Carcinoma-related Death Research Articles

A novel therapy to combat non-small cell lung carcinoma (A549) using platinum (IV) and barium titanate conjugate

Lung cancer is the most commonly diagnosed and leading cause of carcinoma related death in the world. Platinum based chemotherapy through cisplatin is one of the most common drug of choice to the control of disease progression and survival of the non small cell lung carcinoma patients. But cases of drug resistance and harmful side effects of cisplatin treatment motivated us to develop a platinum-based nanoformulation with improved bio-distribution and minimum toxicity. A cisplatin prodrug [Pt(IV) prodrug] was conjugated to functionalized hydrothermally synthesized barium titanate nanoparticles (BTNPs) through coupling reaction to form a novel barium titanate and platinum(IV) prodrug conjugate i.e., BT-Pt(IV) conjugate. In the present study, BTNPs, Pt(IV) prodrug, and BT-Pt(IV)conjugate were characterized by elemental analysis. In vitro assay of cellular uptake and cytotoxicity against non-small cell lung carcinoma (A549) cell line and noncancerous HEK293 cells were evaluated. BT-Pt(IV) conjugate demonstrated greater and sustained antiproliferative activity in a dose and time-dependent manner compared to cisplatin in A549 cells. The IC50 value of BT-Pt (IV) conjugate was estimated to be 5.42 μg/mL which was significantly less (almost 50%) than cisplatin (12.04 μg/mL). The in vitro mechanistic studies revealed that the BT-Pt(IV) conjugate increased the intracellular basal reactive oxygen species levels, which have led to the death of non-small cell lung carcinoma. However, HEK293 cells could escape the anti-proliferative capacity of the new drug conjugate. BaTiO3 has been chosen for its effectiveness as a biocompatible uptake enhancer of drugs. The current study has explored the therapeutic efficacy of a novel nanoformulation based on a clinically approved platinum-based anti-cancer agent with less toxicity and more bioavailability.

A prognostic index model for assessing the prognosis of ccRCC patients by using the mRNA expression profiles of AIF1L, SERPINC1 and CES1

Background: Kidney carcinoma is a major cause of carcinoma-related death, with the prognosis for advanced or metastatic renal cell carcinoma still very poor. The aim of this study was to investigate feasible prognostic biomarkers that can be used to construct a prognostic index model for clear cell renal cell carcinoma (ccRCC) patients. Methods: The mRNA expression profiles of ccRCC samples were downloaded from the The Cancer Genome Atlas (TCGA) dataset and the correlation of AIF1L with malignancy, tumor stage and prognosis were evaluated. Differentially expressed genes (DEGs) between AIF1L-low and AIF1L-high expression groups were selected. Those with prognostic value as determined by univariate and multivariate Cox regression analysis were then used to construct a prognostic index model capable of predicting the outcome of ccRCC patients. Results: The expression level of AIF1L was lower in ccRCC samples than in normal kidney samples. AIF1L expression showed an inverse correlation with tumor stage and a positive association with better prognosis. ccRCC samples were divided into high- and low-expression groups according to the median value of AIF1L expression. In the AIF1L-high expression group, 165 up-regulated DEGs and 601 down-regulated DEGs were identified. Three genes (AIF1L, SERPINC1 and CES1) were selected following univariate and multivariate Cox regression analysis. The hazard ratio (HR) and 95% confidence intervals (CI) for these genes were: AIF1L (HR = 0.83, 95% CI: 0.76–0.91), SERPINC1 (HR = 1.33, 95% CI: 1.12–1.58), and CES1 (HR = 0.87, 95% CI: 0.78–0.97). A prognostic index model based on the expression level of the three genes showed good performance in predicting ccRCC patient outcome, with an area under the ROC curve (AUC) of 0.671. Conclusion: This research provides a better understanding of the correlation between AIF1L expression and ccRCC. We propose a novel prognostic index model comprising AIF1L, SERPINC1 and CES1 expression that may assist physicians in determining the prognosis of ccRCC patients.

Role of Endogenous Serotonin Replica Mediated Through β-Catenin/Wnt Signaling in Lung Cancer Prevention and Prognosis - an in-vitro Study in A549 Cancer Cell Lines

Background: Lung cancer is still the most common cause of carcinoma-related death in the globe. Non-pharmacological treatments such as physical activity and exercise have been shown to improve quality of life and provide better results in lung cancer patients. Lung cancer patients usually lack adequate amounts of physical activity and exercise, both of which can improve quality of life.
 Aim: To analyse Chemotherapeutic potential of endogenous serotonin replica mediated through β-catenin/Wnt signaling in lung tumor cell lines (A549).
 Methods and Materials: The National Centre for Cell Sciences (NCCS), Pune, India, provided the human lung cancer cell line (A549). MTT assay was used to determine cell viability. Real-time PCR was used to examine -Catenin mRNA, Wnt mRNA, and GSK mRNA gene expression. The significance of the acquired data was determined using one-way analysis of variance and Duncan's multiple range test with Graph Pad Prism version 5. Duncan's test was used to determine significance at the 0.05 level.
 Results: The Results suggest that maximum inhibition of cell growth was at concentration (2-4 mM/ml) used in this study when compared to control. The cancer cells were significantly inhibited and it was found that there was notable reduction in GSK mRNA gene expression, β-Catenin, Wnt when compared to control at a dose of 2 mM/ml.
 Conclusion: It may be concluded, based on the analyses' findings and the study's limitations, that the role of exercise induced endogenous serotonin may act as the regulator of wnt/β-catenin signaling in lung cancer cells. The exercise may help in maintaining the equilibrium of the gene expression by modeling Wnt/β-catenin signaling pathway and act as a protective factor in prevention.

KRas-transformed epithelia cells invade and partially dedifferentiate by basal cell extrusion

Metastasis is the main cause of carcinoma-related death, yet we know little about how it initiates due to our inability to visualize stochastic invasion events. Classical models suggest that cells accumulate mutations that first drive formation of a primary mass, and then downregulate epithelia-specific genes to cause invasion and metastasis. Here, using transparent zebrafish epidermis to model simple epithelia, we can directly image invasion. We find that KRas-transformation, implicated in early carcinogenesis steps, directly drives cell invasion by hijacking a process epithelia normally use to promote death—cell extrusion. Cells invading by basal cell extrusion simultaneously pinch off their apical epithelial determinants, endowing new plasticity. Following invasion, cells divide, enter the bloodstream, and differentiate into stromal, neuronal-like, and other cell types. Yet, only invading KRasV12 cells deficient in p53 survive and form internal masses. Together, we demonstrate that KRas-transformation alone causes cell invasion and partial dedifferentiation, independently of mass formation.

Identification of Key Biomarkers and Pathways in Small-Cell Lung Cancer Using Biological Analysis.

Background Small-cell lung cancer (SCLC) is a major cause of carcinoma-related deaths worldwide. The aim of this study was to identify the key biomarkers and pathways in SCLC using biological analysis. Methods Key genes involved in the development of SCLC were identified by downloading three datasets from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using the GEO2R online analyzer; for the functional annotation and pathway enrichment analysis of genes, Funrich software was used. Construction of protein-to-protein interaction (PPI) networks was accomplished using the Search Tool for the Retrieval of Interacting Genes (STRING), and network visualization and module identification were performed using Cytoscape. Results A total of 268 DEGs were ultimately obtained. The enriched functions and pathways of the upregulated DEGs included cell cycle, mitotic, and DNA replication, and the downregulated DEGs were enriched in epithelial-to-mesenchymal transition, serotonin degradation, and noradrenaline. Analysis of significant modules demonstrated that the upregulated genes are primarily concentrated in functions related to cell cycle and DNA replication. Kaplan-Meier analysis of hub genes revealed that they may promote the carcinogenesis and progression of SCLC. The result of ONCOMINE demonstrated that these 10 hub genes were significantly overexpressed in SCLC compared with normal samples. Conclusion Identification of the molecular functions and signaling pathways of participating DEGs can deepen the current understanding of the molecular mechanisms of SCLC. The knowledge gained from this work may contribute to the development of treatment options and improve the prognosis of SCLC in the future.

Effects of LncRNA HCP5/miR-214-3p/MAPK1 Molecular Network on Renal Cell Carcinoma Cells.

BackgroundRecent researches have shown that long non-coding RNA (LncRNA) is often disordered and acts in many carcinomas. Clear cell renal cell carcinoma (ccRCC) is the main reason for carcinoma-related deaths, which are mainly caused by the metastasis. HCP5 is a newly discovered LcnRNA. Early studies have found that HCP5 acts in neoplasm metastasis, but the mechanism of HCP5 in ccRCC is still unclear.MethodsThe expression of HCP5 in human renal cell carcinoma (RCC) was detected by real-time quantitative PCR. The biological effect of LncRNAs in proliferation, migration, invasion and metastasis of RCC cells was explored by gain-of-function and loss-of-function tests. The molecular mechanism of LncRNAs was explored by RNA immunoprecipitation and Western blot.ResultsqRT-PCR revealed that HCP5 was enhanced in neoplasm tissues of ccRCC patients and correlated with the metastatic characteristics of RCC. Over-expression of HCP5 promoted the proliferation, migration and invasion of renal carcinoma cells. The deletion of HCP5 inhibited the proliferation, migration and invasion of RCC in vitro and the metastasis of RCC in vivo. Mechanically, HCP5 inhibited the growth and metastasis of ccRCC cells by regulating miR-214-3p/MAPK1 axis.ConclusionHCP5, as a key LncRNA, can promote ccRCC metastasis by regulating miR-214-3p/MAPK1 axis and may be a biomarker and be helpful for judging the prognosis of ccRCC.

5\u03b1-reductase inhibitors impact prognosis of urothelial carcinoma

Background5α-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients. Since androgen receptor activation may play a role in urothelial tumorigenesis, we conducted this retrospective cohort study to determine whether 5α-reductase inhibitors (5-ARIs) administration is associated with bladder cancer mortality, bladder cancer recurrence and upper tract urothelial carcinoma mortality, using the Taiwan National Health Insurance database.MethodsThe data of this retrospective cohort study were sourced from the Longitudinal Health Insurance Database of Taiwan, compiled by the Taiwan National Health Insurance database from 1996 to 2010. It consists of 18,530 men with bladder cancer, of whom 474 were 5-ARIs recipients and 4384 men with upper tract urothelial carcinoma, of whom 109 were 5-ARIs recipients. Propensity Score Matching on the age and geographic data was done at the ratio of 1:10. We analyzed the odds ratios (OR) and 95% confidence interval (CI) of the risk of bladder cancer death, bladder cancer recurrence rate and upper tract urothelial carcinoma related death by the 5-ARIs administration.ResultsThose who received 5-ARIs showed a lower risk of bladder cancer related death compared to nonusers in multivariable adjusted analysis (OR 0.835, 95% CI 0.71–0.98). However, there was no significant difference in the bladder cancer recurrence rate (OR 0.956, 95% CI 0.82–1.11) and upper tract urothelial carcinoma related mortality in multivariable adjusted analysis (OR 0.814, 95% CI 0.6–1.1).ConclusionsPatients who receive 5-ARIs have lower bladder cancer related mortality compared to those who don’t. 5-ARIs may prove to be a viable strategy to improve bladder cancer outcomes.

Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant

In the context of liver transplantation (LT) for hepatocellular carcinoma (HCC), prediction models are used to ensure that the risk of post-LT recurrence is acceptably low. However, the weighting that 'response to neoadjuvant therapies' should have in such models remains unclear. Herein, we aimed to incorporate radiological response into the Metroticket 2.0 model for post-LT prediction of "HCC-related death", to improve its clinical utility. Data from 859 transplanted patients (2000-2015) who received neoadjuvant therapies were included. The last radiological assessment before LT was reviewed according to the modified RECIST criteria. Competing-risk analysis was applied. The added value of including radiological response into the Metroticket 2.0 was explored through category-based net reclassification improvement (NRI) analysis. At last radiological assessment prior to LT, complete response (CR) was diagnosed in 41.3%, partial response/stable disease (PR/SD) in 24.9% and progressive disease (PD) in 33.8% of patients. The 5-year rates of "HCC-related death" were 3.1%, 9.6% and 13.4% in those with CR, PR/SD, or PD, respectively (p <0.001). Log10AFP (p <0.001) and the sum of number and diameter of the tumour/s (p <0.05) were determinants of "HCC-related death" for PR/SD and PD patients. To maintain the post-LT 5-year incidence of "HCC-related death" <30%, the Metroticket 2.0 criteria were restricted in some cases of PR/SD and in all cases with PD, correctly reclassifying 9.4% of patients with "HCC-related death", at the expense of 3.5% of patients who did not have the event. The overall/net NRI was 5.8. Incorporating the modified RECIST criteria into the Metroticket 2.0 framework can improve its predictive ability. The additional information provided can be used to better judge the suitability of candidates for LT following neoadjuvant therapies. In the context of liver transplantation for patients with hepatocellular carcinoma, prediction models are used to ensure that the risk of recurrence after transplantation is acceptably low. The Metroticket 2.0 model has been proposed as an accurate predictor of "tumour-related death" after liver transplantation. In the present study, we show that its accuracy can be improved by incorporating information relating to the radiological responses of patients to neoadjuvant therapies.

Case-Control Study of Tumor Stage-Dependent Outcomes for Cutaneous Squamous Cell Carcinoma in Immunosuppressed and Immunocompetent Patients.

Immunosuppressed patients have worse outcomes from cutaneous squamous cell carcinomas (cSCCs), although unclear whether it is due to the development of more high-stage tumors or worse outcomes for a given stage. Analyze the impact of immunosuppression on the development of cSCCs and tumor stage-dependent outcomes. Single-institution 1:2 case-control study of primary invasive cSCCs from 2005 to 2015 in 106 mixed-cause immunosuppressed patients and 212 control subjects matched to age, gender, and race. Four hundred twelve cSCCs from 106 immunosuppressed patients and 291 tumors from 212 matched immunocompetent patients were included. Both cohorts had similar T-stage distribution, with <5% high-stage tumors, that is, AJCC-7 T2, AJCC-8 T3, and BWH T2b/T3. Immunosuppression significantly increased the likelihood of poor outcomes (POs) (aggregate of local recurrence (LR), nodal and distant metastasis, and squamous cell carcinoma-related deaths) for low-stage tumors, that is, AJCC-7 T1 (odds ratio [OR], 4.29), AJCC-8 T1 (OR, 3.45), AJCC-8 T2 (OR, 3.75), BWH T1 (OR, 3.53), and BWH T2a (OR, 3.41) tumors. There was no significant difference in the treatment: most tumors were treated with Mohs (71% vs 75%) or excision (21% vs 20%) in both cohorts. Immunosuppressed patients have an increased risk of POs, specifically LRs, from low-stage cSCCs. Definitive treatment of cSCCs is recommended.

The subpopulation of CD44-positive cells promoted tumorigenicity and metastatic ability in lung adenocarcinoma.

Lung cancer is one of the major causes of carcinoma-related deaths in the world. Importantly, lung adenocarcinoma (LAC) is the most common type with poor outcome. However, the progressive clinical phenotype and biomolecular signature of lung cancer presenting the cancer stem-like and metastatic characteristics are still unclear. In this study, we identified CD44 marker in lung cancers. The capabilities, including tumorigenic and migration assays, were analyzed in CD44 expression and CD44 expression subgroups. Meanwhile, the potential bio-signature and properties of lung tumor stem-like cells were further studied. The high expression of CD44 subpopulation (CD44-positive) in isolated lung cancer cells showed significantly higher abilities of tumorigenic colonies, tumor-sphere formation, and migratory properties when compared with the CD44 expression group. These subgroups of CD44-positive lung cancer cells further demonstrated the metastatic potential with epithelial-mesenchymal transition (EMT), as well as the high expression of Twist and Snail gene profile. Importantly, the overexpression of Snail with gene vector in CD44 expression cells further significantly promoted the properties of lung tumor stem-like cells. The results of this study highlighted the role of CD44-posivite subpopulation in modulating tumor initiation and EMT-based metastatic ability of lung malignancy.

Abstract 2656: Estrogen receptor pathway activity in endometrial carcinomas and its relation to tumor grade and recurrence

Abstract Background Immunohistochemical (IHC) loss of expression of the estrogen (ER) and progesterone receptor (PR) from endometrial carcinomas is associated with high tumor grade, and with recurrent disease. However, expression of these receptors is not always indicative of functional pathway activity. A novel approach to predict signaling pathway activity, based on Knowledge-based Bayesian computational models interprets quantitative transcriptome data as the functional output of an active signaling pathway by using expression levels of transcriptional target genes. The objectives of this study were to compare ER pathway activity to ER and PR IHC results with respect to endometrial carcinoma grade and disease recurrences. Materials and Methods Originally for Affymetrix, the pathway analysis was adapted for RT-qPCR enabling use on FFPE tissue. Calibration and threshold definition was performed using tissue with known pathway activity. Pathway analysis was performed on: (1) A public dataset (GSE56026) containing Affymetrix expression microarray data from 62 patients with grade 1 (n=23),2 (n=17) and 3 (n=11) endometrioid and serous (n=12) carcinomas, and (2) formalin fixed, paraffin embedded (FFPE) tissue from endometrioid (n=70) and serous carcinomas (n=15), treated at the Radboud university medical center, which were immunohistochemically stained for ER and PR, and analyzed for pathway activity using qPCR. Results (1) Analysis of the public dataset showed an inverse relation between ER pathway activity score and cancer grade, with the lowest ER activity in serous carcinomas. The Mann-Whitney U test showed significant differences between grade 1 and 2 (p=0.015), grade 1 and 3 (p=0.004), and grade 1 and serous carcinomas (p&amp;lt;0.0001). (2) These results were confirmed in the FFPE tissue. The ER pathway was active in 30% (n=18), and inactive in 70% (n=41) of the samples. In advanced stage endometrioid and all serous carcinomas, ER pathway was active in 8% (n=2) and inactive in 92% (n=24) of the samples (Fisher p=0.03). Endometrial carcinoma related death (ECD) rate was 20% (n=17). While individually, ER pathway activity, ER and PR IHC were all significantly correlated with ECD, (logistic regression odds ratio, OR = 0.53, 0.12, 0.15, and p=0.0004, 0.0005, 0.002, respectively). In a multivariate analysis only ER pathway activity and disease stage remained significantly correlated with ECD (OR=0.52, p=0.03). Conclusion In two independent patient cohorts, the ER pathway model analysis, performed on data from Affymetrix microarrays and qPCR measurements showed an inverse relationship between the pathway activity and increasing tumor grade. While ER activity and ER/PR staining were related, only ER activity and cancer stage remained significant in a multivariate analysis with respect to immunohistochemistry alone when trying to predict recurrent disease. Citation Format: Louis J. van der Putten, Anne van Brussel, Willem Jan van Weelden, Márcia A. de Inda, Leon F. Massuger, Henk van Ooijen, Anja van de Stolpe, Johanna M. Pijnenborg. Estrogen receptor pathway activity in endometrial carcinomas and its relation to tumor grade and recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2656.

Nkx2.8 Inhibits Epithelial-Mesenchymal Transition in Bladder Urothelial Carcinoma via Transcriptional Repression of Twist1.

Epithelial-to-mesenchymal transition (EMT) promotes metastasis, which is the main cause of bladder urothelial carcinoma-related death. Loss of the candidate tumor-suppressor gene Nkx2.8 has been associated with urothelial carcinoma lymph node metastasis. Here, we show that enforced expression of Nkx2.8 is sufficient to inhibit EMT, reduce motility, and blunt invasiveness of urothelial carcinoma cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of the EMT inducer Twist1 in urothelial carcinoma cells, at both the level of mRNA and protein accumulation. Nkx2.8 bound directly to the promoter region of this gene and transcriptionally repressed its expression. Twist1 upregulation reversed EMT inhibition by Nkx2.8, restoring the invasive phenotype of urothelial carcinoma cells. In clinical urothelial carcinoma specimens, expression of Nkx2.8 inversely correlated with Twist1 expression, and urothelial carcinoma patients with Nkx2.8 positivity and low Twist1 expression displayed the best prognosis. Our findings highlight the Nkx2.8-Twist1 axis as candidate target for therapeutic intervention in advanced urothelial carcinoma.Significance: These findings highlight a novel EMT signaling axis as a candidate target for therapeutic intervention in advanced urothelial carcinomas. Cancer Res; 78(5); 1241-52. ©2018 AACR.

RETRACTED ARTICLE: TIPE2 suppresses progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/β-catenin pathway

BackgroundEsophageal carcinoma is the eighth prevalent malignancy and ranks the sixth in carcinoma-related death worldwide. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) has been identified as a tumor suppressor in multiple carcinomas. However, its roles and molecular mechanisms underlying esophageal carcinoma progression are still undefined till now.MethodsRT-qPCR assay was employed to detect the expression of TIPE2 mRNA. TIPE2 protein expression was measured by using western blot assay. Ad-V and Ad-TIPE2 adenoviruses were constructed to overexpress TIPE2. The effects of TIPE2 overexpression on cell proliferation, invasion and apoptosis were assessed by MTT and Edu incorporation assays, transwell invasion assay and flow cytometry analysis, respectively. The effect of TIPE2 overexpression on xenograft tumor growth was determined by measuring tumor volume and weight, together with immunohistochemistry assay. The effect of TIPE2 overexpression on the Wnt/β-catenin signaling pathway was evaluated by detecting the protein levels of β-catenin, c-Myc and cyclinD1 in EC9076 cells and xenograft tumors of esophageal carcinoma.ResultsTIPE2 expression was downregulated in esophageal carcinoma tissues and cells. Adenovirus-mediated TIPE2 overexpression suppressed cell proliferation and invasion, and induced apoptosis in esophageal carcinoma cells. Enforced expression of TIPE2 inhibited tumor growth in vivo, as evidenced by the reduced tumor volume, tumor weight and proliferating cell nuclear antigen expression. Overexpression of TIPE2 inhibited the Wnt/β-catenin signaling pathway in esophageal carcinoma in vitro and in vivo.ConclusionsThese results suggest that TIPE2 suppressed progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/β-catenin pathway.

Upregulation of MiR-212 Inhibits Migration and Tumorigenicity and Inactivates Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma.

Background:MicroRNAs are involved in hepatocellular carcinoma metastasis, a principal cause of hepatocellular carcinoma–related death in patients worldwide. MiR-212 is a microRNA that has been identified in several types of cancers and is postulated to influence cell signaling and subsequent malignant pathogenesis. Despite emerging reports suggesting that miR-212 plays a significant role in the onset, progression, and migration of these types of malignant tumors, its involvement in the development of hepatocellular carcinoma has not been fully elucidated.Materials and Methods:Quantitative reverse transcription polymerase chain reaction, wound healing, transwell migration and invasion assays, Western blotting, and xenograft tumor growth models were performed to test the expression levels and functions of miR-212 in hepatocellular carcinoma. Luciferase reporter assay, quantitative reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry were used to identify and verify the target of miR-212.Results:In this study, we identify significant repression of miR-212 in hepatocellular carcinoma and demonstrate that overexpression of miR-212 inhibits the migration of hepatocellular carcinoma cells in vitro and in vivo. Furthermore, we identify forkhead box M1, whose expression is inversely related to that of miR-212, as a direct target of miR-212. Additionally, reexpression of forkhead box M1 rescues the miR-212-mediated inhibition of cell migration. We observed that inhibition of miR-212 activates forkhead box M1 but inhibits the Wnt/β-catenin pathway by suppressing Wnt, LEF-1, c-Myc, and nuclear β-catenin. Finally, in vivo studies confirmed the inhibitory effect of miR-212 on hepatocellular carcinoma growth.Conclusion:Our present findings indicate that miR-212 is a potential prognostic biomarker of hepatocellular carcinoma and that the miR-212/forkhead box M1 regulatory axis may represent a new therapeutic objective for hepatocellular carcinoma treatment.

Spiradenocarcinoma: A Comprehensive Data Review.

Spiradenocarcinomas (SCs) are rare and potentially aggressive skin adnexal tumors. Optimal treatment has not yet been established. Experiences with this carcinoma are mostly presented in case reports and few case series. To generate to a synopsis of published data on SC with regard to diagnostic procedures, treatment, and outcome. Median patient age was 60 years and sex distribution was balanced. Tumor manifestations were evenly distributed within the sweat gland carrying skin. The most commonly reported symptom was accelerated growth of a longstanding indolent lesion, typically present for more than 2 years. Metastatic spread to the lung, bone, lymph nodes, liver, kidney, and breast has been documented. For staging computed tomography (CT) and positron emission tomography-CT are recommended, especially for detection of hematogenic metastases and lymph node involvement. Clear resection margins and tumor free regional lymph nodes reduce recurrence and carcinoma related death. Although low-grade SCs were reported over 3 times more often, high-grade carcinomas show a greater likelihood for recurrence and lethal outcome. Suspicion of an SC should lead to performance of a magnetic resonance imaging for defining tumor extent, and a fludeoxyglucose positron emission tomography-CT for detection of metastases. Radical tumor excision and resection of tumor involved regional lymph nodes are essential for a curative approach. Histopathological evaluation should involve determination of tumor differentiation grade, because high-grade carcinomas seem to have a much more aggressive behavior. Excision of distant metastases has no therapeutic value. Follow-up needs to be carried out in short intervals with frequent imaging.

MiR-34a modulates ErbB2 in breast cancer.

Breast cancer is the second highest cause of carcinoma-related death caused by distant metastasis in women. Estrogen receptor (ER), human epidermal growth factor receptor 2, (HER2) and progesterone receptor (PR) are three classified makers of breast cancer, which are defined as ER+, HER2+, and the most serious ER-PR-HER2- (triple-negative). It is well known that ErbB2 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2) plays an important part in breast cancer. However, the molecular mechanisms underlying ErbB2 action needs to be well studied. In this report, we discovered that the decreased expression levels of miR-34a were inversely correlated with the increased ErbB2 levels in breast cancer. A luciferase reporter assay was done to understand the potential correlation between ErbB2 and miR-34a. Over-expression of miR-34a reduces ErbB2 expression and suppresses breast cancer cell invasion and growth in vitro. What's more, reduced expression of ErbB2 inhibits breast Cancer cell proliferation and re-expression of ErbB2 reversed miR-34a-dependent tumor suppression. Meanwhile, miR-34a levels were correlated inversely with breast cancer malignancy. Our study demonstrates that miR-34a, like ErbB2, might be a diagnostic target in breast cancer.

Histone Deacetylase Inhibitors: A Novel Therapeutic Weapon Against Medullary Thyroid Cancer?

Medullary thyroid cancer (MTC) is highly malignant, metastatic and recurrent, remaining generally incurable, and responsible for approximately 14% of all thyroid carcinoma-related deaths. MTC can metastasize to lymph nodes, trachea and distant organs, such as brain, lungs, liver and bones. MTC cells are resistant to chemotherapy and traditional external therapies are not showing definite clinical benefits. Scientists are trying to understand the molecular background of carcinogenesis and histone deacetylase (HDAC) seems to play a potential role to gene transcription. On the other hand, HDAC inhibitors (HDACI) hamper the HDAC action giving promising results as new anticancer drugs. The purpose of this review was to evaluate the current status of research considering the role of HDACIs in MTC treatment and to present the latest trends in MTC treatment protocols. This literature review was accomplished using the MEDLINE database. The key words/phrases were; HDACI, medullary thyroid cancer, HDACI in the therapy of neuroendocrine tumors, HDACI in MTC. Forty-one articles were selected from the total number of the search's results. Only sixteen papers focus on the use of HDACIs in the treatment of MTC. In order to extract our conclusions, we took into account some studies whose main topic does not strictly refer to the MTC but they contain noteworthy and useful information. Only English articles published up to August 2016 were assessed and used for writing this review. Molecules, such as valproid acid (VPA), vorinostat, suberoyl bis-hydroxamic acid (SBHA), depsipeptide, belinostat, m-carboxycinnamic acid bis-hydroxamine (CBHA) and AB3 have shown promising antitumor effects against MTC. HDACIs represent a promising field for targeted therapy both for its anticancer properties, as well as for augmenting radiotherapeutic modalities. More trials are needed.

Prognosis and prognostic factors of differentiated thyroid carcinoma after the appearance of metastasis refractory to radioactive iodine therapy.

Differentiated thyroid carcinomas (DTCs) are generally indolent, but few therapeutic strategies are available after a metastatic recurrence that is refractory to radioactive iodine (RAI) therapy. Molecular-target therapy has shown promising results for DTCs with RAI-refractory recurrence. However, not all RAI-refractory recurrences are progressive, and even those that are progressive may not be immediately life-threatening. Here we investigated the prognosis and prognostic factors of 74 DTC patients (52 females, 22 males) in whom RAI-refractory metastases appeared. The five-year and 10-year cause-specific survival (CSS) rates of the 74 patients (8-82 yrs of age; median age at the detection of metastases, 61 yrs) were 95% and 70%, respectively, and the older patients (≥ 60 yrs, n=38) and male patients were significantly more likely to die of carcinoma. Also in multivariate analysis, older age (≥ 60 years) and male gender were independent predictors of carcinoma-related death. Taken together, our data indicate that RAI-refractory metastases of older patients and male patients are more progressive than those of other patients. Further studies are necessary to clarify the appropriate indications for molecular-target therapy for RAI-refractory and progressive metastases.

Prognostic significance of young age in papillary thyroid carcinoma: Analysis of 5,733 patients with 150 months’ median follow-up

Among the several prognostic factors of papillary thyroid carcinoma (PTC), age is the most prominent. It is well known that elderly PTC patients have poorer prognoses. Here we investigated the prognostic impact of young age in univariate and multivariate analyses. We retrospectively analyzed 5,733 PTC patients without distant metastasis at presentation, who underwent initial surgery at Kuma Hospital. The median follow-up period was 150 months. We classified the patients into three groups: young (< 30 years), middle-aged (30-59), and older patients (≥ 60 years). The tumor size was larger and clinical node positivity was higher in the young patients, and significant extrathyroid extension was higher in the older patients compared to the other two groups. In the univariate analysis, the young patients showed poorer extrathyroidal locoregional and distant recurrence rates than the middle-aged patients, but not cause-specific survival rates. In the multivariate analysis, age < 30 years was an independent or marginal predictor of extrathyroidal locoregional and distant recurrence, but not of carcinoma-related death. Age ≥ 60 years independently affected PTC recurrence and death. Taken together, we should carefully treat young PTC patients because of the likeliness of extrathyroidal locoregional and distant recurrence, which may not be life-threatening.

Snail overexpression induces an epithelial to mesenchymal transition and cancer stem cell-like properties in SCC9 cells

Local invasiveness and distant metastasis are critical factors that contribute to oral squamous cell carcinoma-related deaths. Increasing evidence has shown that the epithelial to mesenchymal transition (EMT) is involved in cancer progression and is associated with the ‘stemness' of cancer cells. Snail is a transcriptional factor that can induce EMT and preserve stem-cell function, which may induce resistance to radio- and chemotherapies in the cells. In the present study, SCC9 cells were transfected with an empty vector or a vector encoding human Snail (SCC9-S). Overexpression of Snail induced SCC9 cells to undergo EMT, in which the cells presented a fibroblast-like appearance, downregulated the epithelial markers E-cadherin and β-catenin, upregulated the mesenchymal marker vimentin, and associated with highly invasive and metastatic properties. Furthermore, the induction of EMT promoted cancer stem cell (CSC)-like characteristics in the SCC9-S cells, such as low proliferation, self-renewal, and CSC-like markers expression. These results indicate that overexpression of Snail induces EMT and promotes CSC-like traits in the SCC9 cells. Further understanding the role of Snail in cancer progression may reveal new targets for the prevention or therapy of oral cancers.