VEGF Is Involved in the Increase of Dermal Microvascular Permeability Induced by Tryptase

Tryptases are predominantly mast cell-specific serine proteases with pleiotropic biological activities and play a critical role in skin allergic reactions, which are manifested with rapid edema and increases of vascular permeability. The exact mechanisms of mast cell tryptase promoting vascular permeability, however, are unclear and, therefore, we investigated the effect and mechanism of tryptase or human mast cells (HMC-1) supernatant on the permeability of human dermal microvascular endothelial cells (HDMECs). Both tryptase and HMC-1 supernatant increased permeability of HDMECs significantly, which was resisted by tryptase inhibitor APC366 and partially reversed by anti-VEGF antibody and SU5614 (catalytic inhibitor of VEGFR). Furthermore, addition of tryptase to HDMECs caused a significant increase of mRNA and protein levels of VEGF and its receptors (Flt-1 and Flk-1) by Real-time RT-PCR and Western blot, respectively. These results strongly suggest an important role of VEGF on the permeability enhancement induced by tryptase, which may lead to novel means of controlling allergic reaction in skin

Hyalinizing clear cell carcinoma of salivary gland: a clinicopathological study of 8 cases

Background and purpose: Hyalinizing clear cell carcinoma (HCCC) of salivary gland is a rare tumor with low-grade malignancy, which usually occurs in minor salivary glands. Due to its rarity, the tumor type is not well known to pathologists and misdiagnosis frequently occurred. The aim of this study was to investigate the histologic, immunophenotypic and molecular features of HCCC. Methods: Eight cases of salivary gland HCCC diagnosed at the Department of Pathology, Fudan University Shanghai Cancer Center from January 2015 to October 2019 were collected. Clinicopathologic characteristics were analyzed, and fluorescence in situ hybridization (FISH) assay was used to detect EWSR1 translocation in tumor tissue. Diagnostic criteria and differential diagnosis were summarized, with a review of the literature. Results: All patients were female, aged 26 to 68 years, and the tumor locations included the oral cavity, nasopharynx, parotid gland and other sites of head and neck. Microscopically, the tumors consisted mainly of clear cells and eosinophilic cells with variable proportions, arranged in nests, sheets and trabeculae. In 1 case, the tumor was composed almost entirely of eosinophilic cells; in 6 cases, obvious nuclear pseudo-inclusion bodies were seen; in 1 case, neoplastic cells were connected to the surface squamous epithelium; in 1 case, the glandular structure was seen in some areas of the tumor; in 3 cases, a sheath of lymphocyte was formed around the tumor nests; in 7 cases, there was a sclerosing or hyalinizing stromal reaction, showing desmoplastic changes; and 1 case featured stoma with myxoid changes. There was no definite keratinization or necrosis in all tumors, and mitotic figures were generally rare. Immunohistochemical staining showed that tumor cells of 8 cases were diffusely positive for AE1/AE3 protein, 7 cases expressed P63, and 7 cases focally expressed low molecular weight keratin CK7 or CAM5.2, however, S-100, calponin, PAX-8 and CD10 were all negative. All tumors showed low proliferative activity, with the Ki-67 proliferation index less than 5%. FISH test revealed EWSR1 translocation in all 8 cases. All patients demonstrated no recurrence or metastasis during the follow up ranging 4-50 months. Conclusions: HCCC of salivary gland is a low-grade malignancy occurring mainly in minor salivary glands, with characteristic histological and molecular features. This cancer type needs to be distinguished with many morphologic mimics of salivary gland. Most cases with salivary HCCC feature a good prognosis

Clinicopathological analysis of DLBCL/HGBL with MYC, BCL2 and BCL6 gene rearrangement

Background and purpose: Diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBL) with gene rearrangement of MYC, BCL2 and BCL6, also known as triple-hit lymphoma (THL), has a low incidence and relevant literature is limited. Thus comprehensive and sufficient understanding is lacking. The purpose of this study was to explore the clinicopathological features and prognosis of this rare disease. Methods: Ten cases of THL diagnosed in Department of Pathology, Fudan University Shanghai Cancer Center from June 2016 to December 2021 were collected. Clinical features were analyzed retrospectively. Histopathological features were observed using H-E stain. Immunophenotype was analyzed by immunohistochemistry. The rearrangement of MYC, BCL2 and BCL6 genes was detected by fluorescence in situ hybridization (FISH), and Epstein-Barr virus (EBV) infection was detected by in situ hybridization using EBV-encoded RNA (EBER). Results: Of the 10 cases, 4 cases were male and 6 cases were female. The median age was 54 years (43-80 years). Two cases occurred in lymph nodes, 6 cases involved extranodal organs, and both lymph nodes and extranodal organs were involved in the other 2 cases. There were 4 cases (40%) with clinical stage Ⅲ/Ⅳ disease and 6 cases (60%) with clinical stage Ⅰ/Ⅱ disease. 40% (4/10) patients had international prognostic index (IPI) score ≥3. 50% (4/8) patients had bone marrow invasion. Two (20%) cases had B symptoms. 40% (4/10) patients had a history of hepatitis B virus infection. Five cases had the morphology of DLBCL, not otherwise specified (DLBCL-NOS); Two cases showed morphological features intermediate both DLBCL and Burkitt lymphoma; One case had a blastoid cytomorphology, and the other 2 cases failed to be classified accurately because of serious crushing artifacts of the tissue. Immunophenotypically, 80% of the cases were of germinal center B-cell (GCB) type and 20% were of non-GCB type. MYC/BCL2 double expression accounted for 78% (7/9), BCL6 positivity was found in 80% of the total cases, and the Ki-67 proliferation index was ≥80% in all cases. FISH showed that all 10 cases had MYC, BCL2 and BCL6 gene translocation rearrangement. EBV infection was consistently absent. All except one case received systemic treatment. The overall survival was 2.0-55.5 months (median, 16.8 months), and 1-year overall survival rate was 68.6%. The 1-year overall survival rates of patients with stage Ⅰ/Ⅱ disease and stage Ⅲ/Ⅳ disease were 100% and 25% respectively. Conclusion: THL mainly affects middle-aged and elderly patients, which occured more frequently in extranodal organs, and it is characterized by GCB immunophenotype and MYC/BCL2 double expression. A considerable number of patients have a clinical stage of Ⅰ/Ⅱ disease and a better prognosis in the current series, indicating that early identification of THL is of great importance for timely intervention and improving the prognosis

Retrospective study on MGMT methylation status and its clinical significance in gliomas

Background and purpose: Glioma is a common malignant tumor of central nervous system with poor prognosis. Postoperative concurrent chemoradiotherapy with temozolomide (TMZ) is the main treatment for glioma. The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter can predict the sensitivity of glioma patients to TMZ treatment, however its relationship with clinical pathology and how to better predict treatment and prognosis still need further research. The purpose of this study was to analyze the status of MGMT promoter methylation (MGMTmet) in gliomas and its correlation with clinical pathological features and other common molecular abnormalities, and to explore the value of combined analysis of MGMTmet and other molecular abnormalities in predicting the prognosis of glioma and the efficacy of TMZ treatment. Methods: We retrospectively collected clinical and pathological data from 205 glioma patients diagnosed by the Department of Pathology, Fudan University Shanghai Cancer Center from July 2019 to September 2022. Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) was used to detect MGMTmet status. Sanger sequencing was used to detect the mutation of isocitrate dehydrogenase 1 and 2 (IDH1/2) and telomerase reverse transcriptase (TERT) genes. Fluorescence in situ hybridization (FISH) was used to detect the deletion of the short arm of chromosome 1 and the long arm of chromosome 19 (1p19q). Results: Among 205 patients, the incidence of MGMTmet was higher in female patients than in male patients. Compared to glioblastoma (47.3%), astrocytoma (74.1%) and oligodendroglioma (100.0%) were more prone to methylation of the MGMT gene promoter (P<0.05). In MGMTmet group, IDH1 mutation rate and 1p19q co-deletion rate were significantly increased, and methylation of MGMT promoter was correlated with IDH1 mutation and 1p19q co-deletion (P<0.05). Patients with MGMTmet, age less than 55 years, oligodendroglioma, and World Health Organization (WHO) grade 1-3 all showed longer overall survival (OS), and the difference is statistically significant (P<0.05). Compared with individual influencing factors, dual/triple gene combination analysis (MGMTmet/IDH1 mutation or MGMTmet/1p19q co-deletion or MGMTmet/IDH1 mutation/1p19q co-deletion) had better effect for predicting the patient prognosis (P<0.05), with the latter two being independent prognostic factors. Among TMZ treated patients, MGMTmet (MGMTmet/TMZ+) patients had a better prognosis than other groups. If the patients had combined IDH1 mutations, the prognosis of the patients was further improved (P<0.05). Conclusion: MGMTmet is more common in women and patients with oligodendroglioma. It is positively correlated with IDH1 mutation and 1p19q co-deletion. Patients with MGMTmet are associated with better TMZ treatment efficacy and prognosis, and MGMTmet combined with IDH mutations and 1p19q co-deletion analysis have better TMZ treatment efficacy and prognostic implications

Folate-Mediated Chemotherapy and Diagnostics: An Updated Review and Outlook

Folate receptor (FR) is highly expressed in many types of human cancers, and it has been actively studied for developing targeted chemotherapy and diagnostic agents. Tremendous efforts have been made in developing FR-targeted nanomedicines and nanoprobes and translating them into clinical applications. This article provides a concise review on the latest development of folate-mediated nanomedicines and nanoprobes for chemotherapy and diagnostics with an emphasis on in vivo applications. The cellular uptake mechanisms, pharmacokinetics (PK), administration routes and major challenges in FR-targeted nanoparticles are discussed

Partial omentectomy maybe practicable for T3 or shallower gastric cancer patients

Abstract Background Total omentectomy is often performed with gastrectomy as radical surgery for gastric cancer (GC) patients. However, it remains controversial whether GC patients can benefit from omentectomy. The aim of this study was to analyze the incidence and clinical significance of tumor deposits (TDs) in different anatomical subregions of perigastric omentum in GC patients undergoing gastrectomy with total omentectomy. Methods From October 2011 to December 2013, 1253 patients who underwent gastrectomy with total omentectomy for GC were retrospective reviewed. The TDs in different anatomical subregions of perigastric omentum were examined. Results Of 1253 patients, TDs positivity was 11.2%. Tumor deposits in the omentum of greater curvature and in the omentum of lesser curvature were associated with lymphovascular invasion, perineural invasion, advanced tumor node metastasis stages, and unfavorable survival. Besides, TDs in the proximal omentum of greater curvature and in the omentum of lesser curvature correlated with older patients and larger tumors. Kaplan–Meier curves showed that patients with TDs had worser overall survival (OS) than those without, regardless of TD positions. Patients with TDs in the omentum of greater curvature had the worst prognosis, followed by patients with TDs in the omentum of lesser curvature and patients with no TDs. Tumor deposits in the proximal omentum of greater curvature was an independent prognostic factor for OS. Moreover, only patients classified as pT4 had TDs in the distal omentum of greater curvature. Conclusions Patients with TDs in the omentum of greater curvature had the worst prognosis, followed by patients with TDs in the omentum of lesser curvature and patients with no TDs. In addition, partial omentectomy might be practicable for gastric cancer patients classified as T3 or shallower tumors

External quality assessment for the molecular detection of microsatellite instability in China, 2021-2022

Microsatellite instability (MSI) analysis of tumors informs Lynch syndrome testing, therapeutic choice, and prognosis. The status of MSI is mainly detected by polymerase chain reaction coupled with capillary electrophoresis. However, there are various assays with different detection loci and the obtained results may vary. The objective of this study was to evaluate the concordance among different assays and the performance among different laboratories. External quality assessment (EQA) for the detection of MSI was performed in 2021 and 2022. Each sample panel consisted of five samples, including microsatellite-stable and MSI tumor tissues. The sample panels were coded at random, and the returned results were compared and scored. The fully validated sample panels showed appropriate applicability with commercially available assays. There were eight false-negative results in 2021 and five false results (two false-positives and three false-negatives) in 2022. Among the participating laboratories, in 2021, 20 (74.07%) provided completely correct results; in 2022, 38 (92.68%) obtained an optimal score. The molecular detection of MSI in China exhibited an improvement in a 2-year EQA study. Participation in EQA program is an efficient way of assessing the performance of laboratories and improving their ability.</p