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Background and objectives: The role of ultrasound (US) guided biopsy in selecting patients for an upfront lymph node dissection (ALND) has been controversial following the publication of the American College of Surgeons (ACOSOG) Z0011 data. The purpose of this study was to investigate if patients with positive axillary lymph nodes (LNs) proven by US guided biopsy should be recommended for ALND and to analyze the utility of preoperative US and US guided biopsy in planning axillary surgery to avoid both unnecessary ALND and unnecessary SLNB. Methods: Patients with a positive preoperative LN biopsy were identified and evaluated to determine their suitability for inclusion according to the criteria proposed in the Z0011 data. The correlation of the number of suspicious nodes found using US with the number of positive nodes on ALND was studied. Results: A total of 261 breast cancer patients who had a positive preoperative LN needle biopsy were identified, among them, 79 patients with cT1–2N0 breast cancer and ALND were enrolled in the study. Thirty-one patients (39.2%) had ≤2 positive nodes identified in pathology and 10 patients (12.7%) met all of the Z0011 criteria and might have been spared ALND. A significantly greater proportion of women with ≥3 positive nodes during ALND had >1 abnormal LN identified using US compared to women with ≤2 positive LNs found using ALND (66.7% vs. 6.5%, p<0.0001). Conclusion: US with needle biopsy is valuable to patients with multiple suspicious nodes found using US while SLND without US guided needle biopsy is suggested if only one abnormal LN is detected on US in the post-Z0011 era. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic cancer is the 4th most common cause of cancer death in Japan and exhibits a 5-year overall survival rate of approximately 7%. The accurate diagnosis of pancreatic cancer is important for determining the optimal management strategy. Fludeoxyglucose-positron emission tomography (FDG PET) integrated with computed tomography (18F-FDG PET/CT) has emerged as a powerful imaging tool for detecting and evaluating various cancers, and it is used for staging, detecting local recurrence and distant metastasis, measuring therapeutic effects, and predicting prognosis in pancreatic cancer patients. Lately, FDG PET/CT-derived parameters, such as standardized uptake values (SUV), the metabolic tumor volume (MTV), and total lesion glycolysis (TLG), have been suggested as prognostic factors for various types of cancer, including pancreatic cancer. However, there is no consensus regarding the best parameters for evaluating patient prognosis, operability, etc. The purpose of this study was to examine the differences between operable and non-operable pancreatic cancer using FDG PET/CT-derived parameters, and to investigate whether volumetric parameters (TLG and the MTV) are superior to SUV-based parameters for predicting infiltration status/determining operability. Materials and methods: We conducted a retrospective study of the cases of 48 patients with clinically proven pancreatic adenocarcinoma, who underwent FDG PET/CT imaging before treatment. In the operable group, the surgical specimens were subjected to histopathological examinations, and the cases were separated into those exhibiting less and greater infiltration. SUVmax, SUVpeak, the tumor background ratio (TBR), TLG, and the MTV were compared between these groups as well as between the operable and non-operable groups. Results: Venous infiltration showed significant associations with several metabolic parameters (SUVmax, SUVpeak, and the TBR). However, it did not display any significant associations with volumetric parameters, such as TLG or the MTV. None of the FDG PET/CT-derived parameters exhibited significant associations with lymphatic or neural infiltration. Significant differences in volumetric parameters, such as the MTV and TLG, were detected between the operable and non-operable subgroups. Conclusions: Metabolic 18F-FDG PET/CT-derived parameters, such as SUVmax, SUVpeak, and the TBR, are useful for predicting venous infiltration status in patients with operable pancreatic adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the second leading cause of death due to cancer in women. Triple negative breast cancer (TNBC) is a subgroup with unique behavior. There is a controversy in organ involvement in metastasis. In this study, we planned to define the prognostic factors, survival, and recurrence incidence of patients. Materials and method: Among the 583 patients with breast mass referred to hematology and oncology clinic in Shariati hospital, Tehran, Iran from March 2005 to March 2015, fifty four patients entered the survival analysis whom we followed for two years until March 2017. Overall survival (OS) and disease-free survival (DFS) and Cumulative recurrence incidences (RI) were estimated. Univariate and multivariate Cox proportional hazards regression was performed to assess risk factors in predicting OS and DFS. Results: Median follow up for the patients was 5.00 years. The five-year OS, DFS and RI were 86.13% (95% CI (71.42–93.59), 63.09% (95% CI (47.04–75.49) and 32.15% (95% CI (19.52–47.43) respectively. Among the factors studied OS, DFS and RI differed significantly only between patients with and without nodal involvement (P = 0.004, P = 0.003, and P = 0.02 respectively). On the other hand, based on the univariate modeling, patients with nodal involvement had a higher risk of breast cancer-specific death (HR: 17.99, P = 0.004). Furthermore, patients with nodal involvement had a higher risk of breast cancer-specific death or recurrence (HR = 5.64, P = 0.008). In Multivariate model, just the nodal involvement significantly changed the hazard for OS (HR = 23.91, P = 0.001). As the nodal involvement was the only significant risk factor at the 0.2 level of significance, we can consider the hazard ratio of lymph node positivity in DFS univariate models as adjusted hazard. Conclusion: The only factor with significant effect on OS, DFS and RI was nodal involvement in the pathology report. [ABSTRACT FROM AUTHOR]

Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses. [ABSTRACT FROM AUTHOR]

The majority of cancer-related deaths are due to metastasis, hence improved methods to biologically and computationally model metastasis are required. Computational models rely on robust data that is machine-readable. The current methods used to model metastasis in mice involve generating primary tumors by injecting human cells into immune-compromised mice, or by examining genetically engineered mice that are pre-disposed to tumor development and that eventually metastasize. The degree of metastasis can be measured using flow cytometry, bioluminescence imaging, quantitative PCR, and/or by manually counting individual lesions from metastatic tissue sections. The aforementioned methods are time-consuming and do not provide information on size distribution or spatial localization of individual metastatic lesions. In this work, we describe and provide a MATLAB script for an image-processing based method designed to obtain quantitative data from tissue sections comprised of multiple subpopulations of disseminated cells localized at metastatic sites in vivo. We further show that this method can be easily adapted for high throughput imaging of live or fixed cells in vitro under a multitude of conditions in order to assess clonal fitness and evolution. The inherent variation in mouse studies, increasing complexity in experimental design which incorporate fate-mapping of individual cells, result in the need for a large cohort of mice to generate a robust dataset. High-throughput imaging techniques such as the one that we describe will enhance the data that can be used as input for the development of computational models aimed at modeling the metastatic process. [ABSTRACT FROM AUTHOR]

Metastatic dissemination employs both the blood and lymphatic vascular systems. Solid tumors dynamically remodel and generate both vessel types during cancer progression. Lymphatic vessel invasion and cancer cells in the tumor-draining lymph nodes (LNs) are prognostic markers for breast cancer metastasis and patient outcome, and tumor-induced lymphangiogenesis likely influences metastasis. Deregulated tumor tissue fluid homeostasis and immune trafficking associated with tumor lymphangiogenesis may contribute to metastatic spreading; however, the precise functional characterization of lymphatic endothelial cells (LECs) in tumors is challenged by the lack of specific reagents to decipher their rate-limiting role in metastasis. Therefore, we generated novel transgenic mice (PDPN promoter-driven Cre recombinase transgene [PDPN-Cre] and PDPN promoter-driven thymidine kinase transgene [PDPN-tk]) that allow for the identification and genetically controlled depletion of proliferating podoplanin (Pdpn)-expressing LECs. We demonstrate that suppression of lymphangiogenesis is successfully achieved in lymphangioma lesions induced in the PDPN-tk mice. In multiple metastatic breast cancer mouse models, we identified distinct roles for LECs in primary and metastatic tumors. Our findings support the functional contribution of primary tumor lymphangiogenesis in controlling metastasis to axillary LNs and lung parenchyma. Reduced lymphatic vessel density enhanced primary tumor lymphedema and increased the frequency of intratumoral macrophages but was not associated with a significant impact on primary tumor growth despite a marked reduction in metastatic dissemination. Our findings identify the rate-limiting contribution of the breast tumor lymphatic vessels for lung metastasis. [ABSTRACT FROM AUTHOR]

Homeobox protein Emx2 is a transcription factor that is encoded by the EMX2 gene. In this study, using data from the Cancer Genome Atlas-Thyroid Cancer (TCGA-THCA), we aimed to examine the expression profile of EMX2 and its antisense transcript EMX2OS in papillary thyroid cancer (PTC), their prognostic value and potential regulatory networks. Results showed that in the three variants of PTC, EMX2 was significantly downregulated in classical PTC, while EMX2OS were significantly downregulated in follicular and classical PTC, compared with adjacent normal tissues. Kaplan-Meier survival curves showed that EMX2 and EMX2OS expression was not related to RFS in follicular PTC. In comparison, the high EMX2 or EMX2OS group were associated with better RFS compared with their respective low expression group in classical PTC (p = 0.007 and 0.004 respectively). Correlation analysis showed that EMX2 and EMX2OS were highly co-expressed in PTC tissues (Spearman’s r = 0.83). By performing stepwise regression, we found that EMX2OS was better than EMX2 in predicting RFS in classical PTC. Multivariate analysis confirmed that high EMX2OS expression was an independent indicator of favorable RFS in classical PTC (HR: 0.239, 95%CI: 0.100 = 0.569, p = 0.001), after adjustment of pathological stages and residual tumors. By performing in silico analysis, we found that the genes co-expressed with EMX2 or EMX2OS were highly overlapped. KEGG pathway analysis showed that these genes were enriched in the ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling, protein digestion and absorption and proteoglycans in cancer pathways, which are closely related to cancer initiation and progression. Based on the findings, we infer that decreased EMX2OS expression might be a valuable prognostic biomarker of unfavorable RFS in classical PTC. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OSA) is an aggressive mesenchymal tumor of the bone that affects children and occurs spontaneously in dogs. Human and canine OSA share similar clinical, biological and genetic features, which make dogs an excellent comparative model to investigate the etiology and pathogenesis of OSA. Mitochondrial (mt) defects have been reported in many different cancers including OSA, although it is not known whether these defects contribute to OSA progression and metastasis. Taking a comparative approach using canine OSA cell lines and tumor tissues we investigated the effects of mtDNA content and dysfunction on OSA biology. OSA tumor tissues had low mtDNA contents compared to the matched non-tumor tissues. We observed mitochondrial heterogeneity among the OSA cell lines and the most invasive cells expressing increased levels of OSA metastasis genes contained the highest amount of mitochondrial defects (reduced mtDNA copies, mt respiration, and expression of electron transport chain proteins). While mitochondria maintain a filamentous network in healthy cells, the mitochondrial morphology in OSA cells were mostly “donut shaped”, typical of “stressed” mitochondria. Moreover the expression levels of mitochondrial retrograde signaling proteins Akt1, IGF1R, hnRNPA2 and NFkB correlated with the invasiveness of the OSA cells. Furthermore, we demonstrate the causal role of mitochondrial defects in inducing the invasive phenotype by Ethidium Bromide induced-mtDNA depletion in OSA cells. Our data suggest that defects in mitochondrial genome and function are prevalent in OSA and that lower mtDNA content is associated with higher tumor cell invasiveness. We propose that mt defects in OSA might serve as a prognostic biomarker and a target for therapeutic intervention in OSA patients. [ABSTRACT FROM AUTHOR]

Introduction: [68Ga]PSMA-HBED-CC and [18F]DCFPyL show a high potential for the detection of recurrent prostate cancer. While 18F-based tracers have several advantages in availability and image resolution, their sensitivity in the skeleton might be impaired by released [18F]fluoride due to its high bone affinity. In turn, chemically unbound trivalent 68Ga might also accumulate in osseous tissue, in cases of occupied binding sites of plasma proteins and thereby influence bone signal. Methods: A comparison of average bone SUV was performed in 17 bone-negative and 4 bone-positive patients. All patients underwent PET/CT 125 minutes after application of [18F]DCFPyL and 73 minutes after application of [68Ga]PSMA-HBED-CC at another date. Results: Native SUVs in unaffected bone tissue and SUVs relative to liver uptake were lower in [18F]DCFPyL (0.49) than in [68Ga]PSMA-HBED-CC scans (0.52). SUVs relative to gluteal muscles did not differ between the two tracers. Average lesional SUVs did not differ between tracers. Conclusion: No difference of average bone signal intensity was observed for [18F]DCFPyL-PET/CT in comparison to [68Ga]PSMA-HBED-CC scans indicating that diagnostic assessment of the skeleton is not affected by non-specific accumulation of free [18F]fluoride or 68Ga. [ABSTRACT FROM AUTHOR]

This retrospective study evaluated the expression of β1 integrins and associated proteins as prognostic markers for primary radio(chemo)therapy outcome of patients with locally advanced head and neck squamous cell carcinomas (HNSCC). Tissue microarrays were prepared from 224 HNSCC patients undergoing curative primary radio(chemo)therapy from 1996 to 2005. Staining intensities of β1 integrin and its downstream-proteins FAK, phosphorylated FAK as well as the β1 integrin ECM ligands fibronectin and collagen type-I were determined. Their association to the primary endpoint loco-regional control and the secondary endpoints overall survival and freedom from distant metastasis was analyzed by Cox regression. None of the considered molecular parameters showed a significant association with loco-regional control and freedom from distant metastasis. Patients with p16 positive tumors or tumors with a low intensity of fibronectin showed significantly higher overall survival in univariable regression. In multivariable regression including additional clinical parameters, however, these parameters were not significantly associated with overall survival. Our study in a HNSCC patient cohort treated with primary radio(chemo)therapy does not reveal a prognostic value of β1 integrin expression. [ABSTRACT FROM AUTHOR]

Cutaneous mast cell tumours are one of the most common canine cancers. Approximately 25% of the tumours metastasise. Activating c-kit mutations are present in about 20% of tumours, but metastases occur in the absence of mutations. Tumour metastasis is associated with significantly diminished survival in spite of adjuvant chemotherapy. Available prognostic tests do not reliably predict whether a tumour will metastasise. In this study we compared the global expression profiles of 20 primary cutaneous mast cell tumours that metastasised with those of 20 primary tumours that did not metastasise. The objective was to identify genes associated with mast cell tumour metastatic progression that may represent targets for therapeutic intervention and biomarkers for prediction of tumour metastasis. Canine Gene 1.1 ST Arrays were employed for genome-wide expression analysis of formalin-fixed, paraffin-embedded biopsies of mast cell tumours borne by dogs that either died due to confirmed mast cell tumour metastasis, or were still alive more than 1000 days post-surgery. Decreased gene expression in the metastasising tumours appears to be associated with a loss of cell polarity, reduced cell-cell and cell-ECM adhesion, and increased cell deformability and motility. Dysregulated gene expression may also promote extracellular matrix and base membrane degradation, suppression of cell cycle arrest and apoptosis, and angiogenesis. Down-regulation of gene expression in the metastasising tumours may be achieved at least in part by small nucleolar RNA-derived RNA and microRNA-effected gene silencing. Employing cross-validation, a linear discriminant analysis-based classifier featuring 19 genes that displayed two-fold differences in expression between metastasising and non-metastasising tumours was estimated to classify metastasising and non-metastasising tumours with accuracies of 90–100% and 70–100%, respectively. The differential expression of 9 of the discriminator genes was confirmed by quantitative reverse transcription-PCR. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the commonest cancers associated with diverse prognosis times in different parts of the world. Despite medical interventions, the overall clinical outcomes and survival remains very poor for most patients in developing countries. This study therefore investigated the survival rate of colorectal cancer and its prognostic factors among patients at Komfo Anokye Teaching Hospital, Ghana. Methodology: In this retrospective cohort study, a total of 221 patients diagnosed with CRC from 2009 to 2015 at the Surgical and Oncological units of Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana were employed. The survival graphs were obtained using the Kaplan–Meier method and compared by the Log-rank test. Cox regression analysis was used to assess prognostic factors. All analyses were performed by SPSS version 22. Results: The median survival time was 15 months 95% CI (11.79–18.21). The overall survival rate for CRC over the 5 years period was 16.0%. The survival rates at the 1st, 2nd, 3rd, 4th and 5th years were 64% 95% CI (56.2–71.1), 40% 95% CI (32.2–50.1), 21% 95% CI (11.4–30.6) 16% 95% CI (8.9–26.9) and 16% 95% CI (7.3–24.9). There was a significant difference in the survival rate of colorectal cancer according to the different stages (p = 0.0001). Family history [HR = (3.44), p = 0.029)], Chemotherapy [HR = (0.23), p = <0.0001)], BMI [HR = (1.78), p = 0.017)] and both chemo/radiotherapy (HR = (3.63), p = 0.042)] were the significant social and clinical factors influencing the overall survival. Pathological factors such as TNM tumour stage (p = 0.012), depth of tumour invasion (p = 0.036), lymph node metastasis (p = 0.0001), and distance metastasis (p = 0.001) were significantly associated with overall survival. Conclusion: The study has clearly demonstrated that survival rate for CRC patients at KATH, Ghana is very low in a 5 years period. This is influenced by significant number of clinical and pathological prognostic factors. Identification of prognostic factors would be a primary basis for early prediction and treatment of patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that miRNAs can be promising diagnostic and/or prognostic markers for various cancers. In this study, we identified a novel miRNA, miR-3607-3p, and its targets in non-small cell lung cancer (NSCLC). The expression of miR-3607-3p was measured and its correlation with patient prognosis was determined. Ectopic expression in NSCLC cells, xenografts, and metastasis models was used to evaluate the effects of miR-3607-3p on proliferation and migration of NSCLC. Luciferase assay and western blotting were performed to validate the potential targets of miR-3607-3p after preliminary screening by microarray analysis and computer-aided algorithms. We demonstrated that miR-3607-3p was downregulated in NSCLC tissues and that miR-3607-3p might act as an independent predictor for overall survival in NSCLC. Moreover, serum miR-3607-3p may be a novel and stable marker for NSCLC. We found that overexpression of miR-3607-3p inhibited cell proliferation, colony formation, migration and invasion, and hampered the cell cycle of NSCLC cell lines in vitro. Our results suggested that miR-3607-3p directly targets TGFBR1 and CCNE2. In accordance with in vitro studies, we confirmed that miR-3607-3p functions as a potent suppressor miRNA of NSCLC. We showed that miR-3607-3p agomir could reduce tumor growth and inhibit TGFBR1 and CCNE2 protein expression. Taken together, our findings indicate that miR-3607-3p can inhibit NSCLC cell growth and metastasis by targeting TGFBR1 and CCNE2 protein expression, and provide new evidence of miR-3607-3p as a potential non-invasive biomarker and therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]

Background: Metastasis and multiple myeloma are common malignant bone marrow lesions which may be difficult to distinguish because of similar imaging findings. The purpose of this study was to determine the value of adding diffusion-weighted imaging (DWI) to standard MR imaging to differentiate multiple myeloma from metastasis. Methods: 25 patients with metastasis and 18 patients with multiple myeloma underwent 3T MR imaging with DWI (b = 0, 800 s/mm2) were enrolled. They all had pathologically confirmed bone lesions and were in a treatment naïve state. Two readers who were blind of final diagnosis measured the average ADC (ADCav) and minimum ADC (ADCmin) on the DWI. They then estimated the diagnosis, based on the standard MR imaging and measured ADC values. Another reader performed histogram analysis on the whole tumor volume and obtained mean ADC (ADCvol), standard deviation (SDvol), skewness, and kurtosis. Comparison of the obtained values from DWI was performed by the t-test or Mann-Whitney U test. The receiver operating characteristic (ROC) curve with areas under the curve (AUC) was used to obtain the cut off values and to evaluate the diagnostic performance of the two readers. Results: ADCav, ADCmin, and ADCvol of multiple myeloma were significantly lower than those of metastasis: ADCav, 752 μm2/sec versus 1081 μm2/sec; ADCmin, 704 μm2/sec vs 835 μm2/sec; ADCvol 761 μm2/sec vs 1184 μm2/sec (p < .001). In histogram analysis, ADC values of multiple myeloma showed narrow distribution than metastasis: SDvol, 144 vs 257 (p < .001). Areas under the receiver operating characteristic curve was significantly higher with additive DWI than standard MR alone: 0.762 vs 0.953; 0.706 vs 0.950 (p < .05) for two readers. Conclusions: This study suggested that the addition of axial DWI to standard MR imaging can be helpful to diagnose multiple myeloma from metastasis at 3T. [ABSTRACT FROM AUTHOR]

A bioactive lipid, sphingosine 1-phosphate (S1P), acts extracellularly as a potent mediator, and is implicated in the progression of various cancers including hepatocellular carcinoma (HCC). S1P exerts its functions by binding to five types of specific receptors, S1P receptor 1 (S1PR1), S1PR2, S1PR3, S1PR4 and S1PR5 on the plasma membrane. However, the exact roles of S1P and each S1PR in HCC cells remain to be clarified. In the present study, we investigated the effect of S1P on the hepatocyte growth factor (HGF)-induced migration of human HCC-derived HuH7 cells, and the involvement of each S1PR. S1P dose-dependently reduced the HGF-induced migration of HuH7 cells. We found that all S1PRs exist in the HuH7 cells. Among each selective agonist for five S1PRs, CYM5520, a selective S1PR2 agonist, significantly suppressed the HGF-induced HuH7 cell migration whereas selective agonists for S1PR1, S1PR3, S1PR4 or S1PR5 failed to affect the migration. The reduction of the HGF-induced migration by S1P was markedly reversed by treatment of JTE013, a selective antagonist for S1PR2, and S1PR2- siRNA. These results strongly suggest that S1P reduces the HGF-induced HCC cell migration via S1PR2. Our findings may provide a novel potential of S1PR2 to therapeutic strategy for metastasis of HCC. [ABSTRACT FROM AUTHOR]

Multistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis. Therefore, further modeling subclonal CNAs composition would hold the promise to improve the analysis of tumor heterogeneity and cancer evolution. To address this issue, we developed a two-way mixture Poisson model, named CloneDeMix for the deconvolution of read-depth information. It can infer the subclonal copy number, mutational cellular prevalence (MCP), subclone composition, and the order in which mutations occurred in the evolutionary hierarchy. The performance of CloneDeMix was systematically assessed in simulations. As a result, the accuracy of CNA inference was nearly 93% and the MCP was also accurately restored. Furthermore, we also demonstrated its applicability using head and neck cancer samples from TCGA. Our results inform about the extent of subclonal CNA diversity, and a group of candidate genes that probably initiate lymph node metastasis during tumor evolution was also discovered. Most importantly, these driver genes are located at 11q13.3 which is highly susceptible to copy number change in head and neck cancer genomes. This study successfully estimates subclonal CNAs and exhibit the evolutionary relationships of mutation events. By doing so, we can track tumor heterogeneity and identify crucial mutations during evolution process. Hence, it facilitates not only understanding the cancer development but finding potential therapeutic targets. Briefly, this framework has implications for improved modeling of tumor evolution and the importance of inclusion of subclonal CNAs. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic brain tumors pose a severe problem in the treatment of patients with breast carcinoma. Preclinical models have been shown to play an important role in unraveling the underlying mechanisms behind the metastatic process and evaluation of new therapeutic approaches. As the size of the rat brain allows improved in vivo imaging, we attempted to establish a rat model for breast cancer brain metastasis that allows follow-up by 7 tesla (7T) preclinical Magnetic Resonance Imaging (MRI). Procedures: Green fluorescent protein-transduced (eGFP) MDA-MB-231br breast cancer cells were labeled with micron-sized particles of iron oxide (MPIOs) and intracardially injected in the left ventricle of female nude rats and mice. 7T preclinical MRI was performed to show the initial distribution of MPIO-labeled cancer cells and to visualize metastasis in the brain. Occurrence of potential metastasis outside the brain was evaluated by 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/computed tomography (CT) and potential bone lesions were assessed using [18F]sodium fluoride ([18F]NaF) PET/CT. Results: The first signs of brain metastasis development were visible as hyperintensities on T2-weighted (T2w) MR images acquired 3 weeks after intracardiac injection in rats and mice. Early formation of unexpected bone metastasis in rats was clinically observed and assessed using PET/CT. Almost no bone metastasis development was observed in mice after PET/CT evaluation. Conclusions: Our results suggest that the metastatic propensity of the MDA-MB-231br/eGFP cancer cell line outside the brain is species-dependent. Because of early and abundant formation of bone metastasis with the MDA-MB-231br/eGFP cancer cell line, this rat model is currently not suitable for investigating brain metastasis as a single disease model nor for evaluation of novel brain metastasis treatment strategies. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs), endopeptidases with diverse biochemical functions, can promote cancer cell invasion and metastasis by degrading the extracellular matrix. A high matrix metalloproteinase-14 (MMP-14) expression in gastric cancer tissue has been associated with metastasis and poor prognosis. To further understand this association, we investigated serum MMP-14 as a biomarker in gastric cancer patients. The patient cohort consisted of 240 gastric adenocarcinoma patients who underwent surgery at Helsinki University Hospital, Finland, between 2000 and 2009. We determined the soluble MMP-14 serum levels using an enzyme-linked immunosorbent assay. We then calculated the associations between serum levels and clinicopathologic variables using the Mann-Whitney U-test or the Kruskal-Wallis test. We constructed survival curves using the Kaplan-Meier method and calculating the hazard ratios using the Cox proportional hazard model. We revealed a positive association between a high serum MMP-14 level and stages III–IV (p = 0.029), and between a high serum MMP-14 and distant metastasis (p = 0.022). Patients with a low serum MMP-14 had a 5-year disease-specific survival of 49.2% (95% confidence interval [CI] 45.5–52.9), whereas patients with a high serum MMP-14 had a 5-year survival of 22.1% (95% CI 15.2–29.0; p = 0.001). High serum MMP-14 was a statistically significant prognostic factor among patients with an intestinal type of cancer (hazard ratio [HR] 3.54; 95% CI 1.51–8.33; p = 0.004), but not among patients with a diffuse type. The serum MMP-14 level remained an independent prognostic factor in our multivariate survival analysis (HR 1.55; 95% CI 1.02–2.35; p = 0.040). This study indicates for the first time that high serum soluble MMP-14 levels in gastric cancer serves as a marker for a poor prognosis, possibly indicating the presence of distant metastases. [ABSTRACT FROM AUTHOR]

Purpose: To establish three novel prognostic nomograms with inflammatory factors for advanced colorectal cancer (ACRC), right-sided colon cancer (RSCC) and left-sided colorectal cancer (LSCRC) according to real world data. Materials and methods: ACRC patients receiving medicine therapy from January 1st, 2005 to September 31th, 2015 in Sun Yat-sen University Cancer Center were enrolled. Inflammatory indicators such as the neutrophil-to-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), carcinoembryonic antigen (CEA), carbohydrate antigen 19–9 (CA 19–9), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were analyzed for establishing nomograms predicting overall survival (OS). Concordance index (C-index) determined predictive accuracy and discriminative ability. Results: Our study selected 807 ACRC patients, 29.6% RSCC and 70.4% LSCRC. Median OS was 23.36 months. Patients at lower level of NLR, PLR, CEA, CA 19–9, LDH and CRP showed longer OS (P < 0.001). For all patients, pathological grade (P = 0.018), treatments (P = 0.042), sidedness (P = 0.003), NLR (P < 0.001), CA 19–9 (P < 0.001), LDH (P < 0.001) and CRP (P = 0.0012) contributed to OS independently. For RSCC, pathological grade (P = 0.022), CA 19–9 (P < 0.001), LDH (P < 0.001) and CRP (P = 0.001) were significantly related with OS. For LSCRC patients, treatments (cetuximab vs chemotherapy: P = 0.008; bevacizumab vs chemotherapy: P = 0.166), NLR (P < 0.001), CA 19–9 (P = 0.030) and LDH (P < 0.001) were independent factors for OS. Final models showed acceptable internal validity with C-indexes of 0.687, 0.697 and 0.667 in all, RSCC and LSCRC patients. Conclusions: Inflammatory factors enrolled in the proposed nomograms showed accurately individualized prognostic prediction, and prognostic factors for RSCC and LSCRC were different. [ABSTRACT FROM AUTHOR]

The surgical treatment of primary solitary fibrous tumors (SFT) involving the pelvic ring has not been reported previously. In this study, we aimed to evaluate the efficacy of surgical treatment for this disease. From 2009 to 2015, 13 patients underwent tumor resection at our hospital, with an average age of 49.5 years (27–68 years). Four patients underwent en bloc resection, and 9 patients underwent piecemeal resections. A Chi-square test was used to compare the postoperative recurrence rates between the en bloc resection and the piecemeal resection groups (p = 0.68), and no significant difference was found between the benign and malignant solitary fibrous tumor groups (p = 0.44). The 5-year survival rate of the patients in this study was 83.3%, and the 5-year progression-free survival rate was 63.5%. The progression-free survival rate was not significantly different between the en bloc resection and piecemeal resection groups (p = 0.97). Piecemeal resection can also achieve acceptable local control, particularly for patients with sacral tumors, as they may achieve even better postoperative function with sacral nerve preservation. Recurrence and metastasis occur relatively late in the course of this disease. Therefore, long-term follow-up is required. [ABSTRACT FROM AUTHOR]

Our objective was to investigate direct voxel-wise relationship between dose and early MR biomarker changes both within and in the high-dose region surrounding brain metastases following stereotactic radiosurgery (SRS). Specifically, we examined the apparent diffusion coefficient (ADC) from diffusion-weighted imaging and the contrast transfer coefficient (Ktrans) and volume of extracellular extravascular space (ve) derived from dynamic contrast-enhanced (DCE) MRI data. We investigated 29 brain metastases in 18 patients using 3 T MRI to collect imaging data at day 0, day 3 and day 20 following SRS. The ADC maps were generated by the scanner and Ktrans and ve maps were generated using in-house software for dynamic tracer-kinetic analysis. To enable spatially-correlated voxel-wise analysis, we developed a registration pipeline to register all ADC, Ktrans and ve maps to the planning MRI scan. To interrogate longitudinal changes, we computed absolute ΔADC, ΔKtrans and Δve for day 3 and 20 post-SRS relative to day 0. We performed a Kruskall-Wallice test on each biomarker between time points and investigated dose correlations within the gross tumour volume (GTV) and surrounding high dose region > 12 Gy via Spearman’s rho. Only ve exhibited significant differences between day 0 and 20 (p < 0.005) and day 3 and 20 (p < 0.05) within the GTV following SRS. Strongest dose correlations were observed for ADC within the GTV (rho = 0.17 to 0.20) and weak correlations were observed for ADC and Ktrans in the surrounding > 12 Gy region. Both ΔKtrans and Δve showed a trend with dose at day 20 within the GTV and > 12 Gy region (rho = -0.04 to -0.16). Weak dose-related decreases in Ktrans and ve within the GTV and high dose region at day 20 most likely reflect underlying vascular responses to radiation. Our study also provides a voxel-wise analysis schema for future MR biomarker studies with the goal of elucidating surrogates for radionecrosis. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) can influence the tumour microenvironment (TEM) and play a major role in tumourigenesis. Triple-negative [Ostrogen receptor (ER-), Progesterone receptor (PgR-), and HER2/neu receptor (HER2-)] breast cancer (TNBC) is an aggressive class of BC characterized by poor prognosis and lacks the benefit of routinely available targeted therapies. This study aims to investigate the effect of human placental chorionic villi derived MSCs (CVMSCs) on the behavior of TNBC in vitro. This was done by assaying different cancer hallmarks including proliferation, migration and angiogenesis. Cell proliferation rate of TNBC cell line (MDA-MB231) was monitored in real time using the xCELLigence system. Whereas, Boyden chamber migration assay was used to measure MDA-MB231 motility and invasiveness toward CVMSCs. Finally, a three-dimensional (3D) model using a co-culture system of CVMSCs with MDA-MB231 with or without the addition of human umbilical vein endothelial cells (HUVECs) was created to assess tumour angiogenesis in vitro. CVMSCs were able to significantly reduce the proliferative and migratory capacity of MDA-MB231 cells. Co-culturing of MDA-MB231 with CVMSCs, not only inhibited the tube formation ability of HUVECs but also reduced the expression of the BC characteristic cytokines; IL-10, IL-12, CXCL9 and CXCL10 of CVMSCs. These results support the hypothesis that CVMSCs can influence the behavior of TNBC cells and provides a basic for a potential therapeutic approach in a pre-clinical settings. The data from this study also highlight the complexity of the in vitro cancer angiogenesis model settings and regulations. [ABSTRACT FROM AUTHOR]

Long-term survival of high-risk neuroblastoma (NB) patients still remains under 50%. Here, we report the generation, in vitro characterization and anti-tumor effectivity of a new bicistronic xenogenic DNA vaccine encoding tyrosine hydroxylase (TH) that is highly expressed in NB tumors, and the immune stimulating cytokine interleukin 15 (IL-15) that induces cytotoxic but not regulatory T cells. The DNA sequences of TH linked to ubiquitin and of IL-15 were integrated into the bicistronic expression vector pIRES. Successful production and bioactivity of the vaccine-derived IL-15- and TH protein were shown by ELISA, bioactivity assay and western blot analysis. Further, DNA vaccine-driven gene transfer to the antigen presenting cells of Peyer’s patches using attenuated Salmonella typhimurium that served as oral delivery system was shown by immunofluorescence analysis. The anti-tumor effect of the generated vaccine was evaluated in a syngeneic mouse model (A/J mice, n = 12) after immunization with S. typhimurium (3× prior and 3× after tumor implantation). Importantly, TH-/IL-15-based DNA vaccination resulted in an enhanced tumor remission in 45.5% of mice compared to controls (TH (16.7%), IL-15 (0%)) and reduced spontaneous metastasis (30.0%) compared to controls (TH (63.6%), IL-15 (70.0%)). Interestingly, similar levels of tumor infiltrating CD8+ T cells were observed among all experimental groups. Finally, co-expression of IL-15 did not result in elevated regulatory T cell levels in tumor environment measured by flow cytometry. In conclusion, co-expression of the stimulatory cytokine IL-15 enhanced the NB-specific anti-tumor effectivity of a TH-directed vaccination in mice and may provide a novel immunological approach for NB patients. [ABSTRACT FROM AUTHOR]

Background: There are different opinions of the clinical value of MRS of the brain. In selected materials MRS has demonstrated good results for characterisation of both neoplastic and non-neoplastic lesions. The aim of this study was to evaluate the supplemental value of MR spectroscopy (MRS) in a clinical setting. Material and methods: MRI and MRS were re-evaluated in 208 cases with a clinically indicated MRS (cases with uncertain or insufficient information on MRI) and a confirmed diagnosis. Both single voxel spectroscopy (SVS) and chemical shift imaging (CSI) were performed in 105 cases, only SVS or CSI in 54 and 49 cases, respectively. Diagnoses were grouped into categories: non-neoplastic disease, low-grade tumour, and high-grade tumour. The clinical value of MRS was considered very beneficial if it provided the correct category or location when MRI did not, beneficial if it ruled out suspected diseases or was more specific than MRI, inconsequential if it provided the same level of information, or misleading if it provided less or incorrect information. Results: There were 70 non-neoplastic lesions, 43 low-grade tumours, and 95 high-grade tumours. For MRI, the category was correct in 130 cases (62%), indeterminate in 39 cases (19%), and incorrect in 39 cases (19%). Supplemented with MRS, 134 cases (64%) were correct, 23 cases (11%) indeterminate, and 51 (25%) incorrect. Additional information from MRS was beneficial or very beneficial in 31 cases (15%) and misleading in 36 cases (17%). Conclusion: In most cases MRS did not add to the diagnostic value of MRI. In selected cases, MRS may be a valuable supplement to MRI. [ABSTRACT FROM AUTHOR]

Background: Some researchers reported that pleiotrophin (PTN) is associated with the development and metastasis of various tumors and it is a poor prognostic factor for the tumor patients. However, the results of other researches are inconsistent with them. It is obliged to do a meta-analysis to reach a definite conclusion. Methods: The published studies relevant to PTN were searched in the databases including PubMed, Embase and Web of Science until March 20, 2018. A meta-analysis was conducted to evaluate the role of PTN in clinicopathological characteristics and overall survival (OS) of cancer patients. Results: Our meta-analysis indicated that the high expression of PTN was remarkably associated with advanced TNM stage (OR = 2.79, 95%CI: 1.92–4.06, P<0.00001) and poor OS (HR = 1.77, 95%CI: 1.41–2.22, P<0.00001) in tumor patients. The expression of PTN was not associated with tumor size (OR = 1.12, 95% CI: 0.55–2.26, P = 0.76), lymph node metastasis (LNM) (OR = 1.95, 95%CI: 0.62–6.12, P = 0.25), distant metastasis (DM) (OR = 2.78, 95%CI: 0.72–10.74, P = 0.14) and histological grade (OR = 1.95, 95%CI: 0.98–3.87, P = 0.06). Conclusion: The high expression of PTN is significantly relevant to the advanced TNM stage and poor OS in tumor patients. PTN can serve as a promising biomarker to predict unfavorable survival outcomes, and it may be a potential target for tumor treatment. [ABSTRACT FROM AUTHOR]

Driver mutations are the genetic variants responsible for oncogenesis, but how specific somatic mutational events arise in cells remains poorly understood. Mutational signatures derive from the frequency of mutated trinucleotides in a given cancer sample, and they provide an avenue for investigating the underlying mutational processes that operate in cancer. Here we analyse somatic mutations from 7,815 cancer exomes from The Cancer Genome Atlas (TCGA) across 26 cancer types. We curate a list of 50 known cancer driver mutations by analysing recurrence in our cohort and annotations of known cancer-associated genes from the Cancer Gene Census, IntOGen database and Cancer Genome Interpreter. We then use these datasets to perform binary univariate logistic regression and establish the statistical relationship between individual driver mutations and known mutational signatures across different cancer types. Our analysis led to the identification of 39 significant associations between driver mutations and mutational signatures (P < 0.004, with a false discovery rate of < 5%). We first validate our methodology by establishing statistical links for known and novel associations between driver mutations and the mutational signature arising from Polymerase Epsilon proofreading deficiency. We then examine associations between driver mutations and mutational signatures for AID/APOBEC enzyme activity and deficient mismatch repair. We also identify negative associations (odds ratio < 1) between mutational signatures and driver mutations, and here we examine the role of aging and cigarette smoke mutagenesis in the generation of driver mutations in IDH1 and KRAS in brain cancers and lung adenocarcinomas respectively. Our study provides statistical foundations for hypothesised links between otherwise independent biological processes and we uncover previously unexplored relationships between driver mutations and mutagenic processes during cancer development. These associations give insights into how cancers acquire advantageous mutations and can provide direction to guide further mechanistic studies into cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Finding new markers to assess prognosis of melanoma without the necessity to perform a surgical interventions is an important goal in melanoma research. The current study aimed to assess the correlation of clinical course and prognosis of primary and metastatic melanoma with expression of VEGF family and their receptors. Methods: A ngTMA block was made from the randomly selected paraffin tissue blocks of the patients with melanocytic nevi, primary and metastatic melanoma. Then sections cut from ngTMA-block were immunohistochemically stained with proper antibodies. Expression of these proteins was investigated using automated image analysis and compared among the study groups. Results: We analyzed the tissue of 238 patients with following diagnoses: 101 (42.4%) with a diagnosis of nevus, 86 (36.1%) Malignant melanoma and 51 (21.4%) metastasis. Median follow-up time for the malignant lesions was 5.71 years. Among the tested antigen, VEGF-C (p = 0.016), VEGF-R2 (p<0.001) and VEGF-R3 (p = 0.002) were significantly higher expressed in the metastatic tissues. When these scores were assessed in multiple regression models, the only independent factor linked to patient’s diagnosis was VEGF-R2 (p<0.001). In addition, groups of highly correlated variables (VEGF-C and VEGF-R3, VEGF-A and VEGF-R1) were found to form separate sub-clusters. On the other side, high values of VEGF-C were associated with both overall and disease-free survival with a statically significant HR of 2.76 (95% CI: 1.27, 5.98; p = 0.01) and 2.82 (95%CI: 1.62, 4.91; p<0.001), respectively. Conclusions: This study shows that VEGF-C and VEGF-R2 might represent new prognostic marker in MM. However, further prospective studies are warranted to test their real efficacy as a prognostic marker. [ABSTRACT FROM AUTHOR]

Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up-regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, we uncovered TRIM59 as a key regulator of cell contractility and adhesion to control the plasticity of metastatic tumor cells. At the molecular level, we identified programmed cell death protein 10 (PDCD10) as a target of TRIM59. TRIM59 stabilized PDCD10 by suppressing RING finger and transmembrane domain-containing protein 1 (RNFT1)-induced lysine 63 (K63) ubiquitination and subsequent phosphotyrosine-independent ligand for the Lck SH2 domain of 62 KDa (p62)-selective autophagic degradation. TRIM59 promoted PDCD10-mediated suppression of Ras homolog family member A (RhoA)-Rho-associated coiled-coil kinase (ROCK) 1 signaling to control the transition between amoeboid and mesenchymal invasiveness. PDCD10 overexpression or administration of a ROCK inhibitor reversed TRIM59 loss-induced contractile phenotypes, thereby accelerating cell migration, invasion, and tumor formation. These findings establish the rationale for targeting deregulated TRIM59/PDCD10 to treat breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Radiomics provides quantitative tissue heterogeneity profiling and is an exciting approach to developing imaging biomarkers in the context of precision medicine. Normal-appearing parenchymal tissues surrounding primary tumors can harbor microscopic disease that leads to increased risk of distant metastasis (DM). This study assesses whether computed-tomography (CT) imaging features of such peritumoral tissues can predict DM in locally advanced non-small cell lung cancer (NSCLC). Material and methods: 200 NSCLC patients of histological adenocarcinoma were included in this study. The investigated lung tissues were tumor rim, defined to be 3mm of tumor and parenchymal tissue on either side of the tumor border and the exterior region extended from 3 to 9mm outside of the tumor. Fifteen stable radiomic features were extracted and evaluated from each of these regions on pre-treatment CT images. For comparison, features from expert-delineated tumor contours were similarly prepared. The patient cohort was separated into training and validation datasets for prognostic power evaluation. Both univariable and multivariable analyses were performed for each region using concordance index (CI). Results: Univariable analysis reveals that six out of fifteen tumor rim features were significantly prognostic of DM (p-value < 0.05), as were ten features from the visible tumor, and only one of the exterior features was. Multivariablely, a rim radiomic signature achieved the highest prognostic performance in the independent validation sub-cohort (CI = 0.64, p-value = 2.4×10−5) significantly over a multivariable clinical model (CI = 0.53), a visible tumor radiomics model (CI = 0.59), or an exterior tissue model (CI = 0.55). Furthermore, patient stratification by the combined rim signature and clinical predictor led to a significant improvement on the clinical predictor alone and also outperformed stratification using the combined tumor signature and clinical predictor. Conclusions: We identified peritumoral rim radiomic features significantly associated with DM. This study demonstrated that peritumoral imaging characteristics may provide additional valuable information over the visible tumor features for patient risk stratification due to cancer metastasis. [ABSTRACT FROM AUTHOR]

We have identified nine highly connected and differentially expressed gene subnetworks between aggressive primary tumors and metastatic lesions in endometrial carcinomas. We implemented a novel pipeline combining gene set and network approaches, which here allows integration of protein-protein interactions and gene expression data. The resulting subnetworks are significantly associated with disease progression across tumor stages from complex atypical hyperplasia, primary tumors to metastatic lesions. The nine subnetworks include genes related to metastasizing features such as epithelial-mesenchymal transition (EMT), hypoxia and cell proliferation. TCF4 and TWIST2 were found as central genes in the subnetwork related to EMT. Two of the identified subnetworks display statistically significant association to patient survival, which were further supported by an independent validation in the data from The Cancer Genome Atlas data collection. The first subnetwork contains genes related to cell proliferation and cell cycle, while the second contains genes involved in hypoxia such as HIF1A and EGLN3. Our findings provide a promising context to elucidate the biological mechanisms of metastasis, suggest potential prognostic markers and further identify therapeutic targets. The pipeline R source code is freely available, including permutation tests to assess statistical significance of the identified subnetworks. [ABSTRACT FROM AUTHOR]

Background & aim: Liver metastasis has been found to affect outcome in prostate, pancreatic and colorectal cancers, but its role in lung cancer is unclear. The 5 year survival rate remains extensively low owing to intrinsic resistance to conventional therapy which can be attributed to the genetic modulators involved in the pathogenesis of the disease. Thus, this study aims to generate a model for early diagnosis and timely treatment of liver metastasis in lung cancer patients. Methods: mRNA expression of 15 genes was quantified by real time PCR on lung cancer specimens with (n = 32) and without (n = 30) liver metastasis and their normal counterparts. Principal Component analysis, linear discriminant analysis and hierarchical clustering were conducted to obtain a predictive model. The accuracy of the models was tested by performing Receiver Operating Curve analysis. Results: The expression profile of all the 15 genes were subjected to PCA and LDA analysis and 5 models were generated. ROC curve analysis was performed for all the models and the individual genes. It was observed that out of the 15 genes only 8 genes showed significant sensitivity and specificity. Another model consisting of the selected eight genes was generated showing a specificity and sensitivity of 90.0 and 96.87 respectively (p <0.0001). Moreover, hierarchical clustering showed that tumors with a greater fold change lead to poor prognosis. Conclusion: Our study led to the generation of a concise, biologically relevant multi-gene panel that significantly and non-invasively predicts liver metastasis in lung cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Tumor characteristics in computed tomography (CT) are correlated to pathologic presentation and survival. However, most studies have been based on thin slice thickness CT while lymph node metastatic pattern has remained unclear. The aim of this study was to analyze the correlation between image characteristics under 5 mm slice thickness and pathology findings in non small lung cancer patients who have received curative resection. Materials and methods: From January 2010 to May 2014, 440 patients who underwent curative resection were included and medical records were reviewed retrospectively. The tumor size and consolidation tumor ratio were simultaneously evaluated and measured by a physician, a thoracic surgeon, and a radiologist. The correlation between image and pathology characteristics and its survival impact was analyzed. Results: Tumor sizes, as measured by CT and by pathologic measurement were highly coincident. (p < 0.001) GGO predominant lesions were correlated to well-differentiated adenocarcinoma, (p< 0.001), and less tumor necrosis (p<0.0001), lymphocyte infiltration (p = 0.0042) and tumor purity (p <0.0001). In addition, less risk of visceral pleura (p < 0.0001) and angiolymphatic invasion, and fewer metastases to N1 lymph node (p = 0.004) involvement were identified. No lymph node metastasis (0/12) was identified in sub-centimeter pure GGO lesion. The consolidation tumor ratio could be used to differentiate patients’ survival and excellent 5-year overall survival was identified in pure GGO lesion cases. Conclusion: No lymph node metastasis was identified in sub-centimeter pure GGO lesion. The consolidation tumor ratio could be used to differentiate patients’ disease status and overall survival, while excellent 5-year overall survival was identified in cases with pure GGO lesion. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most frequently diagnosed cancer and the fifth leading cause of death from cancer in men worldwide. Increased understanding of the prostate cancer metastasis mechanisms will help identify more efficient intervention strategies to prevent or treat this deadly disease in the future. To identify the candidate proteins that contribute to metastasis of PCa, isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis was performed to explore differentially expressed proteins between two homologous human prostate cancer cell lines including highly-metastatic PC-3M-1E8 cell line and poorly-metastatic PC-3M-2B4 cell line. Here, a total of 58 proteins were identified to be significantly differentially expressed between PC-3M-1E8 and PC-3M-2B4 cells, which were further verified using real-time quantitative PCR and western blot analysis. The bioinformatic analysis suggested that the differentially expressed proteins, like MMP1 and FHL1, may contribute to the higher metastatic ability of PC-3M-1E8 cells than PC-3M-2B4 cells. In addition, functional analyses proved MMP1’s positive effect on the higher metastatic ability of PC-3M-1E8 cells than PC-3M-2B4 cells. These findings provided a unique resource to specifically reveal the complex molecular regulatory mechanisms underlying the progression of prostate cancer from poorly-metastatic to highly-metastatic stage. [ABSTRACT FROM AUTHOR]

Dogs diagnosed with appendicular osteosarcoma typically succumb to metastatic disease within a year of diagnosis. The current standard of care for curative intent, amputation followed by adjuvant chemotherapy, increases survival time but chemoresistance is a major contributor to mortality. Unfortunately, the mechanisms driving the progression of metastatic disease and the development of chemoresistance are unknown. One theory is that autophagy may contribute to chemoresistance by providing neoplastic cells with a mechanism to survive chemotherapy treatment. Our objective was to evaluate the effect of combining an autophagy inhibitor with a standard chemotherapeutic drug on response to chemotherapy in canine appendicular osteosarcoma cells. We hypothesized that combining the autophagy inhibitor spautin-1 with doxorubicin treatment would enhance chemoresponsiveness. Using commercial (D17) and primary cell lines derived from 1° and 2° sites of osteosarcoma, we showed that this combination treatment enhances cell killing and inhibits colony formation. Our findings support the theory that autophagy contributes to chemoresistance in canine appendicular osteosarcoma and indicate that adding an autophagy inhibitor to the standard of care has the potential to improve outcome. [ABSTRACT FROM AUTHOR]

Background: Activation of Ras oncogene in human tumors is associated with radiation-associated metastatic potential. Although ionizing radiation is one important method of cancer treatments, it has been shown to enhance matrix metalloproteinases (MMPs) activity and facilitates a more aggressive cancer phenotype. Our previous studies showed that andrographolide with lower dose rates of radiation could inhibit RAS-transformed cancer metastasis in vivo; however, the molecular mechanisms are not yet clear. In this study, we aimed to explore the anti-metastatic effect of andrographolide combined with radiation on Ras-transformed cells. Methods: RAS-transformed cells were treated with andrographolide in the presence or absence of irradiation (2–4 Gy) or angiotensin II to examine cell invasion. In vivo tumorigenesis assays were also performed. The MMP-2 activity was detected by using Gelatin zymography. Signal transduction of NF-κB subunit, p65 and phosphor-ERK 1/2, were examined by using Western blotting analysis. Results: Treatment with andrographolide inhibited migration of Ras-transformed cells. Andrographolide treatment with radiation significantly inhibited cancer metastasis in vivo. We found that andrographolide exhibited anti-migration and anti-invasive ability against cancer metastasis via inhibition of MMP2 activity rather than affected MMP-9 and EMT. In addition, combined andrographolide with radiation appeared to be more effective in reducing MMP-2 expression, and this effect was accompanied by suppression of ERK activation that inhibits cancer cell migration and invasion. Conclusions: These findings suggest that andrographolide enhances the anti-metastatic effect of radiation in Ras-transformed cells via suppression of ERK–mediated MMP-2 activity. [ABSTRACT FROM AUTHOR]

Background and aim: Endoscopic submucosal dissection (ESD) has been accepted as the treatment of choice for early gastric cancer (EGC) without lymph node metastasis. However, additional surgical gastrectomy should be considered after non-curative endoscopic resection. We aimed to evaluate the predictive factors associated with non-curative endoscopic resection. Methods: Between November 2008 and June 2015, a retrospective study was conducted in a single, tertiary, referral hospital. A total of 596 EGC lesions resected by ESD were analyzed. Non-curative endoscopic resection was defined as the occurrence of lesions associated with piecemeal resection, positive resection margins, lymphovascular invasion, or lesions that did not meet the expanded indications for ESD. Results: The rate of non-curative endoscopic resection was 16.1%. The mean follow-up period was 35.3 ± 25.0 months. Associated predictive factors for non-curative endoscopic resection were female sex (OR, 2.470; p = 0.004), lesion size ≥ 20 mm (OR 3.714; p < 0.001), longer procedure time (OR 2.449, p = 0.002), ulceration (OR 3.538, p = 0.002), nodularity (OR 2.967, p<0.001), depression (OR 1.806, p = 0.038), undifferentiated carcinoma (OR 2.825, p = 0.031) and lesion located in the mid or upper third of stomach (OR 7.135 and OR 4.155, p<0.001, respectively). As the number of risk factors increased, the risk of non-curative ESD also increased. Conclusions: Prior to selection of ESD, the risks associated with non-curative ESD should be considered so that appropriate treatment modalities may be selected. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is one of the most dangerous and frequently occurring cancers among women, and it also affects men. We aimed to determine the prevalence and factors associated with mortality among patients with breast cancer in Saudi Arabia. Method: Data for this analysis of breast cancer mortality among Saudi Arabians were obtained from the Saudi Arabian Cancer Registry at the King Faisal Hospital and Research Centre. Both descriptive and inferential statistical analyses were conducted using proportions, chi-squared tests, and the Cox regression model. Frequentist and Bayesian inferential statistics were used to estimate the risk ratios. A frailty term was specified to control for suspected heterogeneity across regions. Bayesian and deviance information criteria were used to discriminate between the frequentist and Bayesian frailty models, respectively. Results: Out of 5,411 patients, 708 (13.08%) deaths occurred that were attributable to breast cancer. Of those, 12 (1.69%) were men. Among patients who died of breast cancer, 353 (49.86%) had tumours that originated on the left side and 338 (47.74%) on the right side. In terms of the stage or extent of breast cancer, 318 (44.92%) deaths occurred among patients who had distant metastases, followed by 304 (42.94%) who had regional metastases and 86 (12.15%) with localized cancers. Men were 72% more likely than women to die from breast cancer. Divorcees were twice as likely to die, compared to their married counterparts. Patients whose tumours were classified as Grade IV had the highest mortality rate, which was 5.0 times higher than patients with Grade I tumours (credible interval (CrI); 1.577, 14.085) and 3.7 times higher than patients with Grade II tumours (CrI; 1.205, 9.434). Conclusion: There is a high prevalence of breast cancer mortality among Saudi Arabian women, with the highest prevalence among divorced women. Though the prevalence of breast cancer mortality among men is lower than that of women, men had a higher risk of death. We therefore recommend an intensive health education programme for both men and women. These programmes should discuss the consequences of divorce, the prevalence of breast cancer among men, and early diagnoses and treatments for breast cancer. [ABSTRACT FROM AUTHOR]

We aimed to identify factors predicting parametrial invasion in early-stage cervical cancer patients undergoing radical hysterectomy. We recruited women with invasive cervical cancer who underwent radical hysterectomy at a single medical institute from 2000–2011. The clinical and pathological characteristics and outcomes were retrospectively recorded, and the risk factors for parametrial invasion were analyzed. We enrolled 339 patients, including 7 with stage IA1 carcinomas, 10 with stage IA2, 266 with stage IB1, 39 with stage IB2, 14 with stage IIA1, and 3 with stage IIA2. The majority (237/339, 69.9%) had squamous cell carcinoma, while 32 (12.4%) had parametrial invasion. The 16 patients with stage IB1 tumors and parametrial invasion were older (55.9±9.5vs. 49.0±9.9 years, p = 0.005, Mann-Whitney U test), and had deeper cervical stromal invasion (9.59±4.87 vs. 7.47±5.48 mm, p = 0.048, Mann-Whitney U test), larger tumor size (2.32±1.15 vs. 1.74±1.14cm, p = 0.043, Mann-Whitney U test), higher incidences of lymphovascular space invasion (87.5% vs. 28.8%, p<0.001, chi-square test), and greater lymph node metastasis (68.8% vs. 10.8%, p<0.001, chi-square test) than the 260 patients without parametrial invasion. Among the patients with stage IB1 tumor size >2 cm,10% had parametrial invasion and 24.2% had lymph node metastasis compared with only 4% and 9.4% of stage IB1 patients with a tumor size <2 cm, respectively. Only one (0.9%) of the 109 patients aged less than 50 years had parametrial invasion compared with 6 (9.7%) of the 62 patients aged over 50 years. Patients with stage IA2 and IB1 tumors <2 cm may not need radical hysterectomy owing to the low incidence of parametrial invasion. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is one of the aggressive malignancies and mechanisms underlying its pathogenesis remain unclear. Cyclooxygenase-2 (COX-2) enzyme system plays a crucial role in many gastrointestinal malignancies and is an important regulator of cell growth, proliferation, apoptosis, differentiation and transformation. More precise outcome of COX-2 in ESCC is less investigated. In this study we investigated the risk factors of ESCC and expression of COX-2 in Carcinoma in situ (CIS) and ESCC compared to normal esophageal mucosa. ESCC relationship to clinico-pathological parameters using immunohistochemistry was also part of this investigation. Current study was conducted in the Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. A total of 69 diagnosed patients of ESCC, both Pakistanis and Afghans were enrolled. Various risk factors associated with ESCC were recorded. Mean age at the time of diagnosis was 55 years. Out of 69 patients of ESCC 46 (67%) were users of dipping tobacco (Naswar). Expression of COX-2 was determined in normal esophageal mucosa, CIS and invasive ESCC using Immunohistochemistry (IHC). Differences of mean were computed using ANOVA followed by applying Post Hoc test. Patients were categorized as positive with high expression or negative with low to nil expression. ANOVA showed large differences in expression of COX-2 in normal healthy mucosa compared with CIS and ESCC with the mean difference of -9.529 and -7.370 respectively, p-value being <.05 at 95% confidence interval (CI). No significant difference was noticed in the expression of COX-2 in CIS compared with ESCC with p-value >.05 at 95% CI. Our complete cohort (23–85 years) showed statistically significant difference in the expression of COX-2 gene in ESCC and CIS tissue samples compared with normal healthy mucosa. Results of this study indicate that over-expression of COX-2 is positively associated with ESCC. [ABSTRACT FROM AUTHOR]

Background: Treatment modality of unknown primary squamous cell carcinoma of the head and neck (SCCHN) remains controversial. Objectives: To evaluate the treatment outcomes and prognostic factors of unknown primary SCCHN. Materials and methods: Patients with unknown primary SCCHN from April 1995 to March 2013 were recruited retrospectively. Results: Sixty-nine patients were enrolled. The median time of follow-up was 55.5 months. The 2-year loco-regional control rate of all the patients was 60.4%. Multivariate Cox regression analysis revealed that N3 stage, extracapsular spread, distant metastasis, and treatment modality were significantly associated with neck recurrence. The actuarial 5-year disease-specific survival rates of neck dissection, neck dissection plus adjuvant therapy, radiotherapy alone, and combined therapy were 80.0%, 61.7%, 33.3%, and 68.8%, respectively (p = 0.046). The 5-year disease-specific survival rates of N1/N2a, N2b/N2c, and N3 stage were 83.9%, 64.3%, and 36.7%, respectively (p = 0.013). Univariate regression analysis revealed that neck recurrence, supraclavicular node involvement, distant metastasis, N3 stage, and unhealthy lifestyle habits were correlated with disease-specific mortality, especially the first three parameters. Patient’s occupation and comorbidity were not significantly correlated with survival. Conclusions: Composite therapy is mandatory for advanced unknown primary SCCHN. Supraclavicular node involvement and unhealthy lifestyle habits, such as betel nut chewing, indicate a poor prognosis. [ABSTRACT FROM AUTHOR]

Identifying subgroups of treatment responders through the different phases of clinical trials has the potential to increase success in drug development. Recent developments in subgroup analysis consider subgroups that are defined in terms of the predicted individual treatment effect, i.e. the difference between the predicted outcome under treatment and the predicted outcome under control for each individual, which in turn may depend on multiple biomarkers. In this work, we study the properties of different modelling strategies to estimate the predicted individual treatment effect. We explore linear models and compare different estimation methods, such as maximum likelihood and the Lasso with and without randomized response. For the latter, we implement confidence intervals based on the selective inference framework to account for the model selection stage. We illustrate the methods in a dataset of a treatment for Alzheimer disease (normal response) and in a dataset of a treatment for prostate cancer (survival outcome). We also evaluate via simulations the performance of using the predicted individual treatment effect to identify subgroups where a novel treatment leads to better outcomes compared to a control treatment. [ABSTRACT FROM AUTHOR]

The oncologic risk of ionizing radiation is widely known. Sarcomas developing after radiotherapy have been reported, and they are a growing problem because rapid advancements in cancer management and screening have increased the number of long-term survivors. Although many patients have undergone radiation treatment in Asian countries, scarce reports on post-radiation sarcomas (PRSs) have been published. We investigated the feature and prognostic factors of PRSs in an Asian population. The Eastern Asian Musculoskeletal Oncology Group participated in this project. Cases obtained from 10 centers were retrospectively reviewed. Patients with genetic malignancy predisposition syndrome, or who had more than one type of malignancy before the development of secondary sarcoma were excluded. Forty-two high-grade sarcomas among a total of 43 PRSs were analyzed. There were 29 females and 13 males, with a median age of 58.5 years; 23 patients had bone tumors and 19 had soft tissue tumors. The most common primary lesion was breast cancer. The median latency period was 192 months. There were no differences in radiation dose, latency time, and survival rates between bone and soft tissue PRSs. The most common site and diagnosis were the pelvic area and osteosarcoma and malignant fibrous histiocytoma for bone and soft tissue PRSs. The median follow-up period was 25.5 months. Five-year metastasis-free and overall survival rates were 14.5% and 16.6%, and 39.1% and 49.6% for bone and soft tissue PRSs. Survival differences depending on initial metastasis and surgery were significant in soft tissue sarcomas. Although this study failed to find ethnic differences, it is the largest review on PRS in an Asian population. As early recognition through long-term surveillance is a key to optimal management, clinicians should take efforts to understand the real status of PRS. [ABSTRACT FROM AUTHOR]

Synonymous mutations continue to be filtered out from most large-scale cancer genome studies, but several lines of evidence suggest they can play driver roles in neoplastic disease. We investigated a case of an aggressive, apparently sporadic medullary thyroid carcinoma (MTC) harboring a somatic RET p.Cys634Arg mutation (a known MTC driver). A germ-line RET substitution (p.Cys630=) had also been found but was considered clinically irrelevant because of its synonymous nature. Next generation sequencing (NGS) of the tumor tissues revealed that the RET mutations were in cis. There was no evidence of gene amplification. Expression analysis found an increase of RET transcript in p.Cys630=;p.Cys634Arg patient compared with that found in 7 MTCs harboring p.Cys634 mutations. Minigene expression assays demonstrated that the presence of the synonymous RET mutation was sufficient to explain the increased RET mRNA level. In silico analyses and RNA immunoprecipitation experiments showed that the p.Cys630 = variant created new exonic splicing enhancer motifs that enhanced SRp55 recruitment to the mutant allele, leading to more efficient maturation of its pre-mRNA and an increased abundance of mature mRNA encoding a constitutively active RET receptor. These findings document a novel mechanism by which synonymous mutations can contribute to cancer progression. [ABSTRACT FROM AUTHOR]

Background: Cancers induce gene expression alterations in stroma surrounding tumors that supports cancer progression. However, it is actually not at all known the extent of altered stromal gene expression enacted by tumors nor the extent to which altered stromal gene expression penetrates the stromal tissue. Presently, post-surgical “tumor-free” stromal tissue is determined to be cancer-free based on solely on morphological normality—a criteria that has not changed in more than 100 years despite the existence of sophisticated gene expression data to the contrary. We therefore investigated the extent to which breast tumors alter stromal gene expression in three dimensions in women undergoing mastectomy with the intent of providing a genomic determination for development of future risk of recurrence criteria, and to inform the need for adjuvant full-breast irradiation. Methods and findings: Genome-wide gene expression changes were determined in histopathologically normal breast tissue in 33 women undergoing mastectomy for stage II and III primary invasive ductal carcinoma at serial distances in three dimensions from the tumor. Gene expression was determined by genome-wide mRNA analysis and subjected to metagene mRNA characterization. Tumor-like gene expression signatures in stroma were identified that surprisingly transitioned to a plastic, normalizing homeostatic signature with distance from tumor. Stroma closest to tumor displayed a pronounced tumor-like signature enriched in cancer-promoting pathways involved in disruption of basement membrane, cell migration and invasion, WNT signaling and angiogenesis. By 2 cm from tumor in all dimensions, stromal tissues were in transition, displaying homeostatic and tumor suppressing gene activity, while also expressing cancer supporting pathways. Conclusions: The dynamics of gene expression in the post-tumor breast stroma likely co-determines disease outcome: reversion to normality or transition to transformation in morphologically normal tissue. Our stromal genomic signature may be important for personalizing surgical and adjuvant therapeutic decisions and risk of recurrence. [ABSTRACT FROM AUTHOR]

Background and aims: The clinical value of the prognostic nutritional index (PNI) in hepatocellular carcinoma (HCC) has been investigated in previous studies, but the results remain controversial. Here we present a meta-analysis to systematically review the association between PNI and HCC prognosis. Method: PubMed, EMBASE, Web of Science databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to determine the prognostic and clinic-pathological values of PNI in HCC patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were extracted to estimate the association of PNI with survival and clinic-pathological characteristics, respectively. Results: A total of eleven studies involving 3165 patients were analyzed. The pooled results indicated that low PNI is a significant predictor of poor 1-year, 3-year, 5-year OS (OR, 2.91, 4.05, 3.65; 95%CI, 2.30 to 3.70, 3.27 to 5.03,2.96–4.50; P = 0.14,0.22,0.11 respectively) and disease-free survival (DFS) (OR,2.35, 2.57, 2.75; 95%CI, 1.71 to 3.23, 1.89 to 3.49,2.01 to 3.75; P = 0.39,0.04,0.11, respectively). Moreover, PNI is significantly associated with serum AFP, tumor recurrence, tumor size and TNM stages in HCC patients. However, PNI is not significantly associated with tumor number and the incidence of cirrhosis in HCC patients. Conclusions: PNI is an independent predictive indicator of survival and associated with serum AFP, tumor recurrence, tumor size and TNM stages in HCC patients. [ABSTRACT FROM AUTHOR]

Metformin, a first-line drug used to treat type 2 diabetes, has also been shown to have anticancer effects against a variety of malignancies, including colorectal cancer. Although inhibition of the mTOR pathway is known to be the most important mechanism for the antitumor effects of metformin, other mechanisms remain unclear. The purpose of this study was to identify the antitumor mechanism of metformin in colorectal cancer using high-throughput data, and then test the mechanism experimentally. We identified the gene signature of metformin-treated colon cancer cells. This signature was processed for prediction using colon adenocarcinoma patient data from the Cancer Genome Atlas to classify the patients showing a gene expression pattern similar to that in metformin-treated cells. This patient group showed better overall and disease-free survival. Furthermore, pathway analysis revealed that the metformin-predicted group was characterized by decreased interleukin (IL)-6 pathway signaling, epithelial–mesenchymal transition, and colon cancer metastatic signaling. We induced epithelial–mesenchymal transition in colon cancer cell lines via IL-6 treatment, which increased cell motility and promoted invasion. However, these effects were blocked by metformin. These findings suggest that blockade of IL-6-induced epithelial–mesenchymal transition is an antitumor mechanism of metformin. [ABSTRACT FROM AUTHOR]

Objective: To study the prognostic value of baseline leukocytosis or neutrophiliain two retrospective cohorts of stage III Non-Small Cell Lung Cancer (NSCLC) patients. Materials and methods: Clinical records of consecutive previously untreated NSCLC patients in our Institution between June 2001 and September 2016 for stage III NSCLC were collected. The prognostic value of pretreatment leucocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophil count exceeding 10 and 7 G/L, respectively. Results: We identified 238 patients, displaying baseline leukocytosis or neutrophilia in 39% and 40% respectively. Most were diagnosed with adenocarcinoma (48%), and stage IIIB NSCLC (58%). 3-year actuarial overall survival (OS) and progression-free survival (PFS) were 35% and 27% respectively. Local relapses were reported in 100 patients (42%), and distant metastases in 132 patients (55%). In multivariate analysis, leukocytosis, neutrophilia, and induction chemotherapy regimen based on carboplatin/paclitaxel were associated with worse OS and PFS (p<0.05). Neutrophilia independently decreased Locoregional Control (LRC) (HR = 2.5, p<0.001) and Distant Metastasis Control (DMC) (HR = 2.1, p<0.001). Neutrophilia was significantly associated with worse brain metastasis control (p = 0.004), mostly in adenocarcinoma patients (p<0.001). Conclusion: In stage III NSCLC patients, treated with concurrent cisplatin-based chemoradiation, baseline leukocytosis and neutrophilia were associated with worse OS, PFS, LRC, and DMC. In addition with previously available markers, this independent cost-effective biomarker could help to stratify stage III NSCLC population with more accuracy. [ABSTRACT FROM AUTHOR]

The delivery of blood-borne therapeutic agents to solid tumours depends on a broad range of biophysical factors. We present a novel multiscale, multiphysics, in-silico modelling framework that encompasses dynamic tumour growth, angiogenesis and drug delivery, and use this model to simulate the intravenous delivery of cytotoxic drugs. The model accounts for chemo-, hapto- and mechanotactic vessel sprouting, extracellular matrix remodelling, mechano-sensitive vascular remodelling and collapse, intra- and extravascular drug transport, and tumour regression as an effect of a cytotoxic cancer drug. The modelling framework is flexible, allowing the drug properties to be specified, which provides realistic predictions of in-vivo vascular development and structure at different tumour stages. The model also enables the effects of neoadjuvant vascular normalisation to be implicitly tested by decreasing vessel wall pore size. We use the model to test the interplay between time of treatment, drug affinity rate and the size of the vessels endothelium pores on the delivery and subsequent tumour regression and vessel remodelling. Model predictions confirm that small-molecule drug delivery is dominated by diffusive transport and further predict that the time of treatment is important for low affinity but not high affinity cytotoxic drugs, the size of the vessel wall pores plays an important role in the effect of low affinity but not high affinity drugs, that high affinity cytotoxic drugs remodel the tumour vasculature providing a large window for the normalisation of the vascular architecture, and that the combination of large pores and high affinity enhances cytotoxic drug delivery efficiency. These results have implications for treatment planning and methods to enhance drug delivery, and highlight the importance of in-silico modelling in investigating the optimisation of cancer therapy on a personalised setting. [ABSTRACT FROM AUTHOR]

Purpose: Human papillomavirus (HPV) infected oropharyngeal squamous cell carcinoma (OPSCC) patients have a better prognosis compared to HPV(-) counterparts. However, a subset of HPV(+) patients with a smoking history fail to respond to the standard of care treatments such as radiation and chemotherapy. To understand the underlying mechanism driving HPV(+) OPSCC patient resistance to treatment and recurrence, we sought to identify and characterize the differentially expressed miRNAs and their target genes in HPV(+) smokers and non-smokers. Experimental design: MicroRNA expression analysis was performed using Nanostring in tumor tissues isolated from a prospective cohort of HPV(+) smoking (n = 9) and HPV(+) (n = 13) non-smoking OPSCC patients. Identified miRNAs of interest were further validated using qRT-PCR in cigarette smoke extract (CSE) treated HPV(+) and E6/E7 overexpressing HPV(-) cells. Results: In comparison to OPSCC HPV(+) non-smokers, 38 miRNAs were significantly altered in the HPV(+) smoker patients cohort and out of that 9 were downregulated. Altered miRNA expression was also detected in the serum and metastatic lymph nodes of HPV(+) smokers versus non-smokers. Expression of miR-133a-3p was significantly downregulated in OPSCC smokers, HPV(+) cells and E6/E7 overexpressing HPV(-) cells treated with CSE. Reduction of miR-133a-3p induced the upregulation of miR-133a-3p target mRNAs EGFR and HuR. Conclusions: Our results indicate that miR-133a-3p is a target of smoking-induced changes in HPV(+) patients and alters the expression of EGFR and HuR which may promote HPV associated oropharyngeal cancer. Therefore, future treatment strategies for HPV(+) OPSCC smokers should focus on EGFR inhibition and the development of selective therapies to target HuR. [ABSTRACT FROM AUTHOR]

Objective: PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) regulates components of the cell cycle, including cell growth, immune responses, DNA damage repair, apoptosis, and inflammation. PBK/TOPK may also accelerate tumorigenesis in colorectal cancer. Methods: We investigated the impact of PBK/TOPK on the clinical outcome of colorectal cancer patients to further identify its role in colorectal cancer. PBK/TOPK immunoreactivity was analyzed by immunohistochemistry in 162 cancer specimens from primary colorectal cancer patients. Results: The mean follow-up time after surgery was 5.4 years (medium: 3.9 years; range 0.01 to 13.1 years). The prognostic value of PBK/TOPK on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. PBK/TOPK was expressed in both the cytoplasm and nucleus. High PBK/TOPK expression in tumor cells was significantly associated with advanced T value. The 5-year survival rate was greater for patients with high total PBK/TOPK expression than with low PBK/TOPK expression (58.3% vs 34.4%, P = 0.005). Multivariate analyses showed that low-scoring cytoplasmic PBK/TOPK, negative nuclear PBK/TOPK, low total PBK/TOPK, and advanced tumor stage were correlated with poor overall patient survival. Conclusions: We suggest that PBK/TOPK expression, detected by IHC staining, could be used as an independent prognostic marker for colorectal cancer patients. [ABSTRACT FROM AUTHOR]