bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostate-Specific Antigen Levels among Cirrhotic Patients
Authors: Akdogan M. , Hassoun B.S. , Gurakar A. , El-Sahwi K. , Jazzar A. , Wright H. , Sebastian A. , Nour B.
Published: January 2018

Purpose

The aim of this study was to determine serum prostate-specific antigen (PSA) levels in patients with liver cirrhosis.

Patients and methods

Between January 1995 and August 2001, 216 men with cirrhosis were evaluated. The extent of their liver disease was classified according to the Child-Pugh classification. Serum PSA levels were measured with the Hybritech Tandem-R RIA method and matched with age-related reference PSA levels. Digital rectal examination (DRE) was performed in all patients. Patients with elevated PSA levels and/or abnormal DRE were recommended to undergo further assessment including transrectal ultrasonography (TRUS) and biopsy performed by an urologist.

Results

Two hundred and sixteen men (mean age 54.09±9.09 years, range 25–76) with cirrhosis were examined. Their mean PSA value was 0.57±0.84 ng/mL and tended to be lower than in the normal population. The degree of PSA decrease was found to parallel the severity of the liver disease (p=0.002). The mean serum PSA level increased with each age decade in a statistically significant manner (p<0.001). Four patients (three with elevated PSA values) underwent prostate biopsy. Three biopsies were positive for prostate cancer, the other showed evidence of benign prostatic hyperplasia (BPH).

Conclusion

Serum PSA is influenced by the severity of liver disease and its levels tend to be lower in cirrhotic patients than in the normal population. However, serum PSA can still be considered a reliable marker in the clinical management of prostatic disease in patients with cirrhosis.
Thrombin is Present in the Lungs of Patients with Primary Extremity Osteosarcoma and Pulmonary Metastases
Authors: Hernández-Rodríguez N.A. , Correa E. , Sotelo R. , Gómez-Ruiz C. , Contreras-Paredes A. , Green L.
Published: January 2018

Osteosarcoma is a rare cancer, which metastasizes to the lung in up to 80% of cases. Thrombin is involved in metastasis and is present in the lungs of patients with pulmonary metastases (PM). To identify its role in PM and osteosarcoma, we measured thrombin levels in the bronchoalveolar lavage fluid (BALF) of 15 patients. BALF was collected at different stages of the disease and correlated with the diagnosis of PM. We also assessed fibrinogen overexpression in the tumors. We found that 11/15 (73%) patients with high thrombin levels in the lungs developed PM within the first 12 months from primary surgery. The median thrombin concentration in the BALF of these patients increased up to 8×10-9 M (range, 3×10-9M-15×10-9M), which represents a more than 100-fold increase compared to patients without PM (p<0.0001). Eight of 15 (53%) primary and 11/15 (73%) metastatic samples showed fibrinogen overexpression. A significant difference between high thrombin levels, fibrinogen overexpression and PM was found compared to patients without PM (p=0.00073 and p=0.025). These results show that thrombin levels are increased in the lungs of patients with primary osteosarcoma and a high risk of developing PM. They suggest that thrombin may be involved in the development of PM.
Natural History of Estrogen Receptor-Negative, Progesterone Receptor-Positive Breast Cancer
Authors: Nikolic-Vukosavljevic D. , Kanjer K. , Neskovic-Konstantinovic Z. , Vukotic D.
Published: January 2018

The biological significance of estrogen receptor-negative but progesterone receptor-positive breast carcinomas is not clear. In the present study the aggressiveness of breast carcinomas in relation to ER and PgR status has been investigated. The probability of disease-free survival in 297 node-negative breast carcinoma patients was monitored during a follow-up ranging from six to 96 months (median 45 months). Steroid hormone receptor content was assayed with the biochemical method recommended by the EORTC. The probability of disease-free survival was significantly worse for patients with ER-negative, PgR-positive carcinomas compared to the other three steroid hormone receptor phenotypes. Our results suggest that ER-negative, PgR-positive breast carcinomas are biologically different in terms of aggressiveness from the other steroid hormone receptor phenotypes.
Quality Control for Biomarker Determination in Oncology: The Experience of the Italian Network for Quality Assessment of Tumor Biomarkers (INQAT)
Authors: Paradiso A. , Volpe S. , Iacobacci A. , Marubini E. , Verderio P. , Costa A. , Daidone M.G. , Marchetti A. , Mottolese M. , Amadori D. , De Paola F. , Saragoni L. , Medri L. , Nenci I. , Querzoli P. , Gion M. , Dittadi R. , Plebani M. , Orlando C. , Bevilacqua G. , Silvestrini R.
Published: January 2018

Biomarker analysis and evaluation in oncology is the product of a number of processes (including managerial, technical and interpretation steps) which need to be monitored and controlled to prevent and correct errors and guarantee a satisfactory level of quality. Several biomarkers have recently moved to clinical validation studies and successively to clinical practice without any definition of standard procedures and/or quality control (QC) schemes necessary to guarantee the reproducibility of the laboratory information. In Italy several national scientific societies and single researchers have activated – often on a pilot level – specific external quality assessment protocols, thereby potentially jeopardizing the clinical reality even further. In view of the seriousness of the problem, in 1998 the Italian Ministry of Health sponsored a National Survey Project to coordinate and standardize the procedures and to develop QC programs for the analysis of cancer biomarkers of potential clinical relevance. Twelve QC programs focused on biomarkers and concerning morphological, immunohistochemical, biochemical, molecular, and immunoenzymatic assays were coordinated and implemented. Specifically, external QC programs for the analytical phase of immunohistochemical p53, Bcl-2, c-erb-2/neu/HER2, and microvessel density determination, of morphological evaluation of tumor differentiation grade, and of molecular p53 analysis were activated for the first time within the project. Several hundreds of Italian laboratories took part in these QC programs, the results of which are available on the web site of the Network ( www.cqlaboncologico.it ). Financial support from the Italian Government and the National Research Council (CNR) will guarantee the pursuit of activities that will be extended to new biomarkers, to preanalytical phases of the assays, and to revision of the criteria of clinical usefulness for evaluating the cost/benefit ratio.
Quantitative Assessment of HER-2/Neu Protein Concentration in Breast Cancer by Enzyme-Linked Immunosorbent Assay
Authors: Müller V. , Thomssen C. , Karakas C. , Eustermann I. , Porras J. Ramirez , Coith C. , Berger J. , Löning T. , Jänicke F. , Pantel K.
Published: January 2018

Purpose

The HER-2/neu protein (p185) has become a promising target for antibody therapy in breast cancer. We tested the feasibility of a quantitative approach for HER-2/neu testing based on the analysis of tumor tissue extracts by an enzyme-linked immunosorbent assay (ELISA).

Experimental design

Tumor tissue extracts of primary human breast cancers (n=124) were prepared using a triton-based buffer. HER-2/neu concentration was quantified by ELISA. Paraffin-embedded tissue sections of the same tumors were analyzed by immunohistochemical staining applying the monoclonal HER-2/neu antibody TAB 250 (n=124) and by chromogenic in situ hybridization (CISH) (n=73).

Results

Concentrations of p185 in tissue extracts determined by ELISA varied from 1 to 927 ng per mg protein with a median of 25 ng/mg protein, whereas normal breast tissue showed values from 0.4 to 5.5 ng/mg with a median of 2.2 ng/mg (p<0.0001, Mann-Whitney U test). A significant correlation between p185 concentration and immunohistochemical staining was observed (p<0.0001, Kruskal-Wallis test). In addition, p185 concentration measured by ELISA was correlated with the degree of HER-2/neu gene amplification determined by CISH. HER-2/neu-amplified tumors had significantly higher p185 concentrations (median value 181 ng/mg protein) than non-amplified tumors (median value 20 ng/mg; p<0.0001, Mann-Whitney U test).

Conclusions

ELISA-based measurement of HER-2/neu protein concentration in breast cancer tissue extracts is feasible and provides quantitative results for p185 protein concentrations that correlate closely with HER-2/neu immunoscore and gene amplification.
Prognostic Value of Mutations in TP53 and RAS Genes in Breast Cancer
Authors: Guerra E. , Vacca G. , Palombo B. , Alberti S.
Published: January 2018

The identification of molecular indicators of higher risk for specific subgroups of cancer patients may allow to develop more aggressive therapeutic strategies aimed at cases with the highest likelihood of response. This would avoid unnecessary toxicity to patients and alleviate the burden of cancer care for healthcare systems. Activated oncogenes and mutated tumor suppressor genes are causal determinants of the appearance and progression of tumors in man. They therefore represent potential indicators of prognosis and/or response to therapy. However, even in cases of well-studied oncogenes and tumor suppressor genes such as TP53 and RAS, their attributed prognostic and predictive value is often based on studies of insufficient statistical power that often lead to conflicting conclusions. Findings in favor or against the use of TP53 and RAS as prognostic and predictive indicators in breast cancer are reviewed and discussed here.
Signaling Protein Networks as Targets of New Antineoplastic Drugs
Authors: Alberti S. , Parodi S.
Published: January 2018

In-depth analysis of molecular regulatory networks in cancer holds the promise of improved knowledge of the pathophysiology of tumor cells so that it will become possible to design a detailed molecular tumor taxonomy. This knowledge will also offer new opportunities for the identification and validation of key molecular tumor targets to be exploited for novel therapeutic approaches. Some signaling proteins have already been identified as such, e.g. c-Myc, Cyclin D1, Bcl-XL, kinases and some nuclear receptors. This has led to the successful development of a few function-modulatory drugs (Glivec, SERM, Iressa), providing proof-of-principle of the validity of this approach. Further developments are likely to derive from “-omic” approaches, aimed at the understanding of signaling networks and of the mechanism of action of newfound lead molecules. High-throughput screening of small drug-like molecules from combinatorial chemical libraries or from microbial extracts will identify novel, “intelligent” drug candidates. An additional medicinal chemistry strategy (via 40–50 unit rosary-bead chains) has the potential to be much more effective than small molecules in interfering with protein-protein interactions. This may lead to considerably higher selectivity and effectiveness compared with historical approaches in drug discovery.
Chemoprevention of Tumors: The Role of RAR-Beta
Authors: Toma S. , Emionite L. , Fabia G. , Spadini N. , Vergani L.
Published: January 2018

Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The knowledge of carcinogenic mechanisms provides the scientific rationale for chemoprevention. Epithelial carcinogenesis proceeds through multiple discernible stages of molecular and cellular alterations. Understanding of the multistep nature of carcinogenesis has evolved through highly controlled animal carcinogenesis studies, and these studies have identified three distinct phases: initiation, promotion and progression. Animal model studies have provided evidence that the development of cancer involves many different factors, including alterations in the structures and functions of different genes. Transitions between successive stages can be enhanced or inhibited in the laboratory by different types of agents, such activities providing the fundamental basis for chemoprevention.
Prognostic value of Tumoral Sialyltransferase Expression and Circulating E-Selectin Concentrations in Node-Negative Breast Cancer Patients
Authors: Hebbar M. , Krzewinski-Recchi M.-A. , Hornez L. , Verdière A. , Harduin-Lepers A. , Bonneterre J. , Delannoy P. , Peyrat J.-P.
Published: January 2018

Aims and Background

A crucial step in the metastatic process is the interaction between the endothelial molecule E-selectin and its tumoral ligands sialyl-Lewisx and sialyl-Lewisa. Sialyltranferases are involved in the biosynthesis of these ligands. The aim of this study was to assess the prognostic value of tumoral sialyltransferase expression and of circulating soluble E-selectin (sE-selectin) in node-negative breast cancer patients.

Methods

Using a multiplex RT-PCR method, we measured the expression of five sialyltransferases (ST3Gal III, ST6Gal I, ST3Gal IV, ST3Gal I and ST3Gal II) in tumors of 135 surgically treated node-negative breast cancer patients. Circulating sE-selectin concentrations were measured by an ELISA method prior to surgery. We also analyzed tumor size, histoprognostic grading and steroid hormone receptor status.

Results

The median follow-up was 7.5 years. Expression of estrogen receptors was associated with a good prognosis for relapse-free survival in univariate analysis. A high ST3Gal III/ST6Gal I ratio and a high sE-selectin concentration were associated with a bad prognosis for relapse-free survival and overall survival in univariate and multivariate analysis.

Conclusion

In the present study, tumoral sialyltransferase expression and circulating sE-selectin concentrations had prognostic value in patients with node-negative breast cancer. This result provides further evidence for the important role of these agents in the metastatic process.
Quantitative Real-Time RT-PCR Analysis of Eight Novel Estrogen-Regulated Genes in Breast Cancer
Authors: Sorbello V. , Fuso L. , Sfiligoi C. , Scafoglio C. , Ponzone R. , Biglia N. , Weisz A. , Sismondi P. , De Bortoli M.
Published: January 2018

Background

Biological markers capable of predicting the risk of recurrence and the response to treatment in breast cancer are eagerly awaited. Estrogen and progesterone receptors (ER, PgR) in tumor cells mark cancers that are more likely to respond to endocrine treatment, but up to 40% of such patients do not respond. Here, the expression of a group of estrogen-regulated genes, previously identified by microarray analysis of in vitro models, was measured in breast tumors and possible associations with other clinicopathological variables were investigated.

Methods

The expression of CD24, CD44, HAT-1, BAK-1, G1P3, TIEG, NRP-1 and RXRα was measured by quantitative real-time RT-PCR on RNA from eighteen primary breast tumors. Statistical analyses were used to identify correlations among the eight genes and the available clinicopathological data.

Results

Variable expression levels of all the genes were observed in all the samples examined. Significant associations of CD24 with tumor size, CD44 with lymph node invasion, and HAT-1 and BAK-1 with ER positivity were found. The possible combinatorial value of these genes was assessed. Unsupervised hierarchical clustering analysis demonstrated that the expression profile of these genes was able to predict ER status with an acceptable approximation.

Conclusions

Eight novel potential markers for breast cancer have been preliminarily characterized. As expected from in vitro data, their expression is able to discriminate ER- versus ER+ tumors.
Metallothionein: A Multifunctional Protein from Toxicity to Cancer
Authors: Theocharis S.E. , Margeli A.P. , Koutselinis A.
Published: January 2018

The metallothionein (MT) family is a class of low molecular weight, intracellular and cysteine-rich proteins presenting high affinity for metal ions. Although the members of this family were discovered nearly 40 years ago, their functional significance remains obscure. Four major MT isoforms, MT-1, MT-2, MT-3 and MT-4, have been identified in mammals. MTs are involved in many pathophysiological processes such as metal ion homeostasis and detoxification, protection against oxidative damage, cell proliferation and apoptosis, chemoresistance and radiotherapy resistance. MT isoforms have been shown to be involved in several aspects of the carcinogenic process, cancer development and progression. MT expression has been implicated as a transient response to any form of stress or injury providing cytoprotective action. Although MT participates in the carcinogenic process, its use as a potential marker of tumor differentiation or cell proliferation, or as a predictor of poor prognosis remains unclear. In the present review the involvement of MT in defense mechanisms to toxicity and in carcinogenicity is discussed.
Evaluation of Sample Handling in Relation to Levels of Tissue Inhibitor of Metalloproteinases-1 Measured in Blood by Immunoassay
Authors: Holten-Andersen M.N. , Schrohl A.-S. , Brünner N. , Nielsen H.J. , Høgdall C.K. , Høgdall E.V.S.
Published: January 2018

Background

The possible effect of preanalytical conditions such as blood sample preparation and handling on TIMP-1 levels in blood needs thorough investigation.

Materials and Methods

Blood was collected in dry tubes and tubes containing EDTA and kept at 4°C or 20°C for 1, 3, 8, 24 or 72 hours before processing into serum or EDTA plasma. In addition, serum and EDTA plasma samples were frozen and thawed 1–8 times. TIMP-1 was measured by ELISA.

Results

Time to processing for up to 72 hours did not significantly affect TIMP-1 levels in serum. In EDTA plasma, TIMP-1 levels were stable for up to eight hours; however, if samples were kept for 24 hours or longer the TIMP-1 levels increased (p<0.0001). Repeated freezing and thawing had a significant effect on TIMP-1 levels in serum (p=0.04). In plasma, repeated freezing and thawing for up to six times did not influence TIMP-1. However, in plasma samples exposed to seven or eight freeze/thaw cycles TIMP-1 levels decreased, although not significantly (p=0.23).

Conclusions

Handling and processing of blood samples is crucial for TIMP-1 measurement by immunoassay. In serum, TIMP-1 levels are unaffected by time to processing. Plasma samples should be processed within eight hours to avoid a TIMP-1 increase. For the measurement of TIMP-1 in archival material, serum should not be used because TIMP-1 levels are significantly affected by repeated freezing and thawing; archival plasma can readily be used provided that samples have not been frozen and thawed more than six times.
Genetic Analysis of H-ras Intron-1 Polymorphic and Variable Tandem Repeat Regions in Human Breast Cancer
Authors: Papadakis E.N. , Dokianakis D.N. , Spandidos D.A.
Published: January 2018

H-ras is a member of the ras superfamily of genes. This gene encodes for a 21 kDa protein (p21) which is located on the inner surface of the plasma membrane. Ras genes are involved in a wide variety of human tumors, and there is a known correlation between H-ras activation and breast carcinogenesis. H-ras contains a polymorphic region, a repeated hexanucleotide –GGGCCT - located in intron 1 close to the 5′ of the gene (HRM region). Three alleles of this region, P1, P2 and P3, have been identified that contain two, three and four repeats of the hexanucleotide, respectively. H-ras possesses a minisatellite DNA of the variable tandem repeat (VTR) which is located 1000 bp downstream of the gene displaying linkage disequilibrium with HRM. The purpose of this study was to estimate the frequency of P1, P2 and P3 in the normal population and in patients with breast cancer. We studied 56 biopsy specimens from patients with breast cancer, 61 normal blood samples, and 30 pairs of normal and tumoral breast tissues for VTR analysis. There was a difference in the distribution of P1, P2 and P3 alleles between normal and breast cancer samples. The frequency of P1 homozygosity was shown to be almost twice as high in women with breast cancer compared to healthy women (72% versus 39%). These results suggest that P1 homozygosity may be considered as a potential risk factor in breast carcinogenesis. In VTR analysis one sample presented a shift in mobility, but no polymorphism in the BstN I pattern of the 28 bp repetition core was observed.
Methylenetetrahydrofolate Reductase Genotype in Diffuse Large B-Cell Lymphomas with and without Hypermethylation of the DNA Repair Gene O6-Methylguanine DNA Methyltransferase
Authors: Toffoli G. , Rossi D. , Gaidano G. , Cecchin E. , Boiocchi M. , Carbone A.
Published: January 2018

C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been suggested to affect susceptibility to malignant lymphoma, possibly by altering DNA methylation. The DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in diffuse large B-cell lymphomas (DLBCL). We analyzed the MTHFR677 and MTHFR1298 genotypes in 111 DLBCL patients and 465 controls. No significant difference in the frequency of MTHFR polymorphisms between patients and controls and no significant association between MTHFR677 or MTHFR1298 genotypes and methylation of MGMT promoter were observed. These results indicate that MTHFR variants are not related to DLBCL development and MGMT hypermethylation.
Functional Relationship and Gene Ontology Classification of Breast Cancer Biomarkers
Authors: Arciero C. , Somiari S.B. , Shriver C.D. , Brzeski H. , Jordan R. , Hu H. , Ellsworth D.L. , Somiari R.I.
Published: January 2018

Breast cancer is a complex disease that still imposes a significant healthcare burden on women worldwide. The etiology of breast cancer is not known but significant advances have been made in the area of early detection and treatment. The advent of advanced molecular biology techniques, mapping of the human genome and availability of high throughput genomic and proteomic strategies opens up new opportunities and will potentially lead to the discovery of novel biomarkers for early detection and prognostication of breast cancer. Currently, many biomarkers, particularly the hormonal and epidermal growth factor receptors, are being utilized for breast cancer prognosis. Unfortunately, none of the biomarkers in use have sufficient diagnostic, prognostic and/or predictive power across all categories and stages of breast cancer. It is recognized that more useful information can be generated if tumors are interrogated with multiple markers. But choosing the right combination of biomarkers is challenging, because 1) multiple pathways are involved, 2) up to 62 genes and their protein products are potentially involved in breast cancer-related mechanisms and 3) the more markers evaluated, the more the time and cost involved. This review summarizes the current literature on selected biomarkers for breast cancer, discusses the functional relationships, and groups the selected genes based on a Gene Ontology™ classification.
Prognostic Value of S-Phase Fraction in 920 Breast Cancer Patients: Focus on T1N0 Status
Authors: Largillier R. , Namer M. , Ramaioli A. , Ferrero J.M. , Magné N. , Courdi A. , Leblanc-Talent P. , Formento P. , Ettore F. , Milano G.
Published: January 2018

The aim of this study was to reexamine the prognostic role of tumor cell kinetics measured by S-phase fraction (SPF) and to establish its clinically relevant threshold values. SPF was determined by flow cytometry in a group of 920 consecutive breast cancer patients, all followed at our institute for 10 years (1988 to 1998). Mean age was 60.5 years (27–89 years). Median follow-up was 63 months (3–150 months). All patients had initial surgical treatment. SPF quartiles were: Q1=3.08%, median value = 5.98%, Q3=10.22%. A significant difference in overall specific survival was obtained between two populations divided by a cutoff at Q1 (p<0.0001). A multifactorial analysis including SPF and known prognostic factors such as tumor size, node status, histological grade, ER and PR status was performed using the Cox model in a population of 719 patients: univariate analysis showed that each of these factors had significant influence on overall survival. Multivariate analysis selected three of them, ranked by decreasing order of hazard ratio (HR) value: SPF (HR: 3.88, p<0.001), tumor size (HR: 2.49, p<0.001) and nodal status (HR: 2.28, p<0.001). In addition, when tumors were stratified according to SPF quartile values, there were statistically different overall survival curves in patients with small tumors (<2 cm) and in axillary node-negative patients.
Prognostic value of p53 and MDM2 Expression in Bilharziasis-Associated Squamous Cell Carcinoma of the Urinary Bladder
Authors: El-Kenawy A. El-Meghawry , El-Kott A.F. , Khalil A.M.
Published: January 2018

The aim of this study was to elucidate the associations between immunostaining for MDM2 and p53, their respective expression in squamous cell carcinoma of the urinary bladder, and the value of these variables for predicting treatment outcome after cystectomy. Inactivation of TP53 might play a role in the development and progression of bladder cancer. Complex formation with the MDM2 product is one mechanism that inactivates the p53 protein. Therefore, the MDM2 and the p53 protein were investigated to study potential interactions in bladder cancer. Fifty archival bladder tissue specimens were immunohistochemically stained using monoclonal antibodies against p53 and MDM2. Staining for p53 was observed in 48% of the specimens and staining for MDM2 in 20%. Univariate analysis demonstrated a significant correlation between p53 accumulation and survival (p=0.0101), while the correlation between MDM2 and survival was not significant (p=0.7183). The combined expression of MDM2 and p53 doest not add to the prognostic information provided by p53 alone.
Serum Tumor Markers may Precede Instrumental Response to Chemotherapy in Patients with Metastatic Cancer
Authors: Massacesi C. , Rocchi M.B.L. , Marcucci F. , Pilone A. , Galeazzi M. , Bonsignori M.
Published: January 2018

Purpose

Although serum tumor markers (STMs) are widely used in clinical practice, their predictive role for the response to anticancer treatment is still controversial. The correlation of CEA, CA 15.3, CA 19.9, CA 125 (only with peritoneal involvement) and NSE levels with imaging response and clinical benefit was investigated in 60 non-selected patients with metastatic epithelial cancers treated by single-agent docetaxel chemotherapy.

Methods

STM measurement was performed at baseline and subsequently every three to four weeks. We applied the WHO criteria to evaluate both STM and instrumental responses. Concordance analysis was performed by the Cohen Kw index, and the significance of the results was established using the Fleiss, Cohen & Everitt test. Qualitative interpretation of data was obtained with the Landis & Koch scale. Correlations of STM response with clinical benefit (PS or pain improvement) were evaluated by the chi-square test.

Results

The primary tumors included breast cancers (38 patients), gastrointestinal non-colorectal cancers (12 patients), and lung cancers (10 patients). An overall significant good degree of agreement was observed between STM and instrumental response (p<0.0005). The degree of agreement for each marker was as follows: excellent for CEA (p<0.0005) and CA 125 (p=0.006), good for CA 15.3 (p<0.0005) and CA 19.9 (p=0.011). Restricted analysis for the correlation of each marker with primary tumor origin showed good prediction of radiological response for CA 15.3 and CEA in breast cancer patients (p<0.0005 for both), for CEA and CA 19.9 in gastrointestinal cancer patients (p=0.01 and 0.04, respectively), and for CEA+NSE in lung cancer patients (p=0.01). Conversely, STM response did not correlate significantly with the clinical benefit for the patients, both in terms of PS and pain improvement (p=0.24 and p=0.42, respectively).

Conclusion

This study showed STMs to be good predictors of tumor response. Although STMs cannot replace diagnostic imaging, in metastatic cancer they might be useful to optimize the timing of radiological re-evaluation in the palliative setting.
Phosphorylated Akt1 in Human Breast Cancer Measured by Direct Sandwich Enzyme-Linked Immunosorbent Assay: Correlation with Clinicopathological Features and Tumor VEGF-Signaling System Component Levels
Authors: Gershtein E.S. , Scherbakov A.M. , Anurova O.A. , Krasil'nikov M.A. , Kushlinsky N.E.
Published: January 2018

Protein kinase B (Akt) plays a major role in the regulation of breast cancer growth, survival, hormone, drug and radiosensitivity, but the clinical value of its expression and activation in human tumors is unclear. Activated Akt1 (pAkt1) expression was quantified in a series of 46 breast cancer and adjacent mammary gland samples by a direct Path-Scan™ PhosphoAkt1 (Ser473) sandwich ELISA kit. VEGF, sVEGFR1 and sVEGFR2 levels were measured simultaneously by standard ELISA kits. Forty-nine percent of the tumors had an increased pAkt1 level as compared to adjacent tissue. pAkt1 levels were significantly higher in stage IIb than in stage I-IIa tumors. The frequency of pAkt1 elevation was positively associated with tumor size and malignancy grade. pAkt1 was also twice as frequently increased in PgR-negative as in PgR-positive tumors, while its mean level was significantly higher in ER-positive than in ER-negative tumors. VEGF, sVEGFR1 and sVEGFR2 were increased in 73–85% of the tumors, but no associations with most clinicobiological factors and pAkt1 level were found. In conclusion, activation of Akt1 is not associated with VEGF signaling protein expression in breast cancer but is related to tumor size, grade of malignancy, and steroid receptor status.
Reliability and Discriminant Validity of HER2 Gene Quantification and Chromosome 17 Aneusomy Analysis by Real-Time PCR in Primary Breast Cancer
Authors: Lamy P.-J. , Nanni I. , Fina F. , Bibeau F. , Romain S. , Dussert C. , Llorca F. Penault , Grenier J. , Ouafik L'H. , Martin P.-M.
Published: January 2018

There is an increasing demand for the evaluation of HER2 status in breast cancer. In this study, sections from fixed tissues and triton extracts of tissue homogenates were obtained from 163 malignant breast tumors and analyzed in parallel using immunohistochemistry combined with fluorescence in situ hybridization, as gold standard tests, and an ELISA test (c-erbB2/c-neu Rapid Format ELISA, Oncogene Research Products, USA). Tumor DNA was employed to evaluate two quantitative PCR methods: the HER2/neu DNA Quantification Kit (Roche Diagnostics GmbH, Germany), which uses the gastrin chromosome 17 reference gene, and our recently developed Oncolab qPCR assay, where both a chromosome 17 gene (somatostatin receptor type II (SSTR2)) and a non-chromosome 17 reference gene (glyceraldehyde-3-phosphate deshydrogenase (GAPDH)) were used to detect an increase in HER2 gene copy number and to evaluate the aneusomy of chromosome 17, respectively. By IHC/FISH and ELISA, HER2 was overexpressed in 27 (16.6%) and 24 (14.7%) samples, respectively. With the Roche and Oncolab qPCR assays, 29 (17.8%) samples showed a ratio of HER2/gastrin ≥2.0 and 26 (16.0%) showed a ratio of HER2/SSTR2 ≥ 2.0, respectively. In samples presenting HER2/SSTR2 <2.0 and HER2/GAPDH ≥2.0, which was indicative of a chromosome 17 polysomy, we observed a modest increase in HER2 protein expression. Complete agreement between the four methods for HER2 status determination was obtained for 154 (94.5%) samples. Overall, these results demonstrate that quantitative PCR is a reliable method for analyzing HER2 status and chromosome 17 polysomy.
Simultaneous Quantitative Detection of Relevant Biomarkers in Breast Cancer by Quantitative Real-Time PCR
Authors: Labuhn M. , Vuaroqueaux V. , Fina F. , Schaller A. , Nanni-Metellus I. , Küng W. , Eppenberger-Castori S. , Martin P.M. , Eppenberger U.
Published: January 2018

The assessment of ERα, PgR and HER2 status is routinely performed today to determine the endocrine responsiveness of breast cancer samples. Such determination is usually accomplished by means of immunohistochemistry and in case of HER2 amplification by means of fluorescent in situ hybridization (FISH). The analysis of these markers can be improved by simultaneous measurements using quantitative real-time PCR (Qrt-PCR). In this study we compared Qrt-PCR results for the assessment of mRNA levels of ERα, PgR, and the members of the human epidermal growth factor receptor family, HER1, HER2, HER3 and HER4. The results were obtained in two independent laboratories using two different methods, SYBR Green I and TaqMan probes, and different primers. By linear regression we demonstrated a good concordance for all six markers. The quantitative mRNA expression levels of ERα, PgR and HER2 also strongly correlated with the respective quantitative protein expression levels prospectively detected by EIA in both laboratories. In addition, HER2 mRNA expression levels correlated well with gene amplification detected by FISH in the same biopsies. Our results indicate that both Qrt-PCR methods were robust and sensitive tools for routine diagnostics and consistent with standard methodologies. The developed simultaneous assessment of several biomarkers is fast and labor effective and allows optimization of the clinical decision-making process in breast cancer tissue and/or core biopsies.
Arginase as a Useful Factor for the Diagnosis of Colorectal Cancer Liver Metastases
Authors: Mielczarek M. , Chrzanowska A. , Ścibior D. , Skwarek A. , Ashamiss F. , Lewandowska K. , Barańczyk-Kuźma A.
Published: January 2018

The present work is a continuation of studies on arginase as a marker in the diagnosis of colorectal cancer liver metastases (CRCLM). The purpose of the study was the evaluation of the arginase test in comparison with other colorectal cancer tests such as CEA, CA 19-9 and biochemical markers of liver function such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The studies were conducted on blood serum from 85 patients with CRCLM obtained one to two days before tumor resection. The control group comprised 140 healthy blood donors and 81 patients with various non-malignant gastrointestinal diseases. Raised arginase activity was observed in serum of 85% of CRCLM patients, whereas elevated levels of CEA and CA 19-9 were found in 63% and 42% of patients, respectively. The combination of CEA or CA 19-9 with the arginase assay improved their sensitivity, but the sensitivity of the combined parameters was not higher than that of the arginase test itself. AST and ALT activities were increased in about 30% of CRCLM patients. The specificity of the arginase test calculated for 221 control subjects was 76%. It can thus be concluded that the determination of serum arginase activity can be helpful in the diagnosis of patients with colorectal cancer liver metastases.
Sequential Adjuvant Hormone Therapy in Postmenopausal Breast Cancer: Rationale and Clinical Results
Authors: Longo R. , D'Andrea M.R. , Gasparini G.
Published: January 2018

For the past 15 years tamoxifen has been the standard adjuvant hormone therapy for women with early-stage breast cancer and estrogen receptor (ER)-positive tumors, irrespective of nodal status and other clinicopathological parameters. Recent studies provided evidence that the optimal duration of tamoxifen treatment is 5 years. Based on the positive clinical results obtained with the administration of aromatase inhibitors (AIs) in the metastatic setting, several controlled clinical trials have evaluated the efficacy and side effects of AIs versus standard tamoxifen also as adjuvant therapy in postmenopausal breast cancer patients. The results of the above studies, suggest a therapeutic advantage of AIs over tamoxifen with regard to relapse-free survival and the risk of metachronous contralateral breast cancer.

We review the rationale and the available clinical data on initial or sequential hormone treatment with AIs and we propose a novel scenario for possible therapeutic strategies based on the clinicopathological characteristics of the patients and on the biology of each single tumor.
Is the Urokinase-type Plasminogen Activator System a Reliable Prognostic Factor in Gastric Cancer?
Authors: Luebke T. , Baldus S.E. , Spieker D. , Grass G. , Bollschweiler E. , Schneider P.M. , Thiele J. , Dienes H.P. , Hoelscher A.H. , Monig S.P.
Published: January 2018

Aim

The aim of this prospective study was to evaluate the clinical and prognostic impact of immunohisto-chemically assessed uPA and PAI-1 in patients with gastric cancer.

Methods

This prospective study analyzed specimens obtained from 105 gastric cancer patients who underwent gastrectomy with extended lymphadenectomy. The immunohistochemical expression of uPA and PAI-1 was studied semiquantitatively in the tumor epithelium and was correlated with the clinicopathological features of each patient.

Results

Univariate analysis revealed no statistically significant association of uPA levels with pT and pN category (p=0.655 and 0.053, respectively), grading (p=0.374), depth of tumor invasion (p=0.665), UICC classification (p=0.21) and the Laurén classification (p=0.578). PAI-1 expression showed no statistically significant correlation with pT, pN and M category (p=0.589, 0.414, and 0.167, respectively), grading (p=0.273), and the Laurén classification (p=0.368). Only the UICC classification was significantly correlated with PAI-1 (p=0.016). Kaplan-Meier analysis revealed no significant association of uPA and PAI-1 with overall survival (p=0.0929 and 0.0870, respectively).

Conclusions

Our results could not verify any prognostic value of uPA and PAI-1 levels in patients with gastric carcinoma. Therefore, the uPA-system as a biologically defined prognostic marker to identify high-risk gastric cancers should be applied with caution. However, considering the number of patients involved and the borderline level of significance observed in this study, a larger number of events may have resulted in significant differences.
Stat3 Expression in Oral Squamous Cell Carcinoma: Association with Clinicopathological Parameters and Survival
Authors: Shah N.G. , Trivedi T.I. , Tankshali R.A. , Goswami J.A. , Jetly D.H. , Kobawala T.P. , Shukla S.N. , Shah P.M. , Verma R.J.
Published: January 2018

The present study sought to explore the occurrence of signal transducer and activator of transcription 3 (Stat3) in patients with oral squamous cell carcinoma (n=135) and its potential relationship with clinicopathological parameters and survival. Stat3 expression was studied by immunohistochemistry. Cytoplasmic or nuclear localization of Stat3 was observed in 62% of patients, whereas only nuclear Stat3 expression was found in 44%. Stat3 positivity in early-stage patients was 45% compared to 79% in advanced-stage patients. However, early-stage Stat3-positive patients showed a gradual increase in staining intensity, with intense staining seen in 52% of the tumors compared to 18% in Stat3-positive advanced-stage patients, where a gradual decrease in intensity expression was observed (p=0.001). Stat3 showed a significant positive correlation with disease stage (p=0.001), nodal status (p=0.033) and tumor size (p=0.001). Multivariate survival analysis using the Cox proportional hazard regression model showed that nuclear Stat3 was a significant independent prognosticator for both relapse-free survival (p=0.014) and overall survival (p=0.042) in early-stage patients. Our results indicated that Stat3 activation is an early event in oral squamous cell carcinoma and represents a potential risk factor for poor prognosis in early-stage patients.
Mutations in Exons 6 and 7 of TP53 Gene Correlate Positively with Serum Tumor Necrosis Factor Alpha Independent of Microsatellite Instability in BAT26 Gene in Egyptian Patients with Endometrial Carcinoma
Authors: Diab A.M. , Tawfeek T.A.S. , Moeity F. , Elsammak M.
Published: January 2018

Abnormalities in the TP53 gene are the most frequent genetic alterations in human cancers. The role and mechanism of TP53 mutations have been well studied in many types of human cancer. Similarly, the presence of microsatellite instability (MSI) in the DNA mismatch repair system (hMSH2) may provide evidence of faulty DNA mismatch repair. One of the most important locations of MSI is the BAT26 gene. In addition, deranged serum cytokines, especially elevated levels of the tumor necrosis factor (TNF) alpha, have been found in many gynecological conditions.

Aims

The current study aimed at evaluating mutations in exons 6 and 7 of TP53 and the presence of microsatellite instability in BAT26 of the hMSH2 system in Egyptian patients with endometrial carcinoma. The study also evaluated whether there was a correlation between any of these genetic mutations/instability and the tissue expression of estrogen and progesterone receptors and the serum TNF-alpha level.

Patients and methods

The current study included 2 groups: a control group comprising 20 healthy women aged 52.21 ± 5.80 years attending the clinic for routine checkups and 40 patients with endometrial cancer aged 55.30 ± 6.21 years. Mutations in TP53 and BAT26 were evaluated using polymerase chain reaction–single-strand conformational polymorphism (PCR-SSCP) and automated sequencing while serum TNF-alpha was measured using an ELISA technique. Estrogen and progesterone receptor expression in biopsy tissue was evaluated using immunohistochemical staining.

Results

Seven of the 40 patients (17.5%) were positive for TP53 gene alterations in exon 6, while 9 patients (22.5%) were positive for TP53 alterations in exon 7. Cases positive for TP53 mutations had higher tumor stages. Ten patients (25%) showed MSI in BAT26. Nearly all patients with mutations in BAT26 had a strong family history for endometrial cancer (χ2=13.33, p<0.05). There was no positive correlation between the presence of MSI in the BAT26 gene and mutations in the TP53 gene or high serum TNF-alpha levels. Cases positive for TP53 mutations had a significantly higher level of TNF-alpha than cases negative for TP53 mutations (p<0.05). Cases showing mutations in exon 6 or 7 of TP53 showed a significantly higher intensity of immunohistochemical staining for estrogen and progesterone receptor expression in biopsy tissue than cases negative for mutations. (χ2=8.11, p<0.05).

Conclusion

Our results suggest that the development of endometrial carcinoma is probably mediated through a multi-step carcinogenesis pathway and mutation of TP53 does not necessarily result from the presence of microsatellite instability in BAT26. The high serum TNF-alpha levels detected in our patients may represent an immunological antitumor response that was particularly evident in cases positive for TP53 mutations.
Human Kallikrein 3 (prostate-specific antigen) and Human Kallikrein 5 Expression in Salivary Gland Tumors
Authors: Darling M.R. , Tsai S. , Jackson-Boeters L. , Daley T.D. , Diamandis E.P.
Published: January 2018

The human kallikrein 5 protein (hK5) is expressed in many normal tissues, most notably in skin, breast, salivary gland and esophagus. It has also been shown to be a potential biomarker for breast, ovarian and testicular cancer. Human kallikrein 3 (hK3; prostate-specific antigen) is the most useful marker for adenocarcinoma of the prostate gland. The aim of this study was to determine whether hK3 and hK5 are expressed in salivary gland tissues and salivary gland tumors (both benign and malignant), in order to compare normal with tumor tissues. Pleomorphic adenomas, adenoid cystic carcinomas, polymorphous low-grade adenocarcinomas, acinic cell carcinomas, mucoepidermoid carcinomas and adenocarcinomas not otherwise specified of both minor and major salivary glands were examined. The results of this study indicate that most salivary gland tumors do not show high levels of expression of hK5. Staining was most prominent in keratinizing epithelia in pleomorphic adenomas. hK3 is not expressed in salivary gland tumors.
Serum Ferritin in Colorectal Cancer Patients and its Prognostic Evaluation
Authors: Lorenzi M. , Lorenzi B. , Vernillo R.
Published: January 2018

The aim of this study was to investigate the relationship between preoperative serum ferritin levels, clinicopathological parameters and survival analysis of patients with colorectal cancer. Ninety-four patients (57 males) with a mean age of 65 years (39–87 years) underwent 63 curative and 31 palliative operations. Follow-up was at least 5 years. Patients were categorized with normal (30-215 ng/mL in men and 11-148 ng/mL in women), low, or high serum ferritin levels. Prognostic evaluation was undertaken with stratified survival analysis and Cox's regression model. Twenty-nine of the patients (30.9%) had raised ferritin levels and 14 (14.9%) had low values. Comparisons of the survival curves showed significant differences in stage C disease; specifically, patients with either low or high ferritin levels had a shorter survival than patients with normal levels. Patients who underwent palliative surgery and had high ferritin serum values also had a shorter survival. In multivariate analysis, the variables with a negative effect on survival were stage, serum ferritin levels and age. Our data suggest that patients with advanced colorectal cancer having normal preoperative serum ferritin levels may have a better prognosis, although the prognostic value related to this association requires further investigation.
Strong Association of Interleukin-6 -174 G>C Promoter Polymorphism with Increased Risk of Oral Cancer
Authors: Vairaktaris E. , Yiannopoulos A. , Vylliotis A. , Yapijakis C. , Derka S. , Vassiliou S. , Nkenke E. , Serefoglou Z. , Ragos V. , Tsigris C. , Vorris E. , Critselis E. , Avgoustidis D. , Neukam F.W. , Patsouris E.
Published: January 2018

In view of the recently found contribution of factors associated with thrombosis and inflammation to carcinogenesis, we investigated the possible association of interleukin-6 (IL-6) with an increased risk of oral cancer. In DNA samples of 162 patients with oral squamous cell carcinoma and 156 healthy controls of comparable ethnicity, age and sex, we studied the -174 G>C polymorphism in the IL-6 gene, which affects its transcription. C allele frequencies were significantly increased in patients compared to controls, 42.6% versus 23.1% (p<0.001). The CC homozygotes had a 7-fold greater risk of developing oral cancer (odds ratio 7.39, 95% CI 2.61–20.92), while the GC heterozygotes had a 4-fold greater risk (odds ratio 3.74, 95% CI 2.29–6.11). A significant increase in C alleles was observed in patients regardless of their smoking or alcohol consumption habits, early or advanced stage of cancer, and presence or absence of a family history for cancer or thrombophilia (p<0.001; Fisher's exact test). These findings suggest that the –174 G>C polymorphism, by affecting IL-6 gene expression, is strongly associated with oral oncogenesis.