bluuebunny/crossref_metadata_2025 huggingface dataset:
Significant Changes in Circulating Plasma Levels of IGF1 and IGFBP3 after Conventional or Dose-Intensified Adjuvant Treatment of Breast Cancer Patients with one to three Positive Lymph Nodes
Authors: Kümmel S. , Eggemann H. , Lüftner D. , Gebauer N. , Bühler H. , Schaller G. , Schmid P. , Kreienberg R. , Emons G. , Kriner M. , Elling D. , Blohmer J.-U. , Thomas A.
Published: January 2018

The insulin-like growth factor 1 (IGF1) and its binding protein IGFBP3 (insulin-like growth factor binding protein 3) play a pivotal role during the growth and development of tissues. The purpose of this study was to evaluate the influence of anthracycline- and taxane-containing adjuvant chemotherapy in breast cancer patients on the circulating plasma levels of IGF1 and its main binding protein, IGFBP3. This investigation was part of a prospective randomized phase III study in which breast cancer patients were treated with either conventional or dose-intensified adjuvant chemotherapy. The factors were quantified in the plasma of 151 patients with a commercially available sandwich enzyme immunoassay. Before therapy, both parameters were within the normal range in most patients (n=145 and n=144). After therapy, both factors had increased significantly by 29% (IGF1) and 19% (IGFBP3), with the highest increase being observed in the dose-intensified group. Correlations with patient and tumor characteristics revealed a relatively higher increase in both parameters in premenopausal patients, patients with lower-grade tumors, more positive lymph nodes, larger tumor volume, and positive hormone receptor status. No correlation was found with the HER2 expression of the tumors.
Use of Plasma Epstein-Barr virus DNA Monitoring as a Tumor Marker in follow-up of Patients with Nasopharyngeal Carcinoma: Preliminary Results and Report of two Cases
Authors: Özyar E. , Gültekin M. , Alp A. , Hasçelik G. , Ugur Ö. , Atahan I.L
Published: January 2018

Recent studies suggest that plasma Epstein-Barr virus (EBV) DNA may reflect tumor burden in patients with nasopharyngeal cancer. A prospective study was initiated to investigate this correlation in 125 patients (34 pretreatment [Group A], 78 in remission [Group B] and 13 relapsed [Group C]) and 19 healthy controls. In group A, EBV DNA was detected in plasma samples of 24 (70%) patients. In Group B, EBV DNA was detected in 7 patients (range 77–13,731 copies/mL) and further imaging in all but one of these patients revealed active disease confirmed by ultrasound-guided fine-needle biopsy. There was only one false-positive case; this patient is currently under follow-up. Here we describe 2 of the 7 patients with detectable plasma EBV DNA in whom recurrence was documented by PET scan during follow-up. Our results showed that in group B the positive predictive value of quantitative analysis of plasma EBV DNA was 85%. Quantitative analysis of EBV DNA in plasma seems to become an integral part of screening, staging, monitoring, and prediction of relapse in patients with nasopharyngeal carcinoma. However, previous studies cannot be considered definitive and more reports on the use of this technique are urgently needed from both endemic and non-endemic regions.
Five-Year Stability Study of Free and Total Prostate-Specific Antigen Concentrations in Serum Specimens Collected and Stored at – 70°C or Less
Authors: Scaramuzzino D.A. , Schulte K. , Mack B.N. , Soriano T.F. , Fritsche H.A.
Published: January 2018

The stability of total (t) and free (f) prostate-specific antigen (PSA) in male serum specimens stored at –70°C or lower temperature for 4.7 to 4.9 years was studied. Until now, the stability of these analytes in serum has not been evaluated systematically beyond 2 years of storage at –70°C. Aliquots of frozen serum were thawed in 2001 and 2006 and assayed for tPSA and fPSA using a Dade Behring Dimension(r) RxL analyzer and reagents. tPSA values ranged from 0.07 to 69.94 and 0.00 to 69.83 ng/mL in 2001 and 2006, respectively, whereas fPSA values for the tested specimens ranged from 0.02 to 5.72 and 0.00 to 5.92, respectively. Deming regression analyses showed agreement in assay values over time as tPSA values yielded a slope of 1.0112 and a y-intercept of 0.0195; fPSA values produced a slope 1.0538 and a y-intercept of –0.0442; f/tPSA values yielded a slope of 0.9631 and a y-intercept of 0.1195. A Bland-Altman analysis of the data demonstrated analyte and ratio stability over this time period. We conclude that serum, when collected properly and stored at –70°C or lower temperature, may be used for tPSA and fPSA clinical studies for at least 5 years after collection.
Prognostic Significance of TP53 Mutations in Oral Squamous Cell Carcinoma with Human Papilloma virus Infection
Authors: Kozomara R.J. , Brankovic-Magic M.V. , Jovic N.R. , Stosic S.M. , Magic Z.M.
Published: January 2018

Purpose

The aim of this study was to analyze the prognostic impact of mutated TP53 in patients with oral squamous cell carcinoma (OSCC) whose tumors were infected with human papillomavirus (HPV).

Methods

Thirty-two HPV-positive OSCC patients were included. Most of them were clinically classified as stage III (n=29). All patients underwent postoperative radiotherapy (follow-up from 12 to 60 months, median 32). There were 21 relapses. DNA was isolated by phenol extraction from tumor tissue. HPV DNA (type 16, 18, 31, 33) was detected in genomic DNA of the tumors by the PCR-PAGE method. TP53 mutations (exons 4–8) were detected by the PCR-SSCP method.

Results

A statistically significant difference in the number of relapses in HPV-infected (13/21) versus HPV-infected and TP53-mutated (8/8) patients was observed. Patients with both TP53 mutation and HPV infection had a significantly shorter disease-free interval than patients with HPV infection only (median 6 versus 31 months, respectively).

Conclusions

TP53 mutations are associated with a higher risk of relapse and contribute to an even worse prognosis of patients with OSCC when the tumors are HPV infected. The shorter disease-free interval in patients with TP53 mutations indicates that the response to postoperative radiotherapy may be influenced by TP53 status. The presence of both HPV infection and TP53 mutations may define a particular group of tumors with a more aggressive phenotype in advanced OSCC.
Diagnostic Application of Serum Proteomic Patterns in Gastric Cancer Patients by ProteinChip Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry
Authors: Lim J.Y. , Cho J.Y. , Paik Y.H. , Chang Y.S. , Kim H.G.
Published: January 2018

Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) is one of the currently used techniques to identify biomarkers for cancers. This study was planned to establish a system to accurately distinguish gastric cancer patients by using SELDI-TOF-MS. A total of 100 serum samples obtained from 60 individuals with gastric cancer and 40 healthy individuals were screened. Protein expression profiles were expressed on CM10 ProteinChip arrays and analyzed. Peak intensities were analyzed with the Biomarker Wizard software to identify peaks showing significantly different intensities between normal and cancer groups. Classification analysis and construction of decision trees were done with the Biomarker Pattern software 5.0. Seventeen protein peaks showed significant differences between the two groups. The decision tree which gave the highest discrimination included four peaks at mass 5,919, 8,583, 10,286, and 13,758 as splitters. The sensitivity and specificity for classification of the decision tree were 96.7% (58/60) and 97.5% (39/40), respectively. When the protein biomarker pattern was tested on a blinded test set, it yielded a sensitivity of 93.3% (28/30) and a specificity of 90% (18/20). These results suggest that serum protein profiling by the SELDI system may distinguish gastric cancer patients from healthy controls with relatively high sensitivity and specificity.
Urinary Cell-Free DNA as a Potential Tumor Marker for Bladder Cancer
Authors: Chang H.W. , Tsui K.H. , Shen L.C. , Huang H.W. , Wang S.N. , Chang P.L.
Published: January 2018

The objective was to assess the possibility of measuring urine creatinine (UCr)-adjusted urinary cell-free (ucf) DNA concentration as a noninvasive screening tool for bladder cancer. Using PicoGreen-based detection, the ucf-DNA/UCr concentration was quantified in urine supernatant specimens from 46 bladder cancer patients and 98 controls and compared to 400-bp real-time PCR-based detection, which detected the amplification of 400-bp β-actin (named 400-bp ucf-DNA/UCr). The mean concentrations for both PicoGreen and 400-bp ucf-DNA (ng/mL)/UCr (mg/dL) were significantly higher in bladder cancer patients than in controls: 15.28 vs 6.68 (p<0.001, t-test) and 14.98 vs 1.07 (p<0.001), respectively. Among different stages and grades, no significant difference was found between these two methods. The areas under the ROC curves of PicoGreen and 400-bp ucf-DNA/UCr were 0.571 (95% confidence interval, 0.451–0.692) and 0.805 (95% confidence interval, 0.713–0.896), respectively. In 400-bp ucf-DNA/UCr, the best sensitivity and specificity were 86.1% and 72.0% at the cutoff value of 0.0645. These data indicated that 400-bp ucf-DNA/UCr is more reliable for bladder cancer detection than PicoGreen. In conclusion, our results suggest that ucf-DNA/UCr can be used as a potential tumor marker for bladder cancer, especially for detecting longer DNA fragments.
Serum Anti-p53 Antibodies as a useful Marker for Prognosis of Gastric Carcinoma
Authors: Mattioni M. , Soddu S. , Porrello A. , D'Alessandro R. , Spila A. , Guadagni F.
Published: January 2018

Mutations in the TP53 gene are the most common genetic alterations in cancer. Accumulation of mutated protein may induce circulating anti-p53 antibodies (anti-p53Ab) in sera of cancer patients. The aim of our work was to evaluate the presence and prognostic value of anti-p53Ab in gastric cancer patients and to investigate whether their presence is related to p53 overexpression in tumor tissue. Anti-p53Ab were analyzed in sera from 111 patients with gastric carcinoma and from 64 healthy donors by ELISA. p53 expression was also quantified by ELISA in biopsies of 54 gastric cancers and 22 healthy gastric mucosas. Significant anti-p53Ab levels were found in 15.3% of patients, whereas none of the 64 donor sera were positive. High levels of p53 expression were detected only in tumor tissue, in 72.2% of cases. A significant correlation was observed between anti-p53Ab and high levels of mutated p53 in tissue (p<0.05). The survival time of serum-positive patients was significantly longer than that of patients with low/negative serum levels, with a survival rate of 41.2% and 14.9%, respectively, over 48 months (p<0.05). Thus, detection of serum anti-p53Ab in gastric cancer patients can be useful to identify a subset of patients with better prognosis.
The Potential Role of Akt Phosphorylation in Human Cancers
Authors: Cicenas J.
Published: January 2018

Akt/protein kinase B (PKB) is a serine/threonine kinase which is implicated in mediating a variety of biological responses including cell growth, proliferation and survival. Akt is activated by phosphorylation on two critical residues, namely threonine 308 (Thr308) and serine 473 (Ser473). Several studies have found Akt2 to be amplified or overexpressed at the mRNA level in various tumor cell lines and in a number of human malignancies such as colon, pancreatic and breast cancers. Nevertheless, activation of Akt isoforms by phosphorylation appears to be more clinically significant than Akt2 amplification or overexpression. Many studies in the past 4–5 years have revealed a prognostic and/or predictive role of Akt phosphorylation in breast, prostate and non-small cell lung cancer. Several publications suggest a role of phosphorylated Akt also in endometrial, pancreatic, gastric, tongue and renal cancer. However, different types of assays were used in these studies. Before assessment of P-Akt can be incorporated into routine clinical practice, all aspects of the assay methodology will have to be standardized.
CYP1A1 *2B and *4 Polymorphisms are associated with Lung Cancer Susceptibility in Mexican Patients
Authors: Gallegos-Arreola M.P. , Figuera-Villanueva L.E. , Troyo-Sanroman R. , Morgán-Villela G. , Puebla-Pérez A.M. , Flores-Marquez M.R. , Zúñiga-González G.M.
Published: January 2018

Background

CYP1A1 is a gene involved in the high aryl hydrocarbon hydroxylase -inducible phenotype, which is a genetically-determined variation among individuals that has been associated with lung cancer risk. More specifically, CYP1A1*2B and *4 polymorphisms have been associated with high susceptibility to lung cancer among cigarette smokers. Materials and methods: DNA was obtained from blood samples and we studied by PCR-RFLP the distribution of CYP1A1*2B (n=248) and *4 (n=222) polymorphisms in healthy controls and 222 lung cancer patients from a Mexican population.

Results

Comparisons between groups showed an increased risk for lung cancer patients of *2B/*2B (18%; OR 7.6; 95% CI 3.0–19.2) and *4/*4 genotypes (15%; OR 11.45; 95% CI 2.19–59.85) compared to the control group (1% for *2B/*2B and 4.4% for *4/*4). A significant association between lung cancer and homozygous *2B/*2B passive smokers and *4/*4 ever (cigarettes) and passive smokers was also observed (p<0.05). Multivariate analysis revealed an increased risk for the *2B/2B genotype (OR 6.83), as well as for *4/*4 (OR 28.8).

Conclusion

The results of the study indicate a significant association between *2B/*2B and *4/*4 genotypes and the risk of developing lung cancer among Mexicans.
Antiphospholipid Antibodies and Acute-Phase Response in Non-Metastatic Colorectal Cancer Patients
Authors: Battistelli S. , Stefanoni M. , Petrioli R. , Genovese A. , Dell'Avanzato R. , Donati G. , Vittoria A. , Roviello F.
Published: January 2018

Aim

To investigate the plasma levels and prevalence of the most common antiphospholipid antibodies, as well as their relationships with several plasma markers of inflammation, in order to characterize some aspects of cancer thrombophilia.

Materials and methods

Eighty-three cancer patients with non-metastatic colorectal solid tumors and 94 control subjects were tested for the presence of IgG/IgM/IgA anti-cardiolipin and anti-β2-glycoprotein I antibodies and of several acute-phase reactants, i.e., fibrinogen, factor VIII:C and C4b-binding protein.

Results

In cancer patients the plasma levels of the acute-phase reactants and the IgA/IgG anti-cardiolipin and IgA anti-β2-glycoprotein I antibodies were significantly higher; the acute-phase reactants were significantly correlated with anti-cardiolipin antibodies; the prevalence of antiphospholipid antibodies was not significantly higher.

Conclusions

In patients with non-metastatic colorectal cancer the acute-phase response is associated with antiphospholipid generation. This could represent a further pathogenetic mechanism for the short-term post-surgery thrombotic complications of patients with colorectal cancer.
Coagulation Factor Levels in Non-Metastatic Colorectal Cancer Patients
Authors: Battistelli S. , Stefanoni M. , Lorenzi B. , Dell'Avanzato R. , Varrone F. , Pascucci A. , Petrioli R. , Vittoria A.
Published: January 2018

There is evidence that high plasma levels of factor (F) VIII, FIX, FXI and fibrinogen are independent risk factors for venous thromboembolism.

Aim

To determine the plasma concentrations of several coagulation factors and C4b-binding protein (C4BP) in a group of patients with non-metastatic colorectal cancer in order to investigate some aspects of cancer-acquired thrombophilia. Methods: Plasma fibrinogen, FII, FV, FVII, FVIII, FIX, FX, FXI and FXII activity levels and C4BP concentrations were determined in 73 patients with non-metastatic colorectal cancer (48 colon and 25 rectum) and in 67 matched control subjects. No one in either group had had previous thrombotic events.

Results

Mean plasma concentrations of fibrinogen (functional and antigen), FVIII, FIX, FV and C4BP were significantly higher in colorectal cancer patients than in control subjects, while FVII and FXII levels were significantly decreased. Several correlations were found between the increased coagulation factors and C4BP concentrations, while FVII was highly correlated with FXII.

Conclusions

In colorectal cancer patients high plasma fibrinogen, FVIII and FIX levels might represent further risk factors for venous thrombotic complications in the immediate post-surgery period, while decreased FVII and FXII concentrations may be an index of intravascular coagulation activation, still in a subclinical phase.
Circulating Cytokeratin 19 Fragments in Patients with benign Nodules and Carcinomas of the Thyroid Gland
Authors: Giovanella L. , Ceriani L. , Ghelfo A. , Maffioli M.
Published: January 2018

Cytokeratin 19 (CK19) is an acidic protein of 40 kDa that is part of the cytoskeleton of epithelial cells and is highly expressed by differentiated thyroid carcinomas, mainly of the papillary subtype. The soluble fragments of CK19 (Cyfra 21.1) can be measured by immunometric assays employing specific monoclonal antibodies. The present study was planned to assess the serum expression of Cyfra 21.1 in patients with benign thyroid nodules and thyroid malignancies. We enrolled 135 patients with histologically proven benign thyroid nodules (n=79) and thyroid carcinomas (n=56). No differences were found in serum Cyfra 21.1 levels between patients with benign nodules and patients with carcinomas. When thyroid malignancies were subdivided according to tumor histology, serum Cyfra 21.1 increased significantly from classical differentiated thyroid carcinomas (papillary or follicular) to less differentiated or undifferentiated carcinomas (poorly differentiated or anaplastic). CK19 release into the bloodstream is strongly related to the apoptotic pathway, and particularly to hyperproliferation-related apoptosis. These pathways characterized anaplastic and poorly differentiated thyroid carcinoma but not classical forms of differentiated thyroid carcinoma. Consequently, Cyfra 21.1 may be regarded as a circulating marker of poorly differentiated and anaplastic thyroid carcinoma. Additionally, a role of Cyfra 21.1 as a dedifferentiation marker in patients with classical differentiated thyroid carcinomas may be postulated and should be explored by further focused studies.
Gastrointestinal Stromal Tumors (GISTs): From Science to Targeted Therapy
Authors: Sarmiento R. , Bonginelli P. , Cacciamani F. , Salerno F. , Gasparini G.
Published: January 2018

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs represent a distinct category of tumors characterized by oncogenic mutations of the KIT receptor tyrosine kinase in a majority of patients. KIT is useful not only for the diagnosis but also for targeted therapy of this disease. Imatinib, a tyrosine kinase inhibitor, is widely used in advanced and metastatic GISTs. This agent revolutionized the treatment strategy of advanced disease and is being tested in the neoadjuvant and adjuvant settings with encouraging results. New therapeutic agents like sunitinib have now been approved, enriching the treatment scenario for imatinib-resistant GISTs. The present review reports on the peculiar characteristics of this disease through its biology and molecular patterns, focusing on the predictive value of KIT mutations and their correlation with clinical outcome as well as on the activity of and resistance to approved targeted drugs.
Effect of NBS1 Gene Polymorphism on the Risk of Cervix Carcinoma in a Northern Indian Population
Authors: Sobti R.C. , Shekari M. , Tamandani D.M. Kordi , Kaur P. , Suri V. , Huria A.
Published: January 2018

Cervical cancer is one of the most common neoplastic diseases affecting women, with a worldwide incidence of almost half a million cases. A history of smoking and use of oral contraceptives have been confirmed to be risk factors for cervical cancer. Genetic susceptibility and immune response, especially impaired cellular immune response, may well be related to the development of cervical cancer. NBS1 is one of the key proteins participating in the recognition and repair of double-strand breaks that may lead to genomic instability and cancer if unrepaired. The objective of the present study was therefore to investigate NBS1 Glu185Gln gene polymorphisms and the risk of cervix cancer in a northern Indian population. We found that passive smokers having particular NBS1 genotypes (Glu/Gln, Gln/Gln or Glu/Gln + Gln/Gln) have an increased risk of developing cervix cancer (OR 5.21, p=0.000001; OR 4.60, p=0.001; OR 5.10, p=0.0000009, respectively). The risk was increased 2.4-fold in oral contraceptive users with a Glu/Gln genotype. We conclude that the risk of cervical cancer is increased in passive smokers and in users of oral contraceptives with certain NBS1 genotypes.
Association of EGFR c.2073A>T Polymorphism with Decreased Risk of Diffusely Infiltrating Astrocytoma in a Brazilian Case-Control Study
Authors: Barbosa K.C. , Oba-Shinjo S.M. , Uno M. , Carvalho P.O. , Rosemberg S. , Aguiar P.H.P. , Carlotti C.G. , Malheiros S.M.F. , Toledo S. , Lotufo P. , Marie S.K.N.
Published: January 2018

Epidermal growth factor receptor (EGFR) gene overexpression has been implicated in the development of many types of tumors, including glioblastomas, the most frequent diffusely infiltrating astrocytomas. However, little is known about the influence of the polymorphisms of EGFR on EGFR production and/or activity, possibly modulating the susceptibility to astrocytomas. This study aimed to examine the association of two EGFR promoter polymorphisms (c-191C>A and c.-216G>T) and the c.2073A>T polymorphism located in exon 16 with susceptibility to astrocytomas, EGFR gene expression and survival in a case-control study of 193 astrocytoma patients and 200 cancer-free controls. We found that the variant TT genotype of the EGFR c.2073A>T polymorphism was associated with a significantly decreased risk of astrocytoma when compared with the AA genotype [sex- and age-adjusted odds ratio 0.51, 95% confidence interval 0.26–0.98]. No association of the two promoter EGFR polymorphisms (or combinations of these polymorphisms) and risk of astrocytomas, EGFR expression or survival was found. Our findings suggest that modulation of the EGFR c.2073A>T polymorphism could play a role in future therapeutic approaches to astrocytoma.
TP53 Mutations in Breast Cancer: Association with Ductal Histology and Early Relapse of Disease
Authors: Brankovic-Magic M.V. , Jankovic R.N. , Dobricic J.D. , Borojevic N.D. , Magic Z.M. , Radulovic S.S.
Published: January 2018

Purpose

This study aimed to investigate the incidence of core domain TP53 mutations in Serbian breast cancer patients in view of their possible correlation with prognostic parameters, tumor characteristics and clinical disease course.

Methods

145 breast cancer patients were included. Data on clinical disease course were available for 100 patients including 30 node-negative and 70 node-positive patients. After surgery, node-positive patients underwent adjuvant chemotherapy, mostly CMF. TP53 mutations were detected by PCR-SSCP.

Results

31 mutations were found in 27/145 patients including 4/59 node-negative patients and 23/83 node-positive patients (4 double mutations). 26/31 TP53 mutations were found in patients with invasive ductal carcinoma and only 2 in patients with invasive lobular carcinoma. The presence of TP53 mutations was correlated with clinical disease course in premenopausal node-positive patients (n=70). 11/20 patients with TP53 mutations relapsed. Within the first 24 months of follow-up, significantly shorter disease-free intervals were observed in TP5. 3-mutated patients.

Conclusions

TP53 mutations correlated only with nodal status and ductal histology. The significance of the predominant distribution of TP53 mutations in tumors with a ductal histology for the aggressive behavior of these tumors has yet to be proved, since the favorable biological features of tumors with a lobular histology do not result in a better prognosis. Early relapse in mutated- TP5. 3 carriers may support data on its predictive value with respect to adjuvant CMF.
Osteopontin Expression According to Molecular Profile of Invasive Breast Cancer: A Clinicopathological and Immunohistochemical Study
Authors: Ribeiro-Silva A. , da Costa J.P. Oliveira , Garcia S. Britto
Published: January 2018

Osteopontin (OPN) is a secreted, calcium-binding phosphorylated glycoprotein involved in several physiological and pathological events such as angiogenesis, apoptosis, inflammation, wound healing, vascular remodeling, calcification of mineralized tissues, and induction of cell proteases. There is growing interest in the role of OPN in breast cancer. In an attempt to obtain new insight into the pathogenesis of OPN-associated breast carcinomas, an immunohistochemical panel with 17 primary antibodies including cytokeratins and key regulators of the cell cycle was performed in 100 formalin-fixed paraffin-embedded samples of invasive breast carcinomas. OPN was expressed in 65% of tumors and was negatively correlated with estrogen (p=0.0350) and progesterone (p=0.0069) receptors, but not with the other markers and clinicopathological features evaluated including age, menstrual status, pathological grading, tumor size, and metastasis. There was no correlation between OPN expression and carcinomas of the basal-like phenotype (p=0.1615); however, OPN correlated positively with c-erbB-2 status (p=0.0286) and negatively with carcinomas of the luminal subtype (p=0.0353). It is well known that carcinomas overexpressing c-erbB-2 protein have a worse prognosis than luminal tumors. Here, we hypothesize that the differential expression of OPN in the first subtype of carcinomas may contribute to their more aggressive behavior.
Cathepsin B, Cathepsin H, Cathepsin X and Cystatin C in Sera of Patients with Early-Stage and Inflammatory Breast Cancer
Authors: Decock J. , Obermajer N. , Vozelj S. , Hendrickx W. , Paridaens R. , Kos J.
Published: January 2018

Numerous studies have linked cathepsins and their inhibitor cystatin C to tumor invasion and metastasis. We examined whether cathepsin B, cathepsin H, cathepsin X and cystatin C could be detected in sera from women with early-stage or inflammatory breast cancer and whether they correlated with clinicopathological characteristics. Preoperative serum was obtained from 176 patients with early-stage breast cancer (tumor size <5 cm, negative lymph nodes) and 31 patients with inflammatory breast cancer. Cathepsin and cystatin C levels were measured by ELISA. The patient and tumor characteristics under study were age at diagnosis, menopausal status, tumor size, tumor grade, and steroid hormone receptor status. Serum cathepsin B levels were significantly lower in patients with poorly differentiated tumors. High cystatin C levels were associated with tumor size, postmenopausal status and patient age. Interestingly, significantly lower levels of cathepsin X and H were found in patients with inflammatory breast cancer, a trend also observed for cathepsin B and cystatin C. In conclusion, our results show a limited association of cathepsins B, H, X and cystatin C with established prognostic parameters. These data are promising and encourage future analysis of the clinical outcome of our patients in order to examine the potential prognostic value of these biomarkers. Further, this study indicates a role for cathepsin X and H in inflammatory breast cancer.
SMAD2 and the Relationship of Colorectal Cancer to Inflammatory Bowel Disease
Authors: Mahid S.S. , Minor K.S. , Brangers B.C. , Cobbs G.A. , Galandiuk S.
Published: January 2018

Inflammatory bowel diseases (IBDs) affecting the colon [Crohn's disease (CD) and ulcerative colitis (UC)] are associated with an increased risk of colorectal cancer (CRC). Our previous work using oligonucleotide array data indicated that SMAD2 was significantly underexpressed in UC dysplastic tissue compared to benign UC. The aim of this current study was to determine whether single nucleotide polymorphisms (SNPs) within the SMAD2 gene are associated with IBD dysplasia/cancer. We performed an SNP haplotype-based case-control association study. Leukocyte DNA was obtained from 489 unrelated Caucasians (158 UC, 175 CD, 71 CRC, 85 controls). Eleven SNPs were genotyped. All 11 SNPs were in Hardy-Weinberg equilibrium in the control population. Strong linkage disequilibrium was observed among nearly all SMAD2 SNPs. There were no significant associations between SMAD2 allele or haplotype frequencies. Power calculations indicated good power for single-marker analysis (>0.8) and reasonably good power against effects of 0.1–0.15 for haplotype analysis. SMAD2 SNPs were not associated with the development of IBD dysplasia/cancer. This incongruity between our previous microarray data and the findings from this genotype study may be attributed to mechanisms such as alternative splicing of pre-mRNA SMAD2 and/or cross talk with other cellular pathways.
Expression of Periostin in Patients with Non-Small Cell Lung Cancer: Correlation with Angiogenesis and Lymphangiogenesis
Authors: Takanami I. , Abiko T. , Koizumi S.
Published: January 2018

The aim of this study was to evaluate periostin expression measured immunohistochemically in patients with non-small cell lung cancer (NSCLC) and to determine its association with clinical features, prognosis, angiogenesis, and lymphangiogenesis. We investigated periostin expression in a series of 88 patients with NSCLC. We also determined whether expression of periostin correlated with microvessel density and lymphatic microvessel density. Periostin was expressed in 42% of 88 patients. Its expression was significantly correlated with tumor size, lymph node metastasis, disease stage, and lymphatic invasion (p=0.0128, 0.0015, 0.0310 and 0.0273, respectively). There also was a significant relation between periostin expression and microvessel density and lymphatic microvessel density (all p<0.0001). Five-year survival rates were better in patients with negative periostin expression than in those with positive periostin expression (p=0.0044). Periostin expression was not significant in a multivariate additive model. Our findings show that periostin correlates with increased tumor progression and a worse prognosis in NSCLC, as well as with angiogenesis and lymphangiogenesis.
Circulating Tumor Cells in HER-2 Positive Metastatic Breast Cancer Patients Treated with Trastuzumab and Chemotherapy
Authors: Nunes Raquel A. , Li Xiaochun , Kang Soonmo Peter , Burstein Harold , Roberts Lisa , Carney Walter , Blackwell Kimberly , Ryan Paula , Borges Virginia , Iglehart J. Dirk , Friedman Paula , Harris Lyndsay N.
Published: January 2018

The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge. The goal of this paper is to present a sensitive and specific methodology of detecting CTCs in women with HER-2-positive metastatic breast cancer, and to examine its role as a marker that tracks disease response during treatment with trastuzumab-containing regimens.

The study included patients with HER-2-positive metastatic breast cancer enrolled on two different clinical protocols using a trastuzumab-containing regimen. Serial CTCs were measured at planned time points and clinical correlations were made. Immunomagnetic selection of circulating epithelial cells was used to address the specificity of tumor cell detection using cytokeratin 19 (CK19). In addition, the extracellular domain of the HER-2 protein (HER-2/ECD) was measured to determine if CTCs detected by CK19 accurately reflect tumor burden.

The presence of CTCs at first restaging was associated with disease progression. We observed an association between CK19 and HER-2/ECD. The association of HER-2/ECD with clinical response followed a similar pattern to that seen with CK19. Finally, the absence of HER-2/ECD at best overall response and a change of HER-2/ECD from positive at baseline to negative at best overall response was associated with favorable treatment response.

Our study supports the prognostic and predictive role of the detection of CTCs in treatment of HER-2-positive metastatic breast cancer patients. The association between CK19 and markers of disease burden is in line with the concept that CTCs may be a reliable measure of tumor cells in the peripheral blood of patients with metastatic breast cancer. The association of CTCs at first restaging with treatment failure indicates that CTCs may have a role as surrogate markers to monitor treatment response.
Mutational Analysis of the BRAF Gene in Transitional Cell Carcinoma of the Bladder
Authors: Boulalas Ioannis , Zaravinos Apostolos , Delakas Demetrios , Spandidos Demetrios A.
Published: January 2018

Purpose

Mutational activation of the MAP kinase pathway is frequently found in many types of cancer. Recently, activating mutations in the BRAF gene, an important activator of this pathway, have been described in several tumor types including melanoma, colorectal and papillary thyroid cancer. The most frequent mutation in exon 15 (V600E) as well as several other mutations within exons 11 and 15 result in constitutive activation of the oncoprotein.

Materials and methods

Our study aimed to investigate BRAF mutations in 30 human bladder tumors and their adjacent normal tissues. The V600E mutation was screened by PCR/RFLP and exons 11, 14 and 15 of BRAF including intron-exon boundaries were sequenced.

Results

We detected two tumor specimens bearing two different mutations, both of which were found in exon 15. One sample showed the T1799A (V600E) and the other the G1798T (V600L) mutation. The first specimen was stage pT1a and grade II, whereas the second was stage pT2b and grade III. No mutations within the coding region of exons 11, 14, 15 and the intron-exon junctions for the remaining samples were found.

Conclusions

Our results suggest that involvement of BRAF mutations in the development of transitional cell carcinoma of the bladder is infrequent.
Quantification of VEGF Isoforms and VEGFR Transcripts by qRT-PCR and Their Significance in Acute Myeloid Leukemia
Authors: Mourah Samia , Porcher Raphaël , Lescaille Géraldine , Rousselot Philippe , Podgorniak Marie-Pierre , Labarchède Géraldine , Naïmi Benyoussef , Medioni Jacques , Dombret Hervé , Calvo Fabien
Published: January 2018

Vascular endothelial growth factor (VEGF) and its receptors are known to play an important role in normal and pathological hematopoiesis but the prognostic impact of VEGF isoform transcripts in acute myeloid leukemia (AML) has not been addressed. We conducted a single-institution prospective study to analyze the impact of these angiogenic factors and the expression of their receptors on the survival of adult patients newly diagnosed with AML. We investigated the levels of VEGF transcript isoforms VEGF121, -145, -165, -189 and -206 and their receptors, VEGFR-1 and VEGFR-2, using quantitative reverse transcriptase polymerase chain reaction assays in peripheral blood mononuclear cells (PBMCs) of 67 consecutive AML patients at diagnosis. VEGF total protein was measured for comparison with mRNA levels in PBMCs. The VEGF121 splice variant transcript in AML PBMCs was significantly higher than in the normal controls. VEGF transcripts were quantified in all samples while its protein was detected in 42/67 (63%) of AML samples. High levels of VEGF121, VEGF165 transcripts and VEGF protein in AML were significantly related to a worse prognosis when analyzing overall survival (p<0.0001, p=0.019 and p=0.012, respectively) or event-free survival (p<0.0001, p=0.010 and p=0.047) using univariate analysis. In multivariable analysis only VEGF121 expression remained an independent prognostic factor for either event-free survival or overall survival [aHR=8.83 (3.48–22.4), p<0.0001, and aHR=9.52 (3.41–26.6), p<0.0001]. No prognostic value was observed for the other isoforms and the two receptors. Our findings show that the level of VEGF121 mRNA in circulating cells from AML patients is a strong independent prognostic parameter, which could be useful in the management of unselected AML patients.
Cytokeratin and Vimentin Expression in Breast Cancer
Authors: Vora Hemangini H. , Patel Nupur A. , Rajvik Kruti N. , Mehta Shalvi V. , Brahmbhatt Birwa V. , Shah Manoj J. , Shukla Shilin N. , Shah Pankaj M.
Published: January 2018

Background

The transition from epithelial keratin to mesenchymal vimentin expression marks an important step in the malignant progression of breast cancer. This study analyzed the clinical significance of cytokeratin and vimentin in patients with breast cancer.

Materials and methods

Expression of cytokeratin and vimentin was evaluated by immunohistochemistry on paraffin-embedded tissue sections of patients with breast cancer.

Results

Loss of cytokeratin was seen in 11% of the patients. A clearer trend towards loss of cytokeratin was observed in patients with stage IV disease and PR negativity. Weak cytokeratin expression was present in patients who developed recurrence or metastatic disease. Loss of cytokeratin was associated with reduced overall survival in univariate and multi-variate analysis, gain of vimentin expression was seen in 57% of breast carcinoma patients. It was higher in patients with lymph node positivity, advanced stage, HER2 positivity, and disease recurrence or metastasis. Multivariate survival analysis indicated that gain of vimentin expression was associated with reduced relapse-free survival.

Conclusion

Loss of cytokeratin and gain of vimentin expression are indicators of biologically aggressive breast carcinoma.
Elevated CA 19-9 Levels in Mature Cystic Teratoma of the Ovary
Authors: Kyung Min Sun , Choi Joong Sub , Hong Seung Hwa , Kim Hak Soon
Published: January 2018

The purpose of this study was to evaluate the clinical value of serum tumor markers in patients with ovarian mature cystic teratoma (MCT). We retrospectively evaluated 163 women who underwent surgery for MCT of the ovary between March 2003 and August 2007 and who provided preoperative blood samples for the measurement of CA 19-9 and CA 125. The rates of elevated serum CA 19-9 and CA 125 levels were 31.9% (52/163) and 13.5% (22/163), respectively. The rate of ovarian torsion was 12.9% (21/163). There were significant differences between the elevated CA 19-9 group and the normal CA 19-9 group in the diameters of the tumors and the rates of ovarian torsion. Elevated serum CA 19-9 levels correlated with larger tumor diameters and higher torsion rates. CA 19-9 may be a useful tool for the diagnosis of ovarian MCT. Elevated CA 19-9 levels appear to correlate with larger tumor diameters and higher rates of ovarian torsion.
Gene-Specific Methylation: Potential Markers for Colorectal Cancer
Authors: Prabhu Jyothi S. , Korlimarla Aruna , Banerjee Arindam , Wani Shivangi , Payal K , Sahoo Rashmita
Published: January 2018

Purpose

Aberrant methylation of the promoter region is associated with silencing of many genes in neoplasia. CpG island methylation is an epigenetic mechanism for transcriptional silencing that occurs at various stages of colon tumorigenesis. In this study, we tested the promoter methylation and expression of seven genes from various pathways of DNA repair, apoptosis and inflammation, i.e., sFRP1, MLH1, RASSF1A, CDA, v-fgr, LYN-B, and TNFR10d.

Method

The genes were analyzed by quantitative polymerase chain reaction for the level of gene expression. The promoter methylation status of the genes was studied by methylation-specific polymerase chain reaction.

Result

The correlation of promoter methylation status with suppressed gene expression patterns suggested a potential role for the silencing these genes in colon cancer progression.

Conclusion

Promoter methylations of the studied genes could be explored as promising biomarkers for new diagnostic, prognostic and therapeutic targets of colorectal cancer.
E-Cadherin and Metalloproteinase-1 and -7 Polymorphisms in Colorectal Cancer
Authors: de Lima Jacqueline Miranda , de Souza Lessileia Gomes , da Silva Ismael Dale Cotrim Guerreiro , Forones Nora Manoukian
Published: January 2018

Purpose

E-cadherin (CDH1) and metalloproteinase (MMP) polymorphisms could play a crucial role in cancer invasion. Our aim was to investigate the influence of the -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 polymorphisms on the frequency and progression of colorectal cancer (CRC).

Experimental design

A total of 130 patients with CRC and 130 noncancer controls were studied. The -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism.

Results

Patients with the 1G allele and a family history of CRC showed a six times higher risk of developing CRC (OR: 6.45, 95%CI: 2.02–20.6, p=0.001). The A/A CDH1 genotype was associated with a higher risk of metastatic disease (OR: 3.43, 95%CI: 1.27–9.27, p=0.023). A higher marginal risk of metastatic disease was observed for MMP-1 genotypes 1G/1G and 1G/2G (OR: 2.97, 95%CI: 0.93–9.47, p=0.098).

Conclusions

The -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 single nucleotide polymorphisms did not modify the risk of CRC development. Patients with the 1G/1G or 1G/2G genotype and a family history of CRC presented a higher risk of CRC. The AA CDH1 and 1G/1G and 1G/2G MMP-1 genotypes might be associated with advanced metastatic disease, but are not markers of lymphatic metastasis.
Association of the AA genotype of the BCL2 (–938C>A) promoter polymorphism with better survival in ovarian cancer
Authors: Heubner Martin , Wimberger Pauline , Otterbach Friedrich , Kasimir-Bauer Sabine , Siffert Winfried , Kimmig Rainer , Nückel Holger
Published: January 2018

Background

Bcl-2 plays a key role in the regulation of apoptosis. Recently, a novel regulatory single nucleotide polymorphism (–938C>A) in the inhibitory P2 BCL2 promoter was described. In this study we investigated its potential association with survival in epithelial ovarian cancer.

Experimental design

Patients (n=110) with primary epithelial ovarian cancer were retrospectively genotyped by pyrosequencing.

Results

Genotype distribution was not significantly different between 110 ovarian cancer patients and 120 healthy controls, suggesting that genotypes of this polymorphism do not increase the susceptibility to ovarian cancer. Kaplan-Meier curves showed a significant association of the AA genotype with increased survival (p=0.002). Multivariate analysis revealed that the BCL2–938AC/CC genotype (hazard ratio 4.5; p=0.003) was an independent prognostic factor compared to other prognostic factors such as age, histological grade or tumor stage.

Conclusion

The results suggest a role for the BCL2-938C>A polymorphism as a marker for survival in patients with epithelial ovarian cancer.
Comparative evaluation of the erbB2 and hormone receptor status of neighboring invasive and in situ components of ductal carcinomas of the breast
Authors: Peres Raquel Mary Rodrigues , Serra Kátia Piton , Derchain Sophie F.M. , Yoon Jung Hyun , Pinto Glauce Aparecida , Alvarenga Marcelo , Soares Fernando Augusto , Heinrich Juliana K. , Da Cunha Isabela Werneck , Vassallo Jose , Sarian Luís Otávio
Published: January 2018

Background

It remains unknown whether erbB2 expression and hormone receptor status predict the invasive potential of ductal carcinoma in situ (DCIS) of the breast.

Objectives

To examine erbB2 and estrogen/progesterone receptor (ER/PR) status in the precise areas where DCIS turns into invasive ductal carcinoma (IDC).

Subjects and methods

Eighty-seven cases of breast malignancies harboring contiguous regions of DCIS and IDC were selected. Separate histological samples from the DCIS and the neighboring IDC were obtained using tissue microarrays. The erbB2 and ER/PR statuses were assessed using immunohistochemistry (erbB2 and ER/PR) and fluorescence in situ hybridization (FISH – only erbB2).

Results

The expression of erbB2 did not differ in the DCIS and IDC components of the breast tumors (p=0.35). There was good agreement in sample-by-sample comparisons of erbB2 (intraclass correlation coefficient [ICC]=0.78), PR (ICC=0.61) and ER (ICC=0.70) expression in the DCIS and IDC components.

Conclusion

Our findings suggest that the expressions of erbB2 and ER/PR do not differ in the contiguous regions from DCIS to IDC.
Serum Tissue Inhibitor of Metalloproteinase 1 and 2 (TIMP-1 and TIMP-2) Levels in Colorectal Cancer Patients: Associations with Clinicopathological Variables and Patient Survival
Authors: Giaginis Constantinos , Nikiteas Nikolaos , Margeli Alexandra , Tzanakis Nikolaos , Rallis Georgios , Kouraklis Gregorios , Theocharis Stamatios
Published: January 2018

Tissue inhibitors of metalloproteinases (TIMPs) appear to affect many aspects of cancer biology, playing a crucial role in cell signaling by regulating cell growth, apoptosis, invasion, metastasis, angiogenesis, and genomic instability. The aim of the present study was to elucidate the diagnostic and prognostic utility of TIMP-1 and TIMP-2 in patients with colon cancer. Serum TIMP-1 and TIMP-2 concentrations were quantified using an enzyme-linked immunosorbent assay in 97 colon cancer patients. Elevated serum TIMP-1 levels were found in patients with advanced disease stage (p=0.0512) and poorly differentiated histopathological tumor grade (p=0.0059). Patients with increased TIMP-1 levels had shorter overall survival times (log-rank test, p=0.0143). Multivariate analysis also identified TIMP-1 as an independent prognostic factor (Cox regression analysis, p=0.0149). Serum TIMP-2 levels were not significantly associated with disease stage, histopathological grade or survival. In the subgroup of patients with well and moderately differentiated tumors, TIMP-1 and TIMP-2 were identified as independent prognostic factors (Cox regression analysis, p=0.0379 and p=0.0451, respectively). In conclusion, assessment of serum TIMP-1 can be considered a useful biomarker in colon cancer, whereas TIMP-2 appears to be of limited value.
Cutoff value of carcinoembryonic antigen and carbohydrate antigen 19-9 elevation levels for monitoring recurrence in patients with resectable gastric adenocarcinoma
Authors: Qiu Miao-Zhen , Lin Jun-Zhong , Wang Zhi-Qiang , Wang Feng-Hua , Pan Zhi-Zhong , Luo Hui-Yan , Li Yu-Hong , Zhou Zhi-Wei , He You-Jian , Xu Rui-Hua
Published: January 2018

Background

The aim of this longitudinal study was to try and improve the specificity of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 in monitoring tumor recurrence in patients with resectable gastric adenocarcinoma by setting suitable elevation levels.

Methods

One hundred eighty-one patients with resectable gastric adenocarcinoma were considered. Serum samples were obtained preoperatively and every 3 months postoperatively.

Results

Preoperative CEA and CA19-9 positivity rates were 19.9% and 18.2%. The specificity and sensitivity of CEA elevation to monitor recurrence were 92.9% and 23.4% versus 76.5% and 78.9% in CEA-negative versus CEA-positive patients, respectively. For CA19-9 the specificity and sensitivity were 95.0% and 18.8% versus 60.0% and 83.3% in CA19-9-negative versus CA19-9-positive patients, respectively. When we set the elevation level of CEA at 5 ng/mL, the specificity of CEA elevation to monitor recurrence increased to 94.1% for CEA-positive patients. The specificity increased to 93.3% for CA19-9-positive patients when the CA19-9 elevation level was set at 100 U/mL.

Conclusions

For CEA- or CA19-9-positive patients with resectable gastric adenocarcinoma we can increase the specificity of CEA and CA19-9 by setting the elevation level of CEA at 5 ng/mL and CA19-9 at 100 U/mL.