymphoma (DLBCL), and more than one-third patients will eventually progressed to relapsed/refractory disease with dismal outcomes. Adaptor Related Protein Complex 2 Subunit Mu 1 (AP2M1) is required for the activity of a vacuolar ATPase and may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein. Herein, using both public databases and our own tumor samples, we aimed to demonstrate the prognostic role of AP2M1 and the potential tumor-promoting mechanisms in DLBCL. METHOD: Using public datasets of DLBCL from both GEO and TCGA databases, we analyzed the role of AP2M1 in mediating chemoresistance to R-CHOP and its correlation with various clinical parameters and prognosis. By using various R packages, we evaluated the role of AP2M1 on regulating tumor immune microenvironment. Moreover, tumor samples of DLBCL from Beijing TongRen Hospital were used to validate our findings by immunohistochemistry staining. RESULT: Expression of AP2M1 was significantly increased in DLBCL, which was correlated with poor prognosis and a variety of clinical indicators. On the basis of enrichment analysis, it was found that AP2M1 may be related to intracellular receptor signaling pathway. Through immune analysis and drug prediction, we found that the expression of AP2M1 affected the immune environment and drug response of DLBCL, which further revealed the important role of AP2M1 in DLBCL. By analyzing 61 patients treated uniformly with R-CHOP regimen in our center, we validated the above findings that high expression of AP2M1 correlated with inferior survival outcomes and affected sensitivity to R-CHOP treatment. CONCLUSION: Expression of AP2M1 may affect the prognosis of DLBCL patients probably by affecting the immune environment and the responses to many drugs in treating DLBCL, indicating AP2M1 as a potential therapy target in DLBCL.

Long-term survival outcomes of patients with primary ocular adnexal MALT lymphoma: A large single-center cohort study.

BACKGROUND: Primary ocular adnexal extranodal marginal zone mucosa-associated lymphoid tissue lymphoma (OAML) is a rare subtype of non-Hodgkin's lymphoma, and no consensus has been defined concerning the optimal treatment strategies. This study aims to investigate the associations of disease characteristics and different treatments with long-term outcomes of patients with localized OAML. METHODS: A large retrospective cohort study was conducted in a single-center of China, and 166 patients with newly diagnosed primary localized OAML were enrolled. Detailed data of disease characteristics at diagnosis and treatments were collected for all patients. We compared treatment response and progression-free survival (PFS) among patients with different characteristics and treatments. RESULTS: Of the 166 patients, 52 received complete resection of neoplasm, whereas 114 had residual lesion after surgery. Among the 114 patients, 61 underwent watchful waiting and 53 received further treatment including localized radiotherapy, chemotherapy, or combined radiotherapy and chemotherapy. Median follow-up was 49 months. A total of 31 patients had disease progression or relapse, including four patients with such event more than five years after initial treatment. The 5-year PFS was 73.9%, 70.6%, and 85.9%, whereas the 10-year PFS was 69.3%, 59.2%, and 79.3%, among patients with complete resection of neoplasm, patients in the watchful waiting group and patients with further treatment, respectively. Patients with further treatment had longer PFS, compared with patients in the watchful waiting group (p = 0.011). Bilateral involvement at diagnosis was associated with significantly inferior PFS (p = 0.029), whereas age, IPI score, or TNM staging were not associated with PFS. No serious adverse reaction was reported among patients with further treatment. CONCLUSIONS: Bilateral involvement was associated with poor prognosis. Among patients with residual lesions after surgery, further treatment was associated with improved survival. Patients with OAML might experience disease progression or relapse more than five years after initial treatment.

Angiectatic nasal polyps with pleomorphism ‒ a diagnostic pitfall

Abstract Objective To generalise the features of PANP in case of potential clinical and pathological pitfall of diagnosis. Methods Thirteen patients diagnosed as PANP were retrospectively analyzed in the Pathology Department of Capital Medical University from August 2014 to December 2019. Immunohistochemical staining with CD34, CK, Vim, Calponin, Ki67, Bcl-2, and STAT-6 was performed with envision-two steps method. Results PANP is a benign tumor presenting with gross variegated tan to gray soft fleshy tissue with foci of obvious hemorrhage and necrosis. The imaging shows internal heterogeneous hyperintensity with a peripheral hypointense rim while postcontrast images display a strong nodular and patchy enhancement. Vimentin (Vim) stain was consistently positive, while negative for CD34, STAT-6 and Bcl-2 (focal positive in two cases). Calponin and CK stain was positive in nine cases, respectively. Conclusion PANP is a clinically rare tumor which may simulate malignancy lesion. Recognizing of characteristic features in these thirteen patients would be beneficial to avoid misdiagnosis and unnecessary aggressive treatment. Level of evidence: This work was Level 2 of evidence according to the Guide for Authors.

Secretory carcinoma of the sinonasal cavity and pharynx: A retrospective analysis of four cases and literature review.

Secretory carcinoma (SC) is a recently recognized type of salivary gland tumor characterized by t(12;15) (p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion. Most SCs are located in a main salivary gland, and primary sinonasal secretary carcinoma is rare. We describe three cases of primary SC in the sinonasal cavity with high-grade transformation (HGT) in one case, and the first case in the pharynx. All tumors comprised slightly atypical cells with solid, tubular, microcystic growth patterns. The case with HGT included two components with distinct sharp boundaries and comedo necrosis, high mitotic figures and obvious cellular atypia. Tumor cells were positive for vimentin, S100, and Gata-3 and negative for p63 and DOG-1. Three cases showed nuclear staining of pan-TRK and one showed cytoplasmic staining. All cases harbored ETV6 gene rearrangement, and ETV6-NTRK3 gene fusion was detected in three cases. Most patients were treated with radical resection and adjuvant therapy. After excision, all remained tumor-free for 65-164 months (medium 98.5 months). SC in the sinonasal cavity and pharynx is a low-grade malignant tumor with histologic features overlapping those of other salivary gland tumors. Immunohistochemical analysis and fluorescence in situ hybridization are useful techniques for its differential diagnosis.

Baicalein Induces Apoptosis of Rheumatoid Arthritis Synovial Fibroblasts through Inactivation of the PI3K/Akt/mTOR Pathway.

Purpose: Rheumatoid arthritis (RA) shows abnormal proliferation, apoptosis, and invasion in fibroblast-like synoviocytes (FLSs). Baicalein (BAI), extracted from Scutellaria baicalensis, is used as an anticancer drug through inducing cancer cells apoptosis. However, the mechanism of BAI in RA progression still remains unknown. Here, we demonstrated that BAI inhibited FLS proliferation and migration, whereas it enhanced apoptosis via the PI3K/Akt/mTOR pathway in vitro. Methods: Cell viability and colony formation were analyzed by MTT and plate colony formation assays in SW982 cells, respectively. Apoptosis was detected by flow cytometry and western blotting. Epithelial-mesenchymal transition (EMT), MMP family proteins (MMP2/9), and the PI3K/Akt/mTOR pathway were detected by western blot. Cell migration was detected by scratch healing assay under BAI treatment in SW982 cells. Results: BAI dose-dependently inhibited cell viability and colony forming in SW982 cells. BAI upregulated apoptotic proteins and downregulated EMT-related proteins, resulting in enhanced cell apoptosis and inhibited cell migration in SW982 cells. BAI also dose-dependently inhibited the phosphorylation of PI3K, Akt, and mTOR. Conclusions: These results indicated that BAI inhibited FLSs proliferation and EMT, whereas induced cell apoptosis through blocking the PI3K/Akt/mTOR pathway, supporting clinical application for RA progression.

Quantitative parameters derived from 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging can accurately estimate the histologic grade of hypopharyngeal squamous cell carcinoma preoperatively.

PURPOSE: Among head and neck cancers, hypopharyngeal squamous cell carcinoma (HSCC) shows the highest malignancy, which is associated with histologic grading. This study was designed to investigate whether quantitative parameters derived from 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) can preoperatively estimate the histologic grade of HSCC. METHODS: 18F-FDG PET/MRI of neck was successfully performed in 21 patients with histologically proven HSCC including poorly differentiated group (ten patients) and well-moderately differentiated group (eleven patients). Quantitative parameters derived from FDG-PET, diffusion-weighted imaging (DWI), and dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) were calculated based on volume of interest drawn on the tumor and compared between two groups. The efficacy of quantitative parameters for the estimation of histologic grades of HSCC was evaluated. RESULTS: There were statistically significant differences in mean value of standard uptake value (SUV), apparent diffusion coefficient (ADC), and Ktrans derived from 18F-FDG PET/MRI of HSCC between two groups (p < 0.05). There was no statistically significant difference in other quantitative parameters derived from 18F-FDG PET/MRI of HSCC between two groups. The area under the curve (AUC) of the combination of SUVmean, ADCmean, and Ktrans in the estimation of histologic grade of HSCC was 0.936 with sensitivity of 90.0% and specificity of 81.8%. CONCLUSION: The combination of SUVmean, ADCmean, and Ktrans derived from 18F-FDG PET/MRI can accurately predict the histologic grade of HSCC preoperatively.

Crowberry inhibits cell proliferation and migration through a molecular mechanism that includes inhibition of DEK and Akt signaling in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a rare biliary adenocarcinoma related to poor clinical prognosis. Crowberry is an herbal medicine used to control inflammatory diseases and reestablish antioxidant enzyme activity. Although crowberry shows significant therapeutic efficacy in various tumors and diseases, its anticancer effects and specific molecular mechanisms in CCA are poorly understood. AIM OF THE STUDY: This study was conducted to characterize crowberry effects on CCA cells behavior. MATERIALS AND METHODS: The chemical profiles of crowberry extract was qualitatively analyzed by high-performance liquid chromatography (HPLC) and HPLC-tandem mass spectrometry. MTT, colony formation and EdU assays were performed to measure cell proliferation. The effect of crowberry treatment on CCA cell migration was assessed by wound healing and migration assays. Moreover, Hoechst staining assay and flow cytometry were performed to assess the cell apoptosis rate. Western blotting was used to assess the protein expression levels of key factors associated with apoptosis, the Akt signaling pathway, and the epithelial-mesenchymal transition. A xenograft model was established and immunohistochemical and H&E staining was performed to assess crowberry antitumor effects in vivo. RESULTS: Crowberry clearly inhibited CCA cells proliferation and migration in a dose-dependent manner and induced apoptosis in vitro. Crowberry inactivated the PI3K/Akt signaling pathway by regulating DEK in vitro and significantly inhibited tumor growth by downregulating the DEK expression in xenograft models. CONCLUSION: Crowberry inhibits CCA cells proliferation and migration through a molecular mechanism that includes inhibition of DEK and Akt signaling pathway inhibition in vitro and in vivo.

[Cordycepin inhibits the proliferation and migration of human gastric cancer cells by suppressing lipid metabolism via AMPK and MAPK activation].

Objective To explore the inhibitory effect of cordycepin on the proliferation and migration of gastric cancer cells and its molecular mechanism. Methods MGC-803 cells were treated with 0, 25, 50, 100 µmol/L of cordycepin and HGC-27 cells with 0, 5, 25, 50 µmol/L of cordycepin for 48 hours. The proliferation ability of MGC-803 and HGC-27 cells was detected by MTT assay and EdU assay; the colony formation ability of cells was detected by colony formation assay; both wound healing assay and cell migration assay were applied to detect the cell migration ability of MGC-803 and HGC-27 cells; the chromatin agglutination was detected by Hoechst 33342 staining; the apoptosis of gastric cancer cells was detected by annexin V-FITC/PI double labeling combined with flow cytometry; Western blot was used to measure the protein expression levels of lipid metabolism-related proteins including sterol regulatory element binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), and acetyl coA carboxylase 1 (ACC1), epithelial-mesenchymal transition (EMT)-related proteins including E-cadherin, vimentin, Snail, Slug, matrix metalloproteinase 2 (MMP2), MMP9, AMPK, and phosphorylated AMPK (p-AMPK), MAPK signaling pathway-related proteins including JNK, phosphorylated JNK (p-JNK), p38 MAPK, and p-p38 MAPK, and apoptosis-related proteins including cleaved caspase-9 (c-caspase-9), c-caspase-3, and cleaved poly (ADP-ribose) polymerase (c-PARP). Results Cordycepin significantly inhibited the proliferation, colony formation, and migration of gastric cancer cells. After cordycepin treatment, the karyopycnosis, karyorrhexis, and apoptosis rate of cancer cells increased, and the expressions of apoptosis-related proteins c-caspase-3, c-caspase-9, and c-PARP increased. The expression of E-cadherin increased, while the expressions of vimentin, Snail, Slug, SREBF1, FASN, ACC1, MMP2, MMP9 significantly decreased; the phosphorylation levels of AMPK, JNK and P38 proteins significantly increased. Conclusion Cordycepin inhibits the proliferation and migration of gastric cancer cells by suppressing the lipid metabolism and EMT process via activating AMPK and MAPK signaling pathway.

CD56-Negative Extranodal Natural Killer/T-Cell Lymphoma: A Retrospective Study in 443 Patients Treated by Chemotherapy With or Without Asparaginase.

Objective: Extranodal natural killer/T cell lymphoma (NKTCL) is an aggressive EBV-related lymphoma, originating from NK cells or T cells. Previous study demonstrated that CD56 negative NKTCL should be recognized as a distinct subtype. In this study, the value of CD56 in NKTCL is validated in the era of asparaginase, and genomic analysis was done to dissect the differences between CD56-negative and positive NKTCL. Methods: 443 patients with newly diagnosed NKTCL were enrolled in this retrospective study, and correlation between CD56 positivity and survival outcomes was analyzed. The gene sequencing data was downloaded (http://www.biosino.org/node/project/detail/OEP000498), and bioinformatics analysis was done to delineate the tumor microenvironment and differentially expressed genes. Results: CD56 was expressed in 337 patients (76.1%). Within a median follow-up time of 51 months, the 5-year overall survival (OS) and progression free survival (PFS) rates were 63.8% and 51.9%, respectively. For the whole cohort, patients who were CD56-positive had superior OS (5-year OS, 86.2% vs. 51.9%, p=0.019) and PFS (5-year PFS, 55.9% vs. 40.1%, p=0.016). For patients in early stage disease, CD56 positivity was associated with superior OS and PFS (p=0.008 and 0.005, respectively). In patients who received non-asparaginase-based chemotherapy, CD56-negative was associated with shorter OS and PFS (p<0.001), and in patients who received asparaginase-based chemotherapy, CD56-negative was not related to inferior OS and PFS (p=0.093 and p=0.829, respectively). The genomic analysis demonstrated that CD56 positive NKTCL probably originated from NK cells and CD56 negative NKTCL originated from T cells. CD56 positive NKTCL had significantly higher proportion of resting NK cells, activated NK cells, and activated CD8+ and CD4+ T cells in the tumor microenvironment. Conclusions: CD56 negative NKTCL differs from CD56 positive NKTCL in both the tumor microenvironment and survival outcomes, and asparaginase-based treatment may overcome the poor prognosis brought by CD56 negativity.