Clinicopathological features of non-small cell lung cancer with high PD-L1 expression and positive driver gene mutation / 临床与实验病理学杂志

Purpose To investigate the clinicopathological and histological features of non-small cell lung cancer(NSCLC)patients with high expression of PD-L1 and positive driver muta-tion.Methods The clinical data of 141 patients with PD-L1 high expression and driver mutation-positive NSCLC were col-lected.Immunohistochemical methods,ARMS-PCR,and next-generation sequencing(NGS)were used to detect PD-L1 ex-pression and driver gene mutations.The clinicopathological fea-tures were analyzed and the related literatures were reviewed.Results There were 141 cases NSCLC patients with high ex-pression of PD-L1 in tumor cells,of which 57 cases were≥50％,＜60％;≥60％,＜70％in 18 cases;≥70％,＜80％in 35 cases;≥80％in 31 cases.Among 141 cases NSCLC patients with high PD-L1 expression,53 cases(37.6％)had driver gene mutations,including 4 cases BRAF 15 exon mutations,9 cases MET-associated mutations,17 cases EGFR-associated mutations,16 cases KRAS 2 exon mutations,4 cases EML4-ALK fusion mutations,and 3 cases other rare mu-tations.The high expression of PD-L1 and the occurrence of driver gene mutation were related to the gender,smoking history and pathological type of patients(P＜0.05).MET-related mu-tations and KRAS 2 exon mutations were more common in males than in females.All BRAF 15 exon mutations were female.The mean percentage of PD-L1 expression was highest in patients with MET mutation,KRAS 2 exon mutation,and 3 cases rare mutations.In 33 cases with BRAF 15 exon mutation,MET am-plification or mutation,EGFR-related mutation,and 3 cases oth-er rare mutations,PD-L1 was highly expressed in solid,glandu-lar,and micropapillary tumor cells.In 20 cases with KRAS 2 exon mutation and EML4-ALK fusion mutation,PD-L1 was highly expressed in solid nested tumor cells.Conclusion In NSCLC,high expression of PD-L1 and positive driver gene mu-tation are negatively correlated with the degree of tumor differen-tiation.In the poorly differentiated surgical specimens of lung adenocarcinoma,solid,micropapillary,or glandular tubular tumor tissues should be selected as far as possible for PD-L1 ex-pression and driver gene mutation detection.

Clinical significance of CD8 positive tumor-infiltrating lymphocytes density and programmed-death receptor ligand 1 expression in rectal cancer after neoadjuvant chemoradiotherapy / 肿瘤研究与临床

Objective:To investigate the correlation of CD8 positive tumor-infiltrating lymphocytes (CD8 + TIL) density and programmed-death receptor ligand 1 (PD-L1) expression in rectal cancer with clinicopathological characteristics and prognosis of patients after neoadjuvant chemoradiotherapy. Methods:The clinicopathological data of 166 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgery in the Beijing Chao-Yang Hospital, Capital Medical University from January 2015 to December 2018 were retrospectively analyzed. CD8 + TIL density and PD-L1 expression were detected by using immunohistochemistry. The correlation of CD8 + TIL density and PD-L1 expression with clinicopathological characteristics of patients after neoadjuvant chemoradiotherapy was analyzed. Kaplan-Meier method was used to analyze the disease-free survival (DFS) and Cox regression risk model was used to make univariate and multivariate analysis of the influencing factors for DFS. Results:Among 166 LARC patients, 81 cases (48.8%) had high density of CD8 + TIL, 85 cases (51.2%) had low density of CD8 + TIL; 63 cases (38.0%) had PD-L1 expression, and 103 cases (62.0%) had non-expression of CD8 + TIL. The expression rate of PD-L1 in CD8 + TIL high density group was higher than that in CD8 + TIL low density group [50.6% (41/81) vs. 25.9%(22/85), χ2 = 10.78, P < 0.001]. According to the density of CD8 + TIL and PD-L1 expression, immunophenotype was divided among 4 groups; the 3-year DFS rate of the CD8 + TIL high density /PD-L1 expression group was 87.1%, which was higher than that of the other groups (CD8 + TIL low density /PD-L1 expression group was 72.8%, CD8 + TIL high density /PD-L1 non-expression group was 67.0%, CD8 + TIL low density /PD-L1 non-expression group was 64.3%), and the difference was statistically significant ( P < 0.05). Univariate analysis showed that tumor differentiation degree, TNM stage, CD8 + TIL density, PD-L1 expression and CD8 + TIL density /PD-L1 expression were correlated with the DFS of patients (all P < 0.05). Multivariate analysis results showed that CD8 + TIL high density /PD-L1 expression was an independent protective factor for DFS ( HR = 0.049, 95% CI 0.005-0.497, P = 0.011), while TNM stage 3 was an independent risk factor for DFS ( HR = 2.752,95% CI 1.300-5.825, P = 0.008). Conclusions:In LARC after neoadjuvant therapy, CD8 + TIL density is positively correlated with the expression of PD-L1, and the high density of CD8 + TIL/PD-L1 expression is an independent influencing factor for good prognosis, suggesting that these patients may benefit from the immunotherapy.

Acute Epstein-Barr virus-positive cytotoxic T cell lymphoid hyperplasia in the upper aerodigestive tract, mimicking extranodal natural killer/T cell lymphoma, nasal type.

To describe the clinicopathological features of nine patients with acute Epstein-Barr virus (EBV)-positive cytotoxic T cell lymphoid hyperplasia (EBV+TLH) in the upper aerodigestive tract, in which initial findings led to a preliminary misdiagnosis of extranodal NK/T cell lymphoma, nasal type (ENKTL). A series of nine cases of EBV+TLH in one Chinese institution over a 9-year interval was retrospectively analyzed. Median age was 16 years (range 5-29 years) with a M:F ratio of 5:4. All patients were previously healthy with an acute onset period of < 1 month. Six patients (66%) presented with masses or polypoid protrusions in the upper aerodigestive tract. Nasopharyngeal symptoms, cervical lymphadenopathy, and fever were found in 89%, 78%, and 56% of patients, respectively. In seven cases, morphology mainly showed small-sized irregular cells and in two cases medium-to-large cells. In all cases, the cells diffusely expressed cytoplasmic CD3 and at least one marker for cytotoxic granules, but were negative for CD56. CD5 expression was detected in eight cases (8/9, 89%). In all cases, double staining for CD3 and EBER indicated that most T cells were infected with EBV. T cell receptor gene rearrangement was performed in five cases and all showed polyclonal results. All patients achieved complete remission within 1 month after diagnosis without any chemoradiotherapy and were followed up 19-124 months without recurrent disease. EBV+TLH in the upper aerodigestive tract is occasionally observed in China. The histopathologic features of EBV+TLH can mimic ENKTL. EBV+TLH should be taken into consideration as a potential diagnosis when the disease duration is short, spontaneous remission is achieved without intervention, and when histology shows infiltration with EBV-infected T lymphocytes.

Significance of standardized special staining technology for pathological diagnosis of pulmonary fungal infectious diseases / 临床与实验病理学杂志

To explore the significance of the application of standardized special staining technique in pathologic diagnosis of pulmonary fungal infectious diseases.Methods Final pathologic diagnosis of 104 cases pulmonary fungus infection disease in Beijing Chaoyang hospital from September 2011 to March 2016 were selected;HE staining only,HE staining combined with the traditional manual special staining method PAS and hexamine silver,and HE staining combined with automatic special staining PAS and hexamine-silver were used and compared.The two kinds of special staining technology were compared;the microscopic observation,analysis results (all the first staining results,not including the results of complex staining),the results on the basis of final pathologic diagnosis were also compared with the clinical preliminary diagnosis.Results Lung fungal infectious disease diagnosis rate and fungal classification rate,from low to high order consistence,showed that for the primary clinical diagnosis (29.8％ and 19.2％),HE staining (32.7％ and 32.7％),HE staining combined with traditional manual special staining method PAS and hexamine silver (90.4％ and 87.5％),and HE staining combined with automatic special staining PAS and hexamine-silver (98.1％ and 94.2％).The four methods were statistically significant on two aspects (P ＜ 0.01,P ＜ 0.01);the fourth method was significantly different from the first two (P ＜ 0.01,P ＜ 0.01).The fourth method was significantly different from the third kind of diagnosis rate (P ＜ 0.05),typing rate was no significant difference (P ＞ 0.05).But automatic special dyeing method of PAS and hexamine silver steps were more simple,with standardized chemical reagents,no artificial and environmental factors,short time-consuming,and less number of dropping-off and restaining of the section.Conclusion HE staining and its combination with automatic special staining of PAS and hexamine silver are much more standardized,and help to improve the diagnosis of pulmonary fungal infectious diseases and fungal classification rate.

Correlation between prognosis and expression of EGFR, HER2 and HER3 in non-small cell lung cancer / 肿瘤研究与临床

Objective To investigate the correlation between the clinical pathological factors and the expression of EGFR, HER2 and HER3 in non-small cell lung cancer tissues. Methods The expression of EGFR, HER2 and HER3 in non-small cell lung cancer tissues was detected by MaxVision immunohistochemical. The relationship between the protein expression and the clinical pathologic characteristics was studied. The correlation between the protein expression and the survival was also retrospectively analyzed. Results Increased expression of EGFR, HER2 and HER3 was detected in the NSCLC tissues and their rates were 45.9 % (73/156), 30.8 % (49/156) and 21.4 % (37/156), respectively. There were significant associations between the expression of these proteins and lymph node metastasis, tumor differentiation degree and TNM staging. Conclusions Overexpression of EGFR, HER2, HER3 or all three proteins is a predictor of poor prognosis. Moreover, combined detection of all 3 markers may work better than the individual detection in the prediction of the prognosis to guide the clinical treatment.

Expression profiling of metastasis-related microRNAs in early esophageal squamous cell carcinoma / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the difference of microRNA (miRNA) expression between two groups of early stage (pT1N0) esophageal squamous cell carcinoma (ESCC) patients who had different outcome and the prognostic significance of different miRNA in metastatic of early ESCC, and to identify useful prognostic markers in the selection of appropriate treatment for early ESCC patients.</p><p><b>METHODS</b>TaqMan human miRNA arrays and bioinformatics were used to detect and analyze the expression profiles of miRNAs in the two groups, and RT-PCR was used to verify the differences in miRNA expression.</p><p><b>RESULTS</b>The miRNA arrays revealed a total of 41 markedly changed miRNAs in the survival group compared with the death group. Bioinformatics analysis, prediction and significant function analyses of targeted genes and pathway analysis identified that miR-27a, miR-143 and miR-886-5p levels were increased or decreased by seven-folds or more. The enriched target genes were GRB2, SOS1, MAPK1, EGFR, CBL, SPRY2, RPS6KA5, IGF1R, NGFR, MAPK14 and CREB1. These genes were significantly related to the following signaling pathways, i.e.Sprouty regulation of tyrosine kinase signals pathway, Erk1/Erk2 Mapk signaling pathway and transcription factor CREB and its extracellular signals.</p><p><b>CONCLUSIONS</b>miR-27a, miR-886-5p, and miR-143 may be potential prognostic markers of metastasis for early ESCC. The detection of these miRNAs plays a directive role for the treatment options of early ESCC. The regulation of targeted genes and mechanism remain to be further studied.</p>

Morphologic features suggestive of submucosal invasive adenocarcinoma in colorectal mucosal biopsy specimens / 中华病理学杂志

<p><b>OBJECTIVE</b>To observe and summarize the morphologic features that may suggest submucosal invasive adenocarcinoma in colorectal mucosa biopsy specimens.</p><p><b>METHODS</b>The study cohort included 432 colorectal biopsy specimens were obtained from 2006 to 2012. All the cases had radical surgery. Basing on the pathologic diagnoses, the cases were divided into 366 invasive adenocarcinoma (IAC) and 66 high-grade intraepithelial neoplasms (HGIN). These two groups were compared.</p><p><b>RESULTS</b>In the IAC group, the percentage of tumor forming cribriform structures, acute angle-shaped glands, diffuse carcinoma cell proliferation was 61.2% (224/366) , 33.8% (124/366) and 7.4% (27/366) , respectively. In the HGIN group, cribriform gland structures appeared in 6.0% (4/66) of the cases, while no acute angle-shaped gland or diffuse carcinoma cell proliferation was detected. The difference of these three characteristics in the two group was statistically significant (all P < 0.01). Glandular branching was detected in 89.9% (329/366) of IAC cases and 66.7% (44/66) of HGIN cases; this difference was not significant. There was no difference in cellular atypia between the two groups. Interstitial fibrosis was detected more frequently in the IAC group (85.5%, 313/366 in IAC versus 0 in HGIN, P < 0.01). In biopsy specimens of IAC, a few cases showed neoplastic glands in close contact with large lymphatics, adipose tissue, and ganglion.</p><p><b>CONCLUSIONS</b>In colorectal biopsy specimen, the five features that suggest submucosal invasion of the neoplastic glands including the formation of cribriform structure, angular gland, diffuse carcinoma cells, interstitial fibrosis and neoplastic glands in close contact with the thick-walled vessels.</p>

Effect of Mycophenolic Acid on the proliferation of pulmonary arterial smooth muscle cells in rats / 中华风湿病学杂志

Objective To investigate the effect of mycophenolic acid on the proliferation of smooth muscle cells (SMCs) in rats' pulmonary arterial at cellular level. Methods Growth curve, MTT tests, and flow cytometry were used to detect the number of proliferative cells, the A-value of living cells and the DNA content of the control and drugs groups respectively and the number of cells in G1-phase, S-phase, G2M- phase and the proliferation index were calculated. Results Compared with the control group, the number of living cells in the mycopbenolic acid groups (with the concentration of 1, 10, 100 μmol/L) decreased, except the lowest dosage group (100 nmol/L). The difference was statistically significant (P<0.01). The living cells measured by MTT dose-dependently reduced in the mycophenolic acid groups. In the mycophenolic acid groups, the fraction of living cells in the S-phase and G2M-phase decreased respectively while that in G1- phase increased, and the proliferation index decreased. All these responses presented with a dose-dependent manner. Conclusion Mycophenolic acid can effectively inhibit the proliferation of rats' pulmonary arterial SMCs. This process happens mainly in ONA synthesis phase, and is dose dependent. In addition, these effective concentrations are all in the available range for clinical application.