Pathological Differentiation Grade Research Articles

Rspo2-LGR4 exacerbates hepatocellular carcinoma progression via activation of Wnt/β-catenin signaling pathway

BackgroundThe leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) plays an important role in stem cell differentiation, organ development and cancer. Whether LGR4 affects the progression of hepatocellular carcinoma (HCC) remains unknown. This study aimed to reveal the role of LGR4 in HCC. MethodsClinical samples of HCC were collected to assess the expression of LGR4 and its correlation with patients’ clinical characteristics. The expression level of LGR4 in HCC cells was altered by pharmacological and genetic methods, and the role of LGR4 in HCC progression was analyzed by in vivo and in vitro assays. HCC was induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) in wild-type and LGR4 deficient mice, the effect of LGR4 on HCC was examined by histopathological evaluation and biochemical assays. ResultsLGR4 expression was up-regulated in HCC samples, and its expression level was positively correlated with tumor size, microvascular invasion (MVI), TNM stage and pathological differentiation grade of HCC patients. In the mouse HCC model induced by DEN+CCl4, knockdown of LGR4 effectively inhibited the progression of HCC. Silencing of LGR4 inhibited the proliferation, migration, invasion, stem cell-like properties and Warburg effect of HCC cells. These phenotypes were promoted by R-spondin2 (Rspo2), an endogenous ligand for LGR4. Rspo2 markedly increased the nuclear translocation of β-catenin, whereas IWR-1, an inhibitor of Wnt/β-catenin signaling, reversed its effect. Deficiency of LGR4 significantly reduced the nuclear translocation of β-catenin and the expression of its downstream target genes cyclinD1 and c-Myc. ConclusionsLGR4 promotes HCC progression via Wnt/β-catenin signaling pathway.

Depth of Invasion: Influence of the Latest TNM Classification on the Prognosis of Clinical Early Stages of Oral Tongue Squamous Cell Carcinoma and Its Association with Other Histological Risk Factors.

The American Joint Committee on Cancer (AJCC), in its 8th edition, introduces modifications to the previous TNM classification, incorporating tumour depth of invasion (DOI). The aim of this research is to analyse the prognosis (in terms of disease-free survival and overall survival) of clinical early stage (I and II) squamous cell carcinomas of the oral tongue according to the DOI levels established by the AJCC in its latest TNM classification to assess changes to the T category and global staging system and to evaluate the association between DOI and other histological risk factors. A retrospective longitudinal observational study of a series of cases was designed. All patients were treated with upfront surgery at our institution between 2010 and 2019. The variables of interest were defined and classified into four groups: demographic, clinical, histological and evolutive control. Univariate and multivariate analyses were carried out and survival functions were calculated using the Kaplan-Meier method. Statistical significance was established for p values below 0.05. Sixty-one patients were included. The average follow-up time was 47.42 months. Fifteen patients presented a loco-regional relapse (24.59%) and five developed distant disease (8.19%). Twelve patients died (19.67%). Statistically significant differences were observed, with respect to disease-free survival (p = 0.043), but not with respect to overall survival (p = 0.139). A total of 49.1% of the sample upstaged their T category and 29.5% underwent modifications of their global stage. The analysis of the relationship between DOI with other histological variables showed a significant association with the presence of pathological cervical nodes (p = 0.012), perineural invasion (p = 0.004) and tumour differentiation grade (p = 0.034). Multivariate analysis showed association between depth of invasion and perineural invasion. Depth of invasion is a histological risk factor in early clinical stages of oral tongue squamous cell carcinoma. Depth of invasion impacts negatively on patient prognosis, is capable per se of modifying the T category and the global tumour staging, and is associated with the presence of cervical metastatic disease, perineural invasion and tumoural differentiation grade.

Rspo2-LGR4 exacerbates hepatocellular carcinoma progression via activation of Wnt/β-catenin signaling pathway

BackgroundThe leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) plays an important role in stem cell differentiation, organ development and cancer. Whether LGR4 affects the progression of hepatocellular carcinoma (HCC) remains unknown. This study aimed to reveal the role of LGR4 in HCC. MethodsClinical samples of HCC were collected to assess the expression of LGR4 and its correlation with patients’ clinical characteristics. The expression level of LGR4 in HCC cells was altered by pharmacological and genetic methods, and the role of LGR4 in HCC progression was analyzed by in vivo and in vitro assays. HCC was induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) in wild-type and LGR4 deficient mice, the effect of LGR4 on HCC was examined by histopathological evaluation and biochemical assays. ResultsLGR4 expression was up-regulated in HCC samples, and its expression level was positively correlated with tumor size, microvascular invasion (MVI), TNM stage and pathological differentiation grade of HCC patients. In the mouse HCC model induced by DEN+CCl4, knockdown of LGR4 effectively inhibited the progression of HCC. Silencing of LGR4 inhibited the proliferation, migration, invasion, stem cell-like properties and Warburg effect of HCC cells. These phenotypes were promoted by R-spondin2 (Rspo2), an endogenous ligand for LGR4. Rspo2 markedly increased the nuclear translocation of β-catenin, whereas IWR-1, an inhibitor of Wnt/β-catenin signaling, reversed its effect. Deficiency of LGR4 significantly reduced the nuclear translocation of β-catenin and the expression of its downstream target genes cyclinD1 and c-Myc. ConclusionsLGR4 promotes HCC progression via Wnt/β-catenin signaling pathway.

Combination of neutrophil/lymphocyte ratio and albumin/bilirubin grade as a prognostic predictor for hepatocellular carcinoma patients undergoing curative hepatectomy

Background and aimPrognosis determination is essential for hepatocellular carcinoma (HCC) patient management and treatment planning. The current study aimed to evaluate the prognosis performance of NLR, ALBI, and the combination of NLR-ALBI in determining the overall survival (OS) of HCC patients under curative hepatectomy.Methods144 primary HCC patients with curative hepatectomy were recruited in the retrospective study. The clinicopathologic characteristics and OS were compared between stratified groups. The predictive performance of NLR, ALBI, and the combination of NLR-ALBI was explored by the area under the receiver operating characteristic curve (AUC). Univariate and multivariate analyses were used to determine the risk factors of OS.ResultsAUC determined NLR cutoff > 2.60 for predicting prognosis. The univariate analysis indicated pathological differentiation, tumor size, AFP, TNM stage, NLR score, and ALBI grade were significant indicators of OS. However, only TMN grade, AFP, NLR score, and NLR-ALBI score were identified as independent predictors of OS in the multivariable analysis. The AUC of NLR, ALBI and the combination of NLR-ALBI was 0.618(95%CI 0.56–0.710), 0.533 (95%CI 0.437–0.629), 0.679 (95%CI 0.592–0.767) respectively. Patients with higher NLR-ALBI scores presented worse outcomes than those with lower NLR-ALBI scores.ConclusionNLR is an independent prognostic factor of HCC and a reliable biomarker in predicting the OS of HCC patients. The combination of NLR-ALBI showed a better prognostic performance than using NLR or ALBI alone, implicating the effectiveness and feasibility of combining multiple risk factors for postoperative prognosis assessment.

Characterization of the GATA Transcription Factor Family and Exploration of Their Relevance to Immune Infiltration and Tumor Microenvironment in Pancreatic Cancer.

BackgroundPancreatic cancer (PC) presents a phenomenal disease burden worldwide. The GATA transcription factor family is associated with a variety of human malignancies. However, the relation between GATA family members (GATAs) and PC has not been elucidated.MethodsThis study integrates large-scale bioinformatics database resources to analyze the expression patterns of GATAs in PC patients and explore their underlying function mechanism and relevance to immune infiltration and other different cell types in the tumor microenvironment in pancreatic cancer. First, the expression pattern of GATAs in pancreatic cancer was detected by the Oncomine database and the Gene Expression Profile Interaction Analysis (GEPIA2) database and verified through other datasets in the R2 platform. Then, we used the cBioPortal database and the Human Protein Atlas to assess the correlation between GATAs and clinicopathological features of PC. Then, survival analyses were performed to identify candidate prognostic factors in the GATA family in PC patients. Further, we performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction (PPI) network, immune-infiltration correlation analysis, and cell type analysis of the tumor microenvironment at the single-cell level to explain the function of GATAs in pancreatic cancer.ResultsWe found that GATA3 and GATA6 were highly expressed in pancreatic cancer, and the expression levels of GATA4 and GATA6 correlated with the pathological stage, differentiation grade, and molecular subtype of pancreatic cancer. The survival analysis revealed that lower GATA4 of PC patients was associated with better outcomes, and higher GATA6 might be associated with longer OS. In addition, GATA3 was associated with immune cell infiltration of PC, and GATA6 was mainly distributed in the epithelial cells with ductal phenotype.ConclusionThis work tentatively identified GATA3, GATA4, and GATA6 in the GATA family associated with pancreatic cancer. GATA4 may serve as a prognostic factor for PC patients, and GATA6 may act as a subtype marker for PC. In addition, GATA3 may reflect the immune-infiltration status of PC.

Clinical Characteristics and Prognosis of Patients With Pulmonary Mucoepidermoid Carcinoma: A SEER-Based Analysis.

BackgroundPrimary pulmonary mucoepidermoid carcinoma (PMEC) is an extremely rare malignancy. Its clinical characteristics and prognosis are not fully understood. This study evaluated clinical characteristics and prognostic factors of PMEC and established a nomogram to predict its 1-, 3-, 5- and 10-year cancer-specific survival (CSS) rates.MethodsIn the Surveillance, Epidemiology, and End Results database from January 1, 2016 to December 31, 2016, patients pathologically diagnosed with PMEC were identified. Kaplan–Meier analysis and Cox regression were performed to evaluate the CSS stratified by different covariates. A predictive nomogram model was built and validated by the concordance index (C-index) and calibration curves.ResultsA total of 585 PMEC patients were identified. A total of 408 (70%) of patients were placed into the training cohort, and 177 (30%) patients were placed into the validation cohort. The 5- and 10-year CSS rates of stage I–II PMEC patients were 91.4 and 88.9, respectively. The 1-, 3- and 5-year CSS rates of stage III–IV PMEC were 56.5, 39.45, and 32.1%, respectively. Survival curves showed that older age, large tumor size, poor differentiation, and high TNM stage were associated with a significantly worse prognosis. CSS outcomes were significantly better in patients who received surgical treatments (surgical alone, surgery plus radiation and/or chemotherapy). Patients who received radiation and/or chemotherapy had the worst prognosis. Multivariate Cox results revealed that covariates, including age, tumor laterality, tumor sizes, pathological differentiation, lymph node metastasis, distant metastasis, TNM stage and therapy, were independent prognostic factors for PMEC. These factors were used to construct a nomogram. The C-index of the nomogram was 0.921. The calibration curve presented favorable consistency between the predicted CSS and actual observations. This nomogram was validated by the validation cohort. The C-index of the validation cohort was 0.968.ConclusionAge, bilateral tumors, tumor size, pathological differentiation grade, lymph node metastasis, distant metastasis, TNM stage and therapy were independent prognostic factors of PMEC patients. The first nomogram for predicting the CSS of PMEC was built and validated, showing its potential value in practice.

Preoperative prediction of pathological grade in pancreatic ductal adenocarcinoma based on 18F-FDG PET/CT radiomics

PurposeTo develop and validate a machine learning model based on radiomic features derived from 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) images to preoperatively predict the pathological grade in patients with pancreatic ductal adenocarcinoma (PDAC).MethodsA total of 149 patients (83 men, 66 women, mean age 61 years old) with pathologically proven PDAC and a preoperative 18F-FDG PET/CT scan between May 2009 and January 2016 were included in this retrospective study. The cohort of patients was divided into two separate groups for the training (99 patients) and validation (50 patients) in chronological order. Radiomics features were extracted from PET/CT images using Pyradiomics implemented in Python, and the XGBoost algorithm was used to build a prediction model. Conventional PET parameters, including standardized uptake value, metabolic tumor volume, and total lesion glycolysis, were also measured. The quality of the proposed model was appraised by means of receiver operating characteristics (ROC) and areas under the ROC curve (AUC).ResultsThe prediction model based on a twelve-feature-combined radiomics signature could stratify PDAC patients into grade 1 and grade 2/3 groups with AUC of 0.994 in the training set and 0.921 in the validation set.ConclusionThe model developed is capable of predicting pathological differentiation grade of PDAC based on preoperative 18F-FDG PET/CT radiomics features.

Comparison of risk factors between colon cancer and rectum cancer in a single medical center hospital, Taiwan

IntroductionColorectal cancer (CRC) is rapidly increasing in developed countries. In Taiwan, the incidence rate of CRC has increased during the past decade, but the 5-year survival has remained at approximately 63%. In this study, we sought to determine the 5-year survival rate of patients diagnosed with colon and rectum cancer and to determine factors affecting survival.Material and methodsAll patients from the Taiwan Cancer Database of the medical center hospital in North Taiwan between 2007 and 2013 were identified. Survival analysis was performed using Kaplan-Meier curves, and differences between the curves were analyzed using the log-rank test. Cox proportional hazards regression models were used to analyze survival by each variable.ResultsA total of 869 patients were included: 554 (63.8%) patients had colon cancer and 315 (36.2%) had rectum cancer. The mean survival time was 71.27 ±1.27 months (colon group: 71.90 ±1.58 months; rectum group: 67.88 ±1.95 months). There was no significant difference (p = 0.493) between patients who had colon or rectum cancer. The forward stepwise Cox regression analysis results indicated that perineural invasion, distant metastasis, age, pathological differentiation grade, and obstruction were statistically significant for patients who had CRC, colon cancer or rectum cancer.ConclusionsThe long-term survival from CRC, colon cancer and rectum cancer remains promising, as 68.66%, 69.11% and 67.90% of patients are alive 5 years after being diagnosed, respectively. Perineural invasion was found to be an important factor related to the survival of patients who have CRC. Thus, early detection of CRC may help improve survival.

FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition via Akt signaling in hepatocellular carcinoma.

Fam134b (JK‐1, RETREG1) was first identified as an oncogene in esophageal squamous cell carcinoma. However, the roles of FAM134B during tumorigenesis of hepatocellular carcinoma (HCC) and in epithelial‐to‐mesenchymal transition (EMT) were previously unclear. In this study, we investigated the function of FAM134B in HCC and the related tumorigenesis mechanisms, as well as how FAM134B induces EMT. We detected the expression of FAM134B in a normal hepatic cell line, HCC cell lines, fresh specimens, and a HCC tissue microarray. A retrospective study of 122 paired HCC tissue microarrays was used to analyze the correlation between FAM134B and clinical features. Gain‐ and loss‐of‐function experiments, rescue experiments, Akt pathway activator/inhibitors, nude mice xenograft models, and nude mice lung metastasis models were used to determine the underlying mechanisms of FAM134B in inducing tumorigenesis and EMT in vitro and in vivo. The expression level of FAM134B was highly elevated in HCC, as compared with that in normal liver tissues and normal hepatic cells. Overexpression of FAM134B was significantly associated with tumor size (P = 0.025), pathological vascular invasion (P = 0.026), differentiation grade (P = 0.023), cancer recurrence (P = 0.044), and portal vein tumor thrombus (P = 0.036) in HCC. Patients with high expression of FAM134B had shorter overall survival and disease‐free survival than patients with non‐high expression of FAM134B. Furthermore, knockdown of FAM134B with shRNAs inhibited cell growth and motility, as well as tumor formation and metastasis in nude mice, all of which were promoted by overexpression of FAM134B. Our study demonstrated that Fam134b is an oncogene that plays a crucial role in HCC via the Akt signaling pathway with subsequent glycogen synthase kinase‐3β phosphorylation, accumulation of β‐catenin, and stabilization of Snail, which promotes tumorigenesis, EMT, and tumor metastasis in HCC.

ANXA1 affects cell proliferation, invasion and epithelial-mesenchymal transition of oral squamous cell carcinoma.

Annexin A1 (ANXA1) acts either as a tumor suppressor or an oncogene in different tumor types. Several clinical studies revealed that the expression of ANXA1 is associated with the pathologic differentiation grade in oral squamous cell carcinoma (OSCC) patients. However, the direct function of ANXA1 in OSCC progression has remained to be fully clarified. The present study was designed to investigate the role of ANXA1 in OSCC cell proliferation and invasion in vitro. Furthermore, whether ANXA1 was involved in transforming growth factor β1 (TGFβ1)/epidermal growth factor (EGF)-induced epithelial-mesenchymal transition (EMT) in OSCC was explored. Tca-8113 and SCC-9 cells were transfected with ANXA1-pcDNA3.1 plasmid to overexpress ANXA1. Subsequently, cell proliferation and invasion were examined using MTT and Transwell-Matrigel invasion assays. TGFβ1 and EGF were used to induce EMT in Tca-8113 and SCC-9 cells, and the expression of epithelial (E)-cadherin, neural (N)-cadherin and vimentin was determined by western blot analysis. The results demonstrated that ANXA1 overexpression induced a significant decrease of cell growth and invasiveness in Tca-8113 and SCC-9 cells. The expression of E-cadherin was significantly increased, while the expression of vimentin and N-cadherin was significantly decreased in ANXA1-overexpressing Tca-8113 and SCC-9 cells. ANXA1 expression was significantly decreased in TGFβ1/EGF-treated cells. Furthermore TGFβ1/EGF-induced EMT in OSCC cell lines was attenuated by ANXA1 overexpression. In conclusion, to the best of our knowledge, the present study was the first to evidence that ANXA1 inhibits OSCC cell proliferation and invasion in vitro. TGFβ1/EGF-induced EMT was reversed by ANXA1 in OSCC. ANXA1 was suggested to be a potential marker for OSCC as well as a novel treatment.

Repression of GPRC5A is associated with activated STAT3, which contributes to tumor progression of head and neck squamous cell carcinoma

BackgroundG protein–coupled receptor family C group 5 member A (GPRC5A), a retinoic acid-inducible gene, is a lung tumor suppressor. Previously, we showed that repression of GPRC5A expression was associated with pathologic differentiation grade of oral squamous cell carcinomas (OSCC) and overexpression of GPRC5A gene inhibited the malignant phenotype in OSCC cells, suggesting that GPRC5A also functions as a tumor suppressor in oral cancer. However, the molecular mechanisms underlying GPRC5A deficiency in head and neck squamous cell carcinoma (HNSCC) are still unclear.MethodsIn this study, we used Western blot analysis and immunohistochemical (IHC) staining to investigate the expression of GPRC5A in both HNSCC cell lines and clinical samples. GPRC5A stable transfectants and their parental HNSCC cells were characterized for their biological activities in anchorage-independent growth.ResultsIHC analysis showed that, GPRC5A expression was high in normal tissue, but gradually decreased in oral leukoplakia, a precancerous stage, and greatly suppressed in primary cancer. Repression of GPRC5A was correlated with activated STAT3, which associates with aggressive clinicopathological features in HNSCC patients. Moreover, overexpression of GPRC5A suppressed IL-6-induced-STAT3 activation and inhibited anchorage-independent growth in HNSCC cells.ConclusionsRepressed GPRC5A associates with increased tumor grade and activated STAT3, which may be used as a prognostic marker for tumor progression of HNSCC.

Immunoexpression of cytokeratin-19 in the oral lichen planus and related oral squamous cell carcinoma

Cytokeratin 19 (CK-19) is an epithelium-specific intermediate filament protein that has been investigated in oral lichen planus (OLP) lesions but has not been compared with the expression of CK-19 in the OLP-related oral squamous cell carcinoma (OSCC). The aim of the present study has been to objectively compare the immunohistochemical expression of the CK-19 in OLP lesions and subsequent OSCC lesions that developed over time, to evaluate the change of the staining pattern among OLP and the grades of differentiation in OSCC. Thirty-six formalin-fixed tissues of 18 OLP patients (18 samples from OLP lesion and 18 samples from OLP-related OSCC lesion) were included. The monoclonal antibody for CK-19 was used at 1:100 dilution for the immuno-staining on 4-μm thick sections. Staining pattern of CK-19 was graded into a 4-point scale: (1) no staining, (2) only few cells staining, (3) less than 50% of the cells stained, and (4) 50% or more of the cells stained. Microslides were examined under the light microscope using objective lenses magnifications of 4×, 10×, and 20×. The CK19 positive rate in OLP tissues was 33% (6 out of 18) and 56% (10 out of 18) in OSCC tissues. The CK19 positive score in OSCC tissues was significantly higher than that in the corresponding OLP tissues (Mann-Whitney test, P=0.02). Well-differentiated OSCC showed significantly lower of C-K19 scores than those moderately differentiated grades (Mann-Whitney, P=0.007). The quantity and distribution of CK-19 staining in OSCCs showed relevant difference in comparison with OLP lesions. The increased of CK19 protein expression in OSCC tissues correlates significantly with the pathologic differentiation grade.

Driven Gene in Patients with Lung Squamous Cell Carcinoma: Analysis of Clinicopathologic Characteristics and Prognosis

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）、间变淋巴瘤激酶（anaplastic lymphoma kinase, ALK）以及KRAS基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）常见的驱动基因。多项临床研究已证实，EGFR敏感突变及棘皮动物微管相关类蛋白4-间变淋巴瘤激酶（echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase, EML4-ALK）基因重排的晚期肺腺癌患者，一线治疗选择靶向药物优于化疗，其在总缓解率（overall response rate, ORR）、无进展生存期（progression-free survival, PFS）及生活质量方面均有明显优势。然而，在肺鳞癌患者中，目前尚无明确的基因检测位点及靶向药物来指导临床治疗。本研究旨在分析肺鳞癌患者EGFR、ALK以及KRAS基因的突变状态，以及相关的临床病理特征，从而为今后的治疗提供相应指导。方法回顾性分析已行相关驱动基因检测的肺鳞癌患者90例，利用突变扩增阻滞系统（amplification refractory mutation system, ARMS）的方法进行EGFR及KRAS基因检测，荧光原位杂交（fluorescence in situ hybridization, FISH）技术进行ALK基因融合检测。结果90例患者均进行了EGFR及KRAS基因检测，8例患者为EGFR基因突变（8.8%）；2例患者为KRAS基因突变（2.2%）；18例患者通过FISH方法进行了ALK基因融合检测，1例患者存在EML4-ALK基因融合（5.6%）。女性患者的EGFR基因突变率高于男性（P=0.022）。EGFR突变及野生型患者在病理分期（P=0.042）及分化程度（P=0.003）上均有差异。以胸膜为首发转移部位的EGFR突变患者比率高于EGFR野生型患者（P=0.013）。靶向治疗与化疗对EGFR突变患者的PFS无影响（P=0.607）。结论ALK基因融合患者应用靶向治疗后可获得理想疗效。

Breast cancer and thyroid diseases: analysis of 867 consecutive cases.

The aim of this study was to evaluate the association of breast cancer with thyroid diseases. Many authors have already studied the possible relationship between these two diseases, but the results are nowadays conflicting. Our study examining 867 patients with breast cancer (862 women and 5 men, average age=61years old) of whom 141 also had thyroid disease evaluated the recurrence of thyroid diseases and their association with different types of breast cancer. Statistical analyses were performed using SPSS software for Windows; we used nonparametric tests (Chi-square and Mann-Whitney), and the level of significance was set at p<0.05. We found a significant association between breast cancer diagnosed after menopause and thyroid disease (p<0.003). Moreover, we analyzed the role of thyroid autoimmunity identifying an association between chronic autoimmune thyroiditis and breast cancer diagnosed before menopause (p<0.05). Regarding receptor profile of breast carcinoma, we have found an increased expression of estrogen receptors in patients with autoimmune thyroiditis compared to patients with any other thyroid diseases (p<0.03). Contrariwise, we do not have found any difference between the group with every thyroid disease and the group without thyroid disease (p<1.00). We did not find other statistically significant associations with breast cancer's parameters like family history, tumor size, lymph node metastasis, distant metastasis, cancer clinical and pathological stage, differentiation grade and expression of Ki67, p53 and Her2 in the two main groups with or without thyroid disease. Likewise, we did not found other statistically significant association between hypothyroidism or hyperthyroidism and breast cancer.

Differentiation grade for extrahepatic bile duct adenocarcinoma: Assessed by diffusion-weighted imaging at 3.0-T MR

Purpose—To assess the pathological differentiation grade in the patients with extrahepatic bile duct adenocarcinoma (EBDA) using diffusion-weighted imaging (DWI) at 3.0-T MR. Methods—Sixty-eight patients who were clinically and histologically diagnosed with EBDA underwent abdominal DWI within 2 weeks before surgery. The lesion signal intensity, signal intensity ratio of the lesion and hepar (SIR-LH) value, and apparent diffusion coefficient (ADC) value in patients with EBDA were retrospectively analysed. Results—In the 68 patients, 22 well-differentiated, 36 moderately-differentiated, and 10 poorly-differentiated EBDAs were histopathological confirmed. These EBDAs exhibited hyper-intensity on DWI in 95.59% of patients. Hyper-intensity lesions were found in 90.91% of patients with good-differentiation, in 97.22% with moderate-differentiation and in 100% with poor-differentiation. There showed no statistical difference for the lesion signal intensity (P=0.426) and SIR-LH value (P=0.766) on DWI among three groups. The median ADC value of the well-differentiated, moderately-differentiated and poorly-differentiated EBDAs were 1.506×10−3mm2/s, 1.275×10−3mm2/s and 1.154×10−3mm2/s, respectively. As the pathological differentiation grade decreased, the lesion ADC value of EBDA gradually declined (x2=51.220, P=0.000). The ADC value <1.184×10−3mm2/s can predict the poorly-differentiated EBDA with a sensitivity of 100% and a specificity of 94.83%. The ADC value >1.316×10−3mm2/s can forecast the well-differentiated EBDA with a sensitivity of 100% and a specificity of 84.78%. Conclusions—The histopathological differentiation grade of EBDA can be detected non-invasively using DWI at 3.0-T MR.

Oxidored-nitro domain-containing protein 1 expression is associated with the progression of hepatocellular carcinoma.

Hepatocarcinogenesis is a stepwise process during which multiple genes are altered. Understanding the molecular mechanisms that induce hepatocarcinogenesis may improve the screening, prevention and treatment of patients with hepatocellular carcinoma (HCC). In recent years, the oxidored-nitro domain-containing protein 1 (NOR1) gene has been identified to have an important role in the development of HCC in vitro experiments. The current study aimed to examine the expression of NOR1 mRNA and protein expression in specimens of normal liver, hepatitis, cirrhosis and HCC, together representing the process of HCC development. Furthermore, the association between NOR1 expression and clinicopathological parameters of HCC patients was analyzed. Tissue microarrays containing the specimens of human normal liver, hepatitis, cirrhosis and HCC were purchased, and in situ hybridization and immunohistochemistry were used to detect the expression of NOR1 mRNA and protein expression, respectively. It was revealed that the positive rate of NOR1 protein and mRNA expression in the specimens of hepatitis and cirrhosis were not significantly different from that in the normal liver samples. However, the specimens of HCC exhibited an increased positive rate of NOR1 protein and mRNA expression in comparison with the normal liver samples. In addition, a higher positive rate of NOR1 protein expression was observed in HCC patients with a poor pathological differentiation grade and high tumor node metastasis (TNM) stage. In conclusion, the present study provides evidence, for the first time, of the increased expression of NOR1 in human HCC tissues, and its correlation with the pathological stage and TNM status. These findings indicate that NOR1 may be involved in the progression of HCC and it could be employed as a predictive biomarker in HCC development.

Factors Influencing the Diagnostic Accuracy of Identifying the Histologic Type of Non–Small-Lung Cancer With Small Samples

BackgroundThe pathologic diagnosis has become a greater consideration in decision-making regarding the treatment options for lung cancer. Therefore, the accurate diagnosis of the tumor histologic type is essential, even when only small biopsy or cytology samples are available. However, the risk of a misdiagnosis with smaller biopsy samples is greater. The factors underlying the increased risk of a misdiagnosis in small samples are unknown. The aim of the present study was to identify the clinical and pathologic factors (other than immunohistochemical staining) that influence the pathologic diagnostic accuracy in small biopsy and cytological lung samples obtained by bronchoscopy. Patients and MethodsWe performed transbronchial lung biopsy or brushing and lavage to determine the preoperative diagnosis of 126 of 299 surgically resected lung cancer specimens. We assessed the diagnostic accuracy of the preoperative transbronchoscopic examination findings against that of the surgically resected lung specimens. ResultsOn univariate analysis, the mean pathologic tumor size in the noncorresponding cases was larger than that in corresponding cases. Vascular invasion was also more prevalent in the noncorresponding cases. The tumor differentiation grade in the noncorresponding cases was poorer than in the corresponding cases. The noncorresponding cases were at a more progressed stage. On multivariate analysis, the pathologic tumor size and tumor differentiation grade were associated with the noncorresponding cases. ConclusionWe found a larger tumor size and poor differentiation grade were indicative of lung cancer tissue with a greater content of heterogeneous cells. Therefore, a possibility exists of a false diagnosis using only these factors. Thus, treatment decisions should be made considering the pathologic diagnosis and other relevant factors.

Assessment of Tumor Grade and Angiogenesis in Colorectal Cancer: Whole-volume Perfusion CT

The preoperative evaluation of tumor grading and angiogenesis has important clinical implications in the treatment and prognosis of patients with colorectal cancers (CRCs). The aim of the present study was to assess tumor perfusion with 256-slice computed tomography (CT) using whole-volume perfusion technology before surgery, and to investigate the differences in the perfusion parameters among tumor grades and the correlation between perfusion parameters and pathologic results in CRC. Thirty-seven patients with CRC confirmed by endoscopic pathology underwent whole-volume perfusion CT assessments with a 256-slice CT and surgery. Quantitative values for blood flow, blood volume, and time to peak were determined using commercial software. After surgery, resected specimens were analyzed immunohistochemically with CD105 antibodies for the quantification of microvessel density (MVD). The difference in CT perfusion parameters and MVD among different tumor differentiation grades was evaluated by the Student-Newman-Keuls test. The correlations between CT perfusion parameters and MVD were evaluated using the Pearson correlation analysis. The mean blood flow was significantly different among well, moderately, and poorly differentiated groups (61.17 ± 17.97, 34.80 ± 13.06, and 22.24 ± 9.31 mL/minute/100 g, respectively; P < .05). The blood volume in the well-differentiated group was significantly higher than that in the moderately differentiated group (33.96 ± 24.81 vs. 16.93 ± 5.73 mL/100 g; P = .002) and that in the poorly differentiated group (33.96 ± 24.81 vs. 18.05 ± 6.01 mL/100 g; P = .009). The time to peak in the poorly differentiated group was significantly longer than that in the well-differentiated group (27.81 ± 11.95 vs. 17.60 ± 8.53 seconds; P = .016) and that in the moderately differentiated group (27.81 ± 11.95 vs. 18.94 ± 7.47 seconds; P = .028). There was no significant difference in the MVD among well, moderately, and poorly differentiated groups (33.47 ± 14.69, 28.89 ± 11.82, and 29.89 ± 11.02, respectively; P > .05). There was no significant correlation between CT perfusion parameters and MVD (r = 0.201, 0.295, and -0.178, respectively; P = .233, .076, and .292, respectively). CT whole-volume perfusion technology has the potential to evaluate pathologic differentiation grade of CRC before surgery. However, preoperative perfusion CT parameters do not reflect the MVD of CRC.

Low Annexin A1 expression is predictive for a benefit from induction chemotherapy in oral cancer patients with moderately/poorly pathologic differentiation grade

Background: The benefits of induction chemotherapy in oral squamous cell carcinoma (OSCC) remain to be clearly defined, as trials to date have not shown a major survival benefit when induction chemotherapy plus standard therapy is compared with standard therapy alone. Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients and biomarker development might lead to identification of the patients whose tumors are to respond to a particular treatment. This study investigated the prognostic and predictive values of evaluating Annexin A1 expression in OSCC patients who were treated in a randomized trial comparing surgery and post-operative radiotherapy with induction chemotherapy of docetaxel, cisplatin and 5-fluorouracil (TPF) followed by surgery and post-operative radiotherapy.

Low Annexin A1 expression predicts benefit from induction chemotherapy in oral cancer patients with moderate or poor pathologic differentiation grade

BackgroundThe benefit of induction chemotherapy in locally advanced oral squamous cell carcinoma (OSCC) remains to be clearly defined. Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients and biomarker development might lead to identification of the patients whose tumors are to respond to a particular treatment. Annexin A1 may serve as a biomarker for responsiveness to induction chemotherapy. The aim of this study was to investigate Annexin A1 expression in pre-treatment biopsies from a cohort of OSCC patients treated with surgery and post-operative radiotherapy or docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by surgery and post-operative radiotherapy. Furthermore we sought to assess the utility of Annexin A1 as a prognostic or predictive biomarker.MethodsImmunohistochemical staining for Annexin A1 was performed in pre-treatment biopsies from 232 of 256 clinical stage III/IVA OSCC patients. Annexin A1 index was estimated as the proportion of tumor cells (low and high, <50% and ≥50% of stained cells, respectively) to Annexin A1 cellular membrane and cytoplasm staining.ResultsThere was a significant correlation between Annexin A1 expression and pathologic differentiation grade (P=0.015) in OSCC patients. The proportion of patients with low Annexin A1 expression was significantly higher amongst those with moderate/poorly differentiated tumor (78/167) compared to those with well differentiated tumor (18/65). Multivariate Cox model analysis showed clinical stage (P=0.001) and Annexin A1 expression (P=0.038) as independent prognostic risk factors. Furthermore, a low Annexin A1 expression level was predictive of longer disease-free survival (P=0.036, HR=0.620) and locoregional recurrence-free survival (P=0.031, HR=0.607) compared to high Annexin A1 expression. Patients with moderate/poorly differentiated tumor and low Annexin A1 expression benefited from TPF induction chemotherapy as measured by distant metastasis-free survival (P=0.048, HR=0.373) as well as overall survival (P=0.078, HR=0.410).ConclusionsAnnexin A1 can be used as a prognostic biomarker for OSCC. Patients with moderate/poorly differentiated OSCC and low Annexin A1 expression can benefit from the addition of TPF induction chemotherapy to surgery and post-operative radiotherapy. Annexin A1 expression can potentially be used as a predictive biomarker to select OSCC patients with moderate/poorly differentiated tumor who may benefit from TPF induction chemotherapy.