Indicator Of Lymph Node Metastasis Research Articles

Cytologic hallmarks and differential diagnosis of papillary thyroid carcinoma subtypes

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, characterized by a range of subtypes that differ in their cytologic features, clinical behavior, and prognosis. Accurate cytologic evaluation of PTC using fine-needle aspiration is essential but can be challenging due to the morphologic diversity among subtypes. This review focuses on the distinct cytologic characteristics of various PTC subtypes, including the classic type, follicular variant, tall cell, columnar cell, hobnail, diffuse sclerosing, Warthin-like, solid/trabecular, and oncocytic PTCs. Each subtype demonstrates unique nuclear features, architectural patterns, and background elements essential for diagnosis and differentiation from other thyroid lesions. Recognizing these distinct cytologic patterns is essential for identifying aggressive subtypes like tall cell, hobnail, and columnar cell PTCs, which have a higher risk of recurrence, metastasis, and poorer clinical outcomes. Additionally, rare subtypes such as diffuse sclerosing and Warthin-like PTCs present unique cytologic profiles that must be carefully interpreted to avoid diagnostic errors. The review also highlights the cytologic indicators of lymph node metastasis and high-grade features, such as differentiated high-grade thyroid carcinoma. The integration of molecular testing can further refine subtype diagnosis by identifying specific genetic mutations. A thorough understanding of these subtype-specific cytologic features and molecular profiles is vital for accurate diagnosis, risk stratification, and personalized management of PTC patients. Future improvements in diagnostic techniques and standardization are needed to enhance cytologic evaluation and clinical decision-making in thyroid cancer.

Vulvar Paget’s Disease with Inguinal Lymph Node Metastasis: A Case Report

Vulvar Paget's disease is a clinical condition with an invariable course affecting women of advanced age, and is associated with a significant rate of recurrence and dissemination, especially in its invasive form, which has a high metastatic potential. Here we present details of a unique case involving a 77-year-old woman with a history of disease progression over more than a decade. She initially presented with an erythematous lesion in the vulvar region, which was later diagnosed as adenocarcinoma in situ. During follow-up, the affected area extended to the perineal and gluteal regions, indicating an invasive aspect of the tumor. Due to surgical oncology recommendations, tissue resection was not feasible. The pacient experienced a significant worsening of symptoms, including local peeling of the affected region, and a biopsy confirmed Paget's disease in the vulvar region. Subsequently, imaging tests indicated changes in the volume of the inguinal lymph nodes. The patient underwent lymphadenectomy for histological analysis and to prevent systemic dissemination. Indicators of lymph node metastasis, suggestive of a gynecological primary site, were observed. Our case provides valuable insights for pathologists to consider the differential diagnosis of vulvar lesions.

Periarterial or perivenous invasion is an independent indicator of lymph node metastasis in invasive breast carcinoma of no special type

Pathological diagnosis of breast cancer often includes cases of lymph node metastases without lymphatic or lymphovascular invasion by the primary tumor. In this study, to resolve this discrepancy, we designed a sensitive method to detect lymphatic invasion and correlate it with lymph node metastasis. Elastica van Gieson (EVG) staining and D2–40 immunohistochemistry revealed the abundant distribution of lymphatic vessels around blood vessels in the mammary tissue in close proximity to the elastic fibers around the arteries and veins. Based on the histological location of the blood and lymphatic vessels, we hypothesized that, in breast cancer, perivascular invasion is similar to lymphatic invasion and correlates with the presence of lymph node metastasis. Using EVG staining, perivascular invasion was histologically classified into periarterial invasion (periA), perivenous invasion (periV), and periarterial or perivenous invasion (periA/V). We tested our method and compared it to other methods commonly used for identifying lymphatic invasion in 105 patients with invasive breast carcinoma of no special type (IBC-NST) who received minimal preoperative therapy. The correlation between perivascular invasion and lymph node metastasis in these patients was statistically analyzed, including findings related to lymphatic invasion, such as retractile artifacts and perineural invasion. PeriA, periV, and periA/V showed significant correlations with lymph node metastasis. PeriA/V had high sensitivity and negative predictive value. The odds ratio (OR) for periV was significantly high in the univariate analysis, while the ORs for periA/V, retraction artifacts, and perineural invasion were significantly high in both the univariate and multivariate analyses. In particular, periA/V revealed a strong correlation with lymph node metastasis (OR: 61.8). These findings indicate that the IBC-NST periA/V ratio is a sensitive pointer of lymphatic invasion and could be an independent and reliable indicator of lymph node metastasis.

Identification of PANoptosis-related biomarkers and analysis of prognostic values in head and neck squamous cell carcinoma

PANoptosis plays a crucial role in cancer initiation and progression. However, the roles of PANoptosis-related genes (PARGs) in the prognosis and immune landscape of head and neck squamous cell carcinoma (HNSCC) remain unclear. Integrated bioinformatics analyses based on the data of HNSCC patients in the TCGA database were conducted. We extracted 48 PARGs expression profile and then conducted differentially expressed analysis, following building a Cox model to predict the survival of HNSCC patients. Subsequently, the relationships between the risk score, immune landscape, chemo-, and immune-therapy responses were analyzed, respectively. Moreover, we investigated the prognostic value, and further predicted the pathways influenced by PARGs. Finally, we identified the biological function of crucial PARGs. A total of 18 differentially expressed PARGs were identified in HNSCC, and a Cox model including CASP8, FADD, NLRP1, TNF, and ZBP1 was constructed, which showed that the risk score was associated with the prognosis as well as immune infiltration of HNSCC patients, and the risk score could be regarded as an independent biomarker. Additionally, patients with high-risk score might be an indicator of lymph node metastasis and advanced clinical stage. High-risk scores also contributed to the chemotherapy resistance and immune escape of HNSCC patients. In addition, FADD and ZBP1 played a crucial role in various cancer-related pathways, such as the MAPK, WNT, and MTOR signaling pathways. On the other hand, we suggested that FADD facilitated the progression and 5-fluorouracil (5-FU) resistance of HNSCC cells. A signature based on PANoptosis showed great predictive power for lymph node metastasis and advanced stage, suggesting that the risk score might be an independent prognostic biomarker for HNSCC. Meanwhile, FADD, identified as a prognostic biomarker, may represent an effective therapeutic target for HNSCC.

Clinical Axillary Staging in Breast Cancer Patients Using Ultrasound Imaging

Introduction: The presence of axillary lymph node involvement is an important prognostic factor and has a major impact on treatment decisions in early breast cancer patients. This study aimed to determine the role of cortical thickness in axillary ultrasound (AUS) as an indicator of lymph node metastasis. Methods: 766 patients with primary breast cancer who received AUS during clinical work-up were selected for this retrospective study. Lymph nodes were defined as suspicious if they showed a cortical thickness of >3.0 mm at 11–15 MHz harmonic imaging ultrasound. Lymph node involvement was assessed by core needle biopsy (n = 150), sentinel node dissection or axillary dissection. Extensive axillary spread (EAS) was diagnosed if more than two lymph nodes showed metastatic disease in histology. Results: AUS for detecting all lymph node metastases had a sensitivity of 62.27%, a specificity of 93.15% and a negative predictive value of 81.74%. However, the resulting negative predictive value for transcapsular growth was 93.97%, and for EAS 97.52%. Conclusion: EAS – in contrast to non-palpable involvement of 1 or 2 lymph nodes – contributes relevantly to the individualization of breast cancer treatment. In combination with SNB, AUS using cortical thickness as the main distinctive parameter seems to be an easily available, robust tool of diagnosing extensive axillary metastases. If AUS proves negative, it helps to reduce the number of classic axillary dissections.

Tumor budding and tumor-infiltrating lymphocytes can predict prognosis in pT1b esophageal squamous cell carcinoma.

Tumor budding (TB) and tumor-infiltrating lymphocyte (TIL) are significant predictive indicators of lymph node metastasis (LNM) and unfavorable prognosis in various tumors. Currently, there is no gold standard for TB and TIL evaluation in esophageal squamous cell carcinoma (ESCC). This study aimed to identify the standard of TB and TIL evaluations and build a predictive model for prognosis among patients with pT1b ESCC. We retrospectively analyzed the prognostic values of TB and TIL in 150 pT1b ESCC cases. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) of anti-pan cytokeratin (AE1/AE3) were used to analyze the threshold of TB, and intratumoral TIL and peritumoral TIL (pTIL) were evaluated using the receiver operating characteristic curves (ROC). We found that TB in a three-tiered grading system (low-TB: 0-4; middle-TB: 5-15; high-TB: ≥16) displayed an excellent prognosis prediction for LNM and survival based on IHC staining using a 20× objective lens. Low pTIL level (≤20%) was a significant indicator of LNM and unfavorable prognosis (p < 0.05). Moreover, lower tumor location and lymphovascular invasion (LVI) were correlated with an unfavorable prognosis (p < 0.05). A nomogram developed based on TB, pTIL, LVI, and tumor location showed good discrimination, as shown by the area under the ROC and calibration curves. We therefore recommend identifying TB using a 20× objective lens under IHC staining and TIL adjacent to the tumor. Additionally, a nomogram was built for facilitating individualized prediction of survival for patients with pT1b ESCC.

TPO as an indicator of lymph node metastasis and recurrence in papillary thyroid carcinoma

The objective of this study was to investigate the expression of thyroid peroxidase (TPO) in papillary thyroid carcinoma (PTC) and to preliminarily investigate its value as a marker of lymph node metastasis and recurrence in patients with PTC. Clinical data of PTC patients and TPO expression were collected from The Cancer Genome Atlas (TCGA) database for analysis. We recruited 230 consecutive PTC patients from the Department of Thyroid Surgery of the First Affiliated Hospital of Kunming Medical University, collected their clinicopathological data, and also performed immunohistochemical analysis of TPO expression on their thyroid specimens to validate the results of bioinformatics analysis. In addition, the construction of protein–protein interaction networks was performed too. Functional enrichment analysis and immuno-infiltration analysis characterized the pathways in which TPO genes may be involved. Data mining based on the TCGA database showed that TPO expression in PTC tissues was significantly lower than in paired normal thyroid tissues. The expression level of TPO in PTC tissues correlated with tumor lymph node metastasis and recurrence. Follow-up data from our center also validated the difference in TPO expression and its relationship with lymph node metastasis in PTC patients. Functional enrichment analysis showed that TPO function was significantly associated with signaling pathways related to amino acid metabolism, gene expression regulation and tumorigenesis. TPO expression was also significantly associated with immune infiltration. Our study showed that reduced TPO expression was significantly associated with lymph node metastasis and recurrence in patients with PTC, and we validated this result in our central cohort. These data suggest that TPO may serve as a prognostic indicator for PTC.

Tumor budding as an indicator for lymph node metastasis and prognosis of early gastric cancer.

Tumor budding, considered as an independent risk factor reflecting prognosis of some malignant tumors, has been recognized as an important clinicopathological indicator of colorectal carcinoma. However, the evaluation of tumor budding and its clinicopathological significance in gastric cancer remain controversial. To investigate the relationship between tumor budding and clinical biological behavior of early gastric cancer (EGC) and assess the predictive value of tumor budding for lymph node metastasis as well as its impact on prognosis of EGC patients. Tissue specimens of 164 EGC patients who underwent radical gastrectomy between June 2011 and January 2017 from a single center were selected to carry out HE and CK staining respectively, so as to evaluate tumor budding under light microscopy. Clinicopathological data and follow-up results of all EGC patients were collected for statistical analysis among tumor budding, EGC clinicopathological factors and prognosis. Of all 164 EGC patients, there were 84 (51.2%) cases with mucosal invasion and 80 (48.8%) cases with submucosal invasion. Meanwhile, 32 cases (19.5%) had lymph node metastasis, 19 (11.6%) had lympho-vascular invasion and 4 (2.4%) had early recurrence. Tumor budding were observed in 90 (54.9%) patients, with low-grade budding 68 (41.5%) cases and high-grade budding 22 (13.4%) cases. Tumor budding was closely correlated with tumor size (c2 = 6.609, P = 0.037), tumor histologic differentiation (c2 = 10.522, P = 0.032), depth of invasion (c2 = 8.787, P = 0.012), lymph node metastasis (c2 = 24.226, P < 0.01), TNM stage (c2 = 24.226, P < 0.01), lympho-vascular invasion (c2 = 8.225, P = 0.016) and early recurrence (c2 = 6.462, P = 0.040). Additionally, tumor budding was correlated with postoperative survival rate as well. Multiple regression analysis revealed that tumor budding was an independent influencing factor of postoperative 3-year survival rate, 5-year survival rate, OS, DFS and DSS (P < 0.05). Furthermore, tumor budding was an independent risk factor of lymph node metastasis of EGC patients, and high-grade budding was a high-risk indicator of lymph node metastasis. Tumor budding is related to tumor size, tumor histologic differentiation, depth of invasion, lymph node metastasis, lympho-vascular invasion and early recurrence of EGC. Tumor budding, especially high-grade budding can serve as an indicator for predicting lymph node metastasis of EGC, and high-grade budding could be an important parameter for evaluating prognosis of EGC patients.

Potential diagnostic of lymph node metastasis and prognostic values of TM4SFs in papillary thyroid carcinoma patients.

Background: Although the prognosis of papillary thyroid carcinoma (PTC) is relatively good, it causes around 41,000 deaths per year, which is likely related to recurrence and metastasis. Lymph node metastasis (LNM) is an important indicator of PTC recurrence and transmembrane 4 superfamily (TM4SF) proteins regulate metastasis by modulating cell adhesion, migration, tissue differentiation, and tumor invasion. However, the diagnostic and prognostic values of TM4SF in PTC remain unclear. Methods: This study aimed to identify TM4SF genes with predictive value for LNM and prognostic value in PTC using bioinformatic analysis. We screened the differentially expressed genes (DEGs) of the TM4SF family in PTC using data from TCGA, constructed a PPI network using STRING, and evaluated the predictive role of TM4SF1 in LNM via a binary logistic regression analysis and ROC curve. We assessed the association between TM4SF1 expression and DNA methylation, and determined the functional and mechanistic role of TM4SF1 in promoting LNM via GSEA, KEGG, and GO. We estimated the relationship between each TM4SF gene and overall survival (OS, estimated by Kaplan-Meier analysis) in patients with PTC and established a predictive model of prognostic indicators using a LASSO penalized Cox analysis to identify hub genes. Finally, we explored the correlation between TM4SFs and TMB/MSI. Results: We identified 21 DEGs from the 41 TM4SFs between N0 (without LNM) and N1 (with LNM) patients, with TM4SF1, TM4SF4, UPK1B, and CD151 being highly expressed in the N1 group; several DEGs were observed in the TNM, T, and N cancer stages. The "integrins and other cell-surface receptors" pathway was the most significantly enriched functional category related to LNM and TM4SFs. TM4SF1 was identified as an indicator of LNM (AUC= 0.702). High levels of TM4SF1 might be related to Wnt/β-catenin pathway and epithelial-mesenchymal transition (EMT) process in PTC. The higher expression of TM4SF1 was also related to DNA promoter hypomethylation. CD9, TM4SF4, TSPAN2, and TSPAN16 were associated with OS in PTC patients and TSPAN2 has great potential to become a prognostic marker of PTC progression. For the prognostic model, the riskscore = (-0.0058)*CD82+(-0.4994)*+(0.1584)*TSPAN11+(1.7597)*TSPAN19+(0.2694)*TSPAN2 (lambda.min = 0.0149). The AUCs for 3-year, 5-year, and 10-year OS were 0.81, 0.851, and 0.804. TSPAN18, TSPAN31, and TSPAN32 were associated with both TMB and MSI in PTC patients. Conclusion: Our findings identified TM4SF1 as a potential diagnostic marker of LNM and TSPAN2 as a prognostic factor for patients with PTC. Our study provides a novel strategy to assess prognosis and predict effective treatments in PTC.

The clinicopathological and microrna expression signature associated with lymphovascular invasion in squamous cell carcinoma: A basic descriptive study.

Lymphovascular invasion (LVI) is an indicator of lymph node metastasis and poor prognosis in various cancers including squamous cell carcinoma (SCC). Despite being easily resectable and having little potential for LVI; SCC displays aggressive behavior and often results in the death of the patient. With this in mind, it may be useful to investigate the clinical, pathological, and microRNA expression profile associated with LVI in SCC. We evaluated the histological hallmarks associated with LVI from 16 formalin fixed paraffin embedded (FFPE) tissue samples (10 LVI-, 6 LVI+). We also quantified the expression of 10 microRNAs (hsa-miR-21-5p, hsa-miR-21-3p, hsa-miR-155-5p, hsa-miR-196a-5p, hsa-miR-375, hsa-let-7d-5p, hsa-miR-146b-3p, hsa-miR-221-5p, hsa-miR-205-5p, hsa-miR-491-5p), which have been previously identified to play a role in SCC development, using real time-PCR with the Qiagen miRCURY LNA SYBR Green PCR Kit. We observed a significant upregulation of microRNA-155, microRNA-196a, microRNA-375, and microRNA-221 in cases with lymphovascular invasion. Morphologically, we identified poor differentiation, dysplasia, loss of membrane polarity, high nuclear to cytoplasmic ratio, and the presence of squamous nests as defining features of LVI. Additionally, we found a gender bias and observed a tendency toward lymphatic invasion in lesions presenting around the perineal and abdominal regions. We speculate that this profile may have prognostic significance and could guide the clinician in their treatment protocols for patients matching our genetic, demographic, and morphologic profile.

Identification of miR-203a, mir-10a, and miR-194 as predictors for risk of lymphovascular invasion in head and neck cancers.

Lymphovascular invasion (LVI) is an important prognostic indicator of lymph node metastasis and disease aggressiveness but clear molecular mechanisms mediating this in head and neck cancers (HNSC) remain undefined. To identify important microRNAs (miRNAs) in HNSC that associate with and are also predictive of increased risk of LVI, we used a combination of clustering algorithms, multiple regression analyses and machine learning approaches and analyzed miRNA expression profiles in the TCGA HNSC database. As the first step, we identified miRNAs with increased association with LVI as a binary variable. In order to determine whether the identified miRNAs would show functional clusters that are also indicative of increased risk for LVI, we carried out unsupervised as well as supervised clustering. Our results identified distinct clusters of miRNAs that are predictive of increased LVI. We further refined these findings using a Random forest approach, and miR-203a-3p, mir-10a-5p, and miR-194-5p to be most strongly associated with LVI. Pathway enrichment analysis showed these miRNAs targeted genes involved in Hippo signaling and fatty acid oxidation pathways that are mediators of lymph node metastasis. Specific association was also identified between the miRNAs associated with LVI and expression of several lymphangiogenic genes that could be critical for determination of therapeutic strategies.

A study of the correlation between M2 macrophages and lymph node metastasis of colorectal carcinoma

BackgroundLymph node metastasis is a major prognostic sign of colorectal carcinoma and an important indicator for individualized treatment. M2 macrophages play a key role in carcinogenesis and tumor development by enhancing invasiveness and promoting lymph node metastasis. The purpose of this study was to investigate the effect of CD163-positive M2 macrophages on lymph node metastasis in colorectal carcinoma.MethodsPostoperative lymph node tissues were obtained from 120 patients with colorectal carcinoma who underwent radical surgery in the First Affiliated Hospital of Jinzhou Medical University between December 2019 and May 2020. We detected the expression of the CD163 protein in lymph nodes using immunohistochemistry. Furthermore, the relationships between M2 macrophages identified by expression of CD163 and lymph node metastasis were analyzed using the independent sample t-test and Chi-square test.ResultsM2 macrophages were increased in metastatic lymph nodes and non-metastatic lymph nodes adjacent to the cancer. The M2 macrophage count was higher in patients with macro-metastases than in patients with micro-metastases.ConclusionsThe presence of M2 macrophages represents an important indicator for lymph node metastasis in colorectal carcinoma and may be a potential marker for its prediction. Thus, M2 macrophage localization might offer a new target for the comprehensive treatment of colorectal carcinoma.

IGFBP3 as an indicator of lymph node metastasis and unfavorable prognosis for papillary thyroid carcinoma

Lymph node metastasis (LNM) is a usual event in papillary thyroid carcinoma (PTC) patients, which usually leads to poor prognosis. However, the molecular mechanisms of LNM remain unclear. Thus, we aimed to screen the possible key genes in the progression of LNM in PTC patients and further validate their roles. The study involved two phases: a discovery phase and a validation one. In the former phase, the candidate genes were screened by using bioinformatics methods. In the latter one, the genes were firstly assessed in a cohort from the cancer genome atlas (TCGA) to evaluate the associations of their expressions with clinical features and the prognostic values, and then, they were assessed at protein levels by using an immunohistochemical assay. Consequently, IGHBP3 was selected as the candidate gene, which might be enriched in several metabolism-related pathways and cancer progression-related pathways. High expressions of IGHBP3 have an association with gender, advanced clinical stages, high T stages, and the presence of LNM. Survival analysis indicated that IGHBP3 may affect the prognosis of PTC patients. The use of a tissue chip confirmed the view that IGHBP3 might play a crucial role in the LNM of PTC. In conclusion, IGHBP3 might be involved in the development of LNM in PTC patients. IGHBP3 over-expression might be a novel indicator and a potential target for PTC therapy.

Variant allele frequency of circulating tumor DNA mutations detected in preoperative blood is indicator for lymph node metastasis in early stage lung cancer.

e21057 Background: The advances in deep sequencing technologies makes circulating tumor DNA (ctDNA) detection in preoperative plasma a more and more significant indicator in early stage cancers. In particular, it allows us to learn a lot about tumor progression before surgery. Plasma variant allele frequency (VAF) of preoperative ctDNA mutations had been verified to correlate with tumor sizes in early lung cancers. Identification of lymph node (LN) metastasis status before surgery in patients with lung cancer is valuable for prognosis and treatment strategy decisions. To evaluate whether ctDNA predict the LN metastasis status, we conducted this analysis. Methods: Preoperative plasma and the matched leukocyte before treatment were collected from 38 early stage lung cancer patients, in which 8 cases with lymph node metastasis. 150-gene panel sequencing were performed on the specimens and the sequencing data were used as primary cohort. Multivariable logistic regression analysis was used to develop a prediction model based on the DNA and other clinical characteristics. The performance of the model was assessed by its calibration, discrimination and clinical usefulness in the public TRACERx 100 early lung cancers cohort. Results: The proportion of high variant allele frequency (HAF proportion) of mutations was significantly associated with LN status (p &lt; 0.05, for both primary and validation cohorts). A prediction model was developed and predictors included the HAF proportion, smoking status and tumor size. The C-index of the model was 0.419 in primary cohort. In external validation cohort, the AUCs for LN positive was 0.678. Conclusions: Based on pan-gene panel deep sequencing, a big proportion of high variant allele frequency mutations in a single patient indicates advanced disease progression, which may reflect in LN involvement status. A logistic regression model was constructed using ctDNA and clinical characteristics. It showed considerable performance in the prediction of LN metastasis in early lung cancers.

Plasma Exosomal miR-146b-5p and miR-222-3p are Potential Biomarkers for Lymph Node Metastasis in Papillary Thyroid Carcinomas.

BackgroundLymph node metastasis (LNM) is associated with increased risk of recurrence and poor prognosis in papillary thyroid cancer (PTC). Novel non-invasive biomarkers for the prediction of LNM in PTC patients are still urgently needed. In this study, the relationship between the expression of plasma exosomal microRNAs (miRNAs) and LNM was analyzed. Further, we aimed to explore if exosomal miRNAs can serve as indicators of LNM in PTC patients.MethodsA total of 64 PTC patients who underwent total thyroidectomy and neck dissection from June 2018 to July 2018 in West China Hospital were enrolled in this study. Plasma exosomes were isolated by exoRNeasy Serum/Plasma Maxi Kit. The levels of selected exosomal miRNAs were detected by real-time quantitative PCR (qRT-PCR). Cox proportional hazard analyses and receiver operating characteristic (ROC) curves were conducted to evaluate the predictive efficiency. Furthermore, PTC cell lines with transfection of miRNA mimics/inhibitors were used to verify the functions of exosomal miRNAs.Results49 PTC patients with LNM and 15 without LNM were included in the present study. Exosomal miR-146b-5p and miR-222-3p were both significantly upregulated in patients with LNM (P values were 0.008 and 0.015, respectively). ROC analyses revealed that the areas under the curves (AUCs) of miR-146b-5p and miR-222-3p for LNM prediction were 0.811 and 0.834, respectively. Moreover, the AUC increased to 0.895 when the two miRNAs used together. Wound healing assays and transwell assays showed that miR-146b-5p and miR-222-3p significantly enhanced the migration and invasion ability of PTC cells in vitro.ConclusionPlasma exosomal miR-146b-5p and miR-222-3p could serve as potential biomarkers for LNM in PTC.

AR-42: A Pan-HDAC Inhibitor with Antitumor and Antiangiogenic Activities in Esophageal Squamous Cell Carcinoma.

PurposeEsophageal squamous cell carcinoma (ESCC) is a refractory malignancy with high morbidity and mortality. Thus, there is an urgent need to find effective targets and agents for ESCC treatment. The purpose of this study was to assess the anti-ESCC effects of a pan-histone deacetylase (HDAC) inhibitor AR-42 and its mechanisms of action.MethodsImmunohistochemical staining was performed to detect HDAC1 expression in ESCC and adjacent tissue samples. MTT assay, Edu cell proliferation test, flow cytometry, and subcutaneous xenograft were used to assess the anti-ESCC effects of AR-42; furthermore, the antiangiogenic activity of AR-42 was evaluated using endothelial cell migration, invasion, and tube formation assays as well as zebrafish angiogenesis assay. Western blot analysis was performed to explore the underlying mechanism of the anti-ESCC activity of AR-42.ResultsHDAC1-positive expression was much higher in ESCC cells than in paracancerous tissues, and the elevated HDAC1 expression was a strong indicator of lymph node metastasis and a more advanced TNM stage of ESCC. Moreover, AR-42 potently suppressed ESCC cell growth through cellular proliferation inhibition and apoptosis induction. Moreover, AR-42 displayed a moderate antiangiogenic activity, and it could significantly inhibit the migration, invasion and tubulogenesis of human umbilical vein endothelial cells as well as intersegmental vessel formation in zebrafish at micromolar concentrations. More importantly, the inhibitory activity of AR-42 on ESCC cells and angiogenesis could also be observed in the TE-1 xenograft model. Further studies showed that AR-42 exerts its anti-ESCC effects mainly by upregulating the expression of p21 and blocking the transduction of multiple signaling cascades related to tumor growth, especially Stat3-mediated signaling.ConclusionOverall, AR-42 has significant potency for inhibiting ESCC cell growth and shows moderate effect in suppressing angiogenesis, displaying strong anti-ESCC effects in vitro and in vivo. Thus, AR-42 deserves further evaluation as a potential candidate for ESCC therapy.

Lymph Node Size on Computed Tomography Images Is a Predictive Indicator for Lymph Node Metastasis in Patients with Colorectal Neuroendocrine Tumors.

Colorectal neuroendocrine tumors (NET) are a rare manifestation of colorectal neoplasia, requiring for radical dissection of the regional lymph nodes along with colorectal resection similar to that required for colorectal cancer. However, thus far, no reports have described the ability of computed tomography (CT) to predict lymph node involvement. In this study, we revealed the prediction rate of lymph node metastasis using contrast-enhanced CT. A total of 21 patients with colorectal NET undergoing colorectal resection were recruited from January 2010 to June 2016. We compared the CT findings between samples with or without pathologically proven lymph node metastasis, in each field (pericolic/perirectal and intermediate nodes). Within the pericolic/perirectal field, any lymph node larger than 5 mm in the CT images was a predictive indicator of lymph node metastasis with a sensitivity, specificity, and area under ROC curve (AUC) of 66.7%, 87.5%, and 0.844, respectively. Within the intermediate field, any visible lymph node on the CT was a predictive indicator of lymph node metastasis with a sensitivity, specificity, and AUC of 100%, 76.4%, and 0.890, respectively. In addition, when we observed lymph nodes larger than 3 mm on the CT images, the sensitivity and specificity were 100% and 82.4%, respectively, with an AUC of 0.8971. CT images provide predictive information for lymph node metastasis with a high rate of accuracy.

Prognostic Value of P63, Maspin, and MMP-2 Expression in Salivary Gland Adenoid Cystic Carcinoma

Abstract Background: As one of the most malignant neoplasm of salivary glands, adenoid cystic carcinoma (ACC) displays epithelial and myoepithelial differentiation. The myoepithelial cells seem to act as tumor-suppressor via their secretory properties. Objectives: The present study was designed to evaluate the prognostic significance of p63 (myoepithelial cell marker), maspin, and MMP-2 expression in samples of ACC. Methods: P63, maspin, and MMP-2 expression were examined immunohistochemically in 32 cases with ACC. The relationship between markers expression and clinicopathologic data was assessed, using non-parametric tests and t test. Results: P63 and maspin expression demonstrated inverse significant correlation with histologic grade, respectively (P = 0.045, P = 0.019). Indeed, association between P63 and maspin expression was observed (r = 0.588, P < 0.001). Correlation between tumor size and lymph node metastasis was also found (P = 0.016). Conclusions: According to the correlation of P63 and maspin expression with histologic grade, as a prognostic determinant of ACC, P63 and maspin can be useful markers for predicting biologic behavior of ACC, whichmaylead tonewtreatment modality in salivary gland tumors containing myoepithelial cell. Furthermore, tumor size can be considered as an indicator of lymph node metastasis.

Span-1 and CA19-9 as Predictors of Early Recurrence and Lymph Node Metastasis for Patients with Invasive Pancreatic Cancer after Pancreatectomy

Because pancreatic cancer is a disease with a dismal prognosis due to the high rate of early recurrence even after curative surgery, selecting the most effective treatment in an individual requires preoperative assessment of the tumor characteristics, including the potential for early recurrence. The study cohort included 84 patients undergoing surgical resection of pancreatic cancer. Univariate and multivariate analyses were conducted to identify the risk factors for early recurrence within six months after curative resection. Early recurrence was associated with a platelet-lymphocyte ratio ≥0.23 (P = 0.04), carbohydrate antigen 19-9 (CA19-9) ≥200 (P = 0.01), and S-pancreas-1 antigen (Span-1) ≥37 (P = 0.0004) by univariate analysis. Multivariate analysis identified CA19-9 ≥200 and Span-1 ≥37 as independent risk factors for early recurrence. Patients with both risk factors had a significantly higher rate of lymph node metastasis than those with no or one risk factor. Span-1 ≥ 37 and CA19-9 ≥ 200 are independent risk factors for early recurrence in patients who underwent surgical resection, and the combination of Span-1 ≥37 and CA19-9 ≥200 is a useful indicator of lymph node metastasis.

MMP-2 together with MMP-9 overexpression correlated with lymph node metastasis and poor prognosis in early gastric carcinoma.

The aim of this study was to correlate matrix metalloproteinase-2 and matrix metalloproteinase-9 expression with the clinicopathological features and outcome of patients with early gastric cancer and to clinically elucidate more information on the role of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein overexpression with regard to lymph node metastasis of early gastric cancer. The levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein expression were assessed by immunohistochemistry. An association was observed between matrix metalloproteinase-2, matrix metalloproteinase-9, and matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression and clinicopathological factors, such as ulceration and lymph node metastasis. Furthermore, matrix metalloproteinase-9 and matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression both were strongly correlated with histological grade. In addition, matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression correlated with deep invasion. Multivariate Cox regression analysis revealed that matrix metalloproteinase-2 and matrix metalloproteinase-9 expression were both independent factors of overall survival in patients with early gastric cancer. In novelty, we found that matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression was an independent indicator of lymph node metastasis in early gastric cancer which will be helpful in clinic to select the appropriate treatment of these patients.