bluuebunny/crossref_metadata_2025 huggingface dataset:
c-erbB-2 Oncoprotein Content in Gastric Cancer and in Adjacent Mucosa
Authors: García I. , Vizoso F. , Andicoechea A. , Fernandez P. , Suarez C. , García-Muñiz J.L. , Allende M.T.
Published: March 2018

The aim of this study was to evaluate, by means of an immunoenzymatic assay, the membranous and cytosolic c-erbB-2 oncoprotein contents in primary tumors and in adjacent mucosa from gastric cancer patients. Fifty-two patients with primary gastric adenocarcinomas were enrolled in this prospective study. c-erbB-2 protein levels were significantly higher in membranous than in cytosolic samples, both in neoplastic tissues (median: 3602 vs 525 NHU/mg protein; p<0.0001) and in adjacent mucosa samples (median: 3174 vs 509 NHU/mg protein; p<0.0001). Nevertheless, there was a significant positive relation between membranous and cytosolic c-erbB-2 protein contents in both neoplastic tissue (p<0.001) and adjacent mucosa (p<0.001) samples. There was no significant difference in the membranous c-erbB-2 protein content between neoplastic tissues and adjacent mucosa samples. However, the cytosolic c-erbB-2 content was significantly higher in neoplastic tissues than in adjacent mucosa (p<0.05). Finally, the results did not show any significant correlations of these oncoprotein contents with patient characteristics, clinicopathologic parameters and overall survival of the study population.
Clinical Evidence for Correlation of Insufficient Tissue Oxygen Supply (Hypoxia) and Tumor-Associated Proteolysis in Squamous Cell Carcinoma of the Head and Neck
Authors: Stadler P. , Feldmann H.J. , Creighton C. , Zeilhoffer H.-F. , Zimmermann V. , Schmitt M. , Molls M.
Published: March 2018

Hypoxic tumors of patients with squamous cell carcinoma of the head and neck show a consistent trend towards poor treatment outcome. We now report that tumor hypoxia in these patients is correlated with elevated antigen content of the tumor-associated serine protease uPA (urokinase-type plasminogen activator), a marker of tumor cell invasion and metastasis.
Early 5-Fluorouracil-Induced Changes of Poly(A) Polymerase in Hela and Wish Cells
Authors: Balatsos N.A.A. , Havredaki M. , Tsiapalis C.M.
Published: March 2018

5-Fluorouracil (5-FU), a drug with numerous mechanisms of action which has a long-term suppressive effect on human cancer cell proliferation, mediates both partial dephosphorylation and inactivation of poly(A) polymerase (PAP) [EC. 2.7.7.19] as detected by immunoblotting analysis and non-specific enzyme assay, respectively, in human carcinoma HeLa and diploid WISH cells at a concentration of 100 μM. When the same experiment is done in the presence of phosphatase inhibitors, 5-FU-induced partial PAP dephosphorylation is abolished. Moreover, a cell type-modulated, differential response of HeLa cells (5-FU chemosensitive cells) versus WISH cells (drug-resistant diploid cells) is observed. These results suggest that 5-FU induces early direct or indirect changes in the structure and function of PAP and may regulate premRNA cleavage-polyadenylation.
Molecular Detection of Codon 12 K-RAS Mutations in Circulating DNA from Serum of Colorectal Cancer Patients
Authors: Salbe C. , Trevisiol C. , Ferruzzi E. , Mancuso T. , Nascimbeni R. , Di Fabio F. , Salerni B. , Dittadi R.
Published: March 2018

Point mutations of the K-RAS gene at codon 12 are found in about 40% of cases with colorectal cancer. The diagnostic implications of the detection of these mutations and their clinical utility are still unclear. The aim of this study was to test both the feasibility of the detection of the mutated K-RAS gene in serum and its potential role in colorectal cancer detection and monitoring.

Codon 12 K-RAS mutations were examined in DNA extracted from the serum of 35 patients with colorectal cancer and were compared with the K-RAS status in the corresponding primary tumor. Molecular detection was performed by the mutant-enriched PCR (ME-PCR) assay, a sensitive method capable of distinguishing a small quantity of mutated DNA in the presence of abundant wild-type DNA. The occurrence of mutations was compared with clinicopathological parameters as well as CEA and CA19.9 serum levels.

We found codon 12 K-RAS mutations in the tissue of 13/35 (37%) patients. Serum mutations were detected in 5/13 (38.5%) patients with mutated K-RAS in the tissue. 26/35 (74%) patients showed an identical K-RAS pattern in tissue and serum. No codon 12 K-RAS alterations were found in serum samples of 22 patients with benign gastrointestinal diseases. Elevated serum CEA levels were detected in 16 patients, four of whom also presented serum RAS mutations.

Our results confirm that K-RAS mutations can be found in circulating DNA extracted from serum samples of patients with colorectal cancer and show that there is a correspondence between serum and tissue K-RAS patterns.
Two Novel Monoclonal Antibodies against the MUC4 Tandem Repeat Reacting with an Antigen Overexpressed by Lung Cancer
Authors: Botti C. , Seregni E. , Ménard S. , Collini P. , Tagliabue E. , Campiglio M. , Vergani B. , Ghirelli C. , Aiello P. , Pilotti S. , Bombardieri E.
Published: March 2018

In this study we investigated the immunochemical and cytochemical reactivity of two monoclonal antibodies against the 16-amino acid tandem repeat of MUC4 to demonstrate a possible variation of the mucin core peptide expression related to lung cancer. The immunocytochemical anti-MUC4 reactivity was analyzed in four lung cancer cell lines (Calu-1, Calu-3, H460, SKMES) and in other tumor cell lines, as well as in frozen materials from 21 lung adenocarcinomas (ACs), including five bronchioloalveolar carcinomas (BACs), and 11 squamous cell lung carcinomas (SqCCs). A weak fluorescence anti-MUC4 positivity (range: 10.3–16.2) was observed only in acetone-fixed lung cancer cell lines Calu-1, Calu-3 and H460. These three lung cancer cell lines also showed a cytoplasmic immunoperoxidase reactivity. The immunostaining in lung cancer tissues showed a granular cytoplasmic reactivity: 15/21 (71%) and 17/21 (80%) ACs were positive with BC-LuC18.2 and BC-LuCF12, respectively. All BACs were positive. Moderate to strong reactivity was present in well-differentiated ACs. In the normal lung parenchyma counterparts weak reactivity was found only in bronchiolar cells. All SqCCs were negative. Anti-MUC4 reactivity was also observed in the alveolar mucus. In conclusion, our anti-MUC4 MAbs detect a secretion product present in mucus and this product is elaborated by lung cancer cells and overexpressed in well-differentiated lung ACs.
CA 15–3: A Prognostic Marker in Breast Cancer
Authors: Duffy M.J. , Shering S. , Sherry F. , McDermott E. , O'Higgins N.
Published: March 2018

CA 15–3 (also known as MUC1) is the most widely used serum marker in breast cancer. MUC1 is a large transmembrane glycoprotein which is frequently overexpressed and aberrantly glycosylated in cancer. Physiologically, MUC1 appears to play a role in cell adhesion and the high levels present in cancer may be causally involved in metastasis. At present the main uses of CA 15–3 are in preclinically detecting recurrent breast cancer and monitoring the treatment of patients with advanced breast cancer. In a prospective study of 368 patients we show that patients with high preoperative levels of CA 15–3 (>30.4 U/mL) had a worse outcome than patients with low levels of the marker. In multivariate analysis CA 15–3 as a prognostic marker was independent of both tumor size and nodal status. Furthermore, in multivariate analysis the prognostic impact of CA 15–3 was stronger than that of tumor size and at least as strong as nodal status. CA 15–3 may thus be the first independent prognostic serum marker in breast cancer.
The Prognostic Value of the Tumor Marker CA 15–3 at Initial Diagnosis of Patients with Breast Cancer
Authors: McLaughlin R. , McGrath J. , Grimes H. , Given H.F.
Published: March 2018

CA 15–3 has been most widely used as a serum tumor marker in follow-up and detection of breast cancer recurrence. In this study we have specifically focused upon the prognostic implications and utility of preoperative CA 15–3 levels. We have identified on our database 414 patients with breast cancer in whom serial levels of the serum tumor marker CA 15–3 had been determined at diagnosis and follow-up. We have analyzed the follow-up and clinical outcomes in these patients and from this data we have assessed the potential of CA 15–3 as a predictor of five-year overall and disease-free survival.

Our results show that an initially elevated CA 15–3 level is associated with a very poor prognosis in both early and late stage disease. Elevated pre-biopsy CA 15–3 levels are associated with 14% five-year disease-free survival rates and 17% overall survival rates at five years. In contrast, normal CA 15–3 levels are associated with 47% five-year disease-free survival rates and 54% overall survival rates at five years (p<0.01). Comparison of five-year survival rates between patients with elevated and normal CA 15–3 levels in early breast cancer (stage I and II) also showed significant differences, with survival being 41% and 75%, respectively (p<0.01).
Human MUC1 Mucin: A Multifaceted Glycoprotein
Authors: von Mensdorff-Pouilly S. , Snijdewint F.G.M. , Verstraeten A.A. , Verheijen R.H.M. , Kenemans P.
Published: March 2018

Human MUC1 mucin, a membrane-bound glycoprotein, is a major component of the ductal cell surface of normal glandular cells. MUC1 is overexpressed and aberrantly glycosylated in carcinoma cells. The role MUC1 plays in cancer progression represents two sides of one coin: on the one hand, loss of polarity and overexpression of MUC1 in cancer cells interferes with cell adhesion and shields the tumor cell from immune recognition by the cellular arm of the immune system, thus favoring metastases; on the other hand, MUC1, in essence a self-antigen, is displaced and altered in malignancy and induces immune responses. Tumor-associated MUC1 has short carbohydrate sidechains and exposed epitopes on its peptide core; it gains access to the circulation and comes into contact with the immune system provoking humoral and cellular immune responses. Natural antibodies to MUC1 present in the circulation of cancer patients may be beneficial to the patient by restricting tumor growth and dissemination: early stage breast cancer patients with a humoral response to MUC1 have a better disease-specific survival. Several MUC1 peptide vaccines, differing in vectors, carrier proteins and adjuvants, have been tested in phase I clinical trials. They are capable of inducing predominantly humoral responses to the antigen, but evidence that these immune responses may be effective against the tumor in humans is still scarce.
Circulating Angiogenesis Regulators in Cancer Patients
Authors: Kuroi K. , Toi M.
Published: March 2018

Background/Aims

To date, numerous studies have demonstrated that several angiogenesis regulators circulate in the blood and may function as endocrine factors in cancer patients. This review aims to give a comprehensive insight into the possible clinical value of circulating angiogenesis regulators, mainly basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF), angiogenin, pleiotrophin, thrombospondin (TSP) and endostatin (ES) in cancer patients.

Methods

A computerized (MEDLINE) and a manual search based on the reference lists of the publications were performed to identify articles published on this topic.

Results

In a detailed literature search, approximately 100 publications were found up to the end of 1999. Circulating angiogenic factors such as bFGF, VEGF, HGF and angiogenin have been evaluated not only as diagnostic and/or prognostic factors but also as predictive factors in cancer patients. On the other hand, little is known about the clinical significance of negative regulators. Neither the source nor the mechanism of protein externalization has been clarified in detail.

Conclusions

Although there are no known factors with established clinical utility, circulating angiogenesis regulators may be useful in several situations. They could be used to determine the risk of developing cancer, to screen for early detection, to distinguish benign from malignant disease, and to distinguish between different types of malignancies. In patients with established malignancies such factors might be used to determine prognosis, to predict the response to therapy, and to monitor the clinical course. Further investigations are warranted to assess the specific utility of each factor.
Relationship between Mesenteric and Peripheral Blood Levels of CA 19-9 in Patients with Colorectal Cancer
Authors: Forones N. M. , Tanaka M. , Matos D.
Published: March 2018

Introduction

CA19-9 is one of the most important tumor markers used in patients with colorectal cancer, mainly in radical surgery follow-up. Aim: The purpose of this study was to evaluate the preoperative CA19-9 level obtained from a peripheral vein (PV) and compare it to the level obtained from the mesenteric vein (MV).

Materials and methods

Blood was collected from a PV of the arm and from the MV of 59 patients with colorectal cancer before primary surgery. Of these 59 patients fourteen had stage I disease, 10 stage II, 22 stage III, and 13 stage IV. CA19-9 was determined in serum by immunoenzymatic assay (Abbott Diagnostica).

Results

Fifteen patients (24%) had elevated serum levels of CA19-9 in the MV and 13 (22%) in the PV. None of the stage I or II patients had elevated serum levels of CA19-9. There were no differences between marker levels in blood collected from the MV or PV, independent of clinical stage. The CA19-9 values obtained from the MV differed significantly in the different stages of the disease according to the Kruskal-Wallis analysis (p=0.026); this difference was not statistically significant (p=0.08) in serum from the PV. There was no correlation between venous infiltration by the tumor and positivity of CA19-9 serum levels collected from the mesenteric vein. We observed a close correlation between the serum levels of CA19-9 collected from the PV and from the MV (r=0.9).

Conclusion

The current study demonstrates a close correlation between the serum levels of CA19-9 collected from a peripheral vein and from the mesenteric vein. Our results confirmed the poor sensitivity of serum CA19-9 at diagnosis, independent of the collection site.
Histological Grade in Breast Cancer: Association with Clinical and Biological Features in a Series of 229 Patients
Authors: Ruibal A. , Arias J.I. , Del Río M C. , Lapeña G. , Schneider J. , Tejerina A.
Published: March 2018

In order to study the association of histological grade (HG) with specific clinical and biological parameters which may influence the clinical behavior of infiltrating ductal carcinomas of the breast (IDC), we analyzed in 229 tissue samples the cytosolic concentrations of estrogen receptor (ER), progesterone receptor (PR), pS2, cathepsin D, hyaluronic acid (HA) and tissue-type plasminogen activator (t-PA), as well as those of the erbB2 oncoprotein, epidermal growth factor receptor (EGFR), HA, CD44v5 and CD44v6 in the cell membrane fraction. Likewise, we considered size, ploidy, S-phase fraction and axillary node involvement as variables of the study. The transition from HG1 to HG2 and from HG2 to HG3 was accompanied by a number of common features: global increase in size, greater number of tumors >2.0 cm, decrease in membrane hyaluronic acid concentrations, increased cell proliferation (S-phase >7%) and greater aneuploidy. Other events observed during the transition from HG2 to HG3 were a decrease in ER, PR, t-PA and cytosolic hyaluronic acid. These results led us to consider that HG is associated with certain clinical-biological changes that may help explain its value as a prognostic factor in breast carcinomas.
Biomarkers and Imaging in Non-Malignant and Malignant Osteomalacia
Authors: Lüftner D. , Bollow M. , Stürzenbecher A. , Kaufmann O. , Priem F. , Richter A. , Günther S. , Geppert R. , Petrides P.E. , Wernecke K.D. , Possinger K.
Published: March 2018

Deoxypyridinium (DPD) cross-links are a specific parameter for collagen type I degradation. We report the longitudinal tracking of DPD in relation to other bone markers and imaging techniques in a patient with osteomalacia and secondary hyperparathyroidism from reduced light exposure due to attire. This patient was first admitted for diffuse skeletal pain. X-rays showed general demineralization and Looser's transformation zones in the neck of the left femur. MRI examinations of the pelvis and the proximal femora demonstrated bilateral signs of acute sacroiliitis, as well as edema-like lesions in the femoral heads and necks bilaterally. The baseline parathyroid hormone level was 8 times higher than the normal upper limit, whereas 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were significantly reduced. A 7fold increase in free urinary DPD and a 17-fold increase in bone-specific alkaline phosphatase (bone-AP) were also measured. Percutaneous transiliac bone biopsy revealed markedly increased osteoidosis. Osteomalacia was diagnosed due to chronically reduced sun exposure caused by restrictive attire, and cholecalciferol substitution therapy was begun. After a follow-up of 28 weeks, non-specific parameters of bone turnover (parathyroid hormone, total alkaline phosphatase, serum calcium and serum phosphate) had normalized, while DPD, as a specific bone degradation marker, and bone-AP, as a bone formation parameter, both remained elevated. This example underlines the validity of DPD and bone-AP as indicators of increased bone metabolism: not only were they the parameters with the highest baseline deviation, but they were also the last to normalize.
Loss of Heterozygosity on Chromosomes 1, 2, 8, 9 and 17 in Cerebral Atherosclerotic plaques
Authors: Miniati P. , Sourvinos G. , Michalodimitrakis M. , Spandidos D.A.
Published: March 2018

Objective

Atherosclerosis is a fibroproliferative disease which has been attributed to several factors including genetic and molecular alterations. Initial studies have shown genetic alterations at the microsatellite level in the DNA of atherosclerotic plaques. Extending our initial findings, we performed a microsatellite analysis on cerebral atherosclerotic plaques.

Methods

Twenty-seven cerebral atherosclerotic plaques were assessed for loss of heterozygosity (LOH) and microsatellite instability (MI) using 25 microsatellite markers located on chromosomes 2, 8, 9 and 17. DNA was extracted from the vessels as well as the respective blood from each patient and subjected to polymerase chain reaction.

Results

Our analyses revealed that specific loci on chromosomes 2, 8, 9 and 17 exhibited a significant incidence of LOH. Forty-six percent of the specimens showed loss of heterozygosity at 2p13–p21, 48% exhibited LOH at 8p12–q11.2, while allelic imbalance was detected in 47% of the cases. The LOH incidence was 39%, 31% and 27% at 17q21, 9q31–34 and 17p13, respectively. Genetic alterations were detected at a higher rate as compared to the corresponding alterations observed in plaques from other vessels.

Discussion

This is the first microsatellite analysis using atherosclerotic plaques obtained from cerebral vessels. Our results indicate an elevated mutational rate on specific chromosomal loci, suggesting a potential implication of these regions in atherogenesis.
Immunohistochemical Study of the BCAR1/p130Cas Protein in Non-Malignant and Malignant Human Breast Tissue
Authors: van der Flier S. , van der Kwast T.H. , Claassen C.J.C. , Timmermans M. , Brinkman A. , Henzen-Logmans S.C. , Foekens J.A. , Dorssers L.C.J.
Published: March 2018

BCAR1/p130Cas is a docking protein involved in intracellular signaling pathways and in vitro resistance of estrogen-dependent breast cancer cells to antiestrogens. The BCAR1/p130Cas protein level in primary breast cancer cytosols was found to correlate with rapid recurrence of disease. A high BCAR1/p130Cas level was also associated with a higher likelihood of resistance to first-line tamoxifen treatment in patients with advanced breast cancer. Using antibodies raised against the rat p130Cas protein, we determined by immunohistochemical methods the BCAR1/p130Cas localization in primary breast carcinomas, in tumors of stromal origin, and in non-neoplastic breast tissues. The BCAR1/p130Cas protein was detected in the cytoplasm of non-malignant and neoplastic epithelial cells and in the vascular compartment of all tissue sections analyzed. Immunohistochemistry demonstrated variable intensity of BCAR1/p130Cas staining and variation in the proportion of BCAR1/p130Cas-positive epithelial tumor cells for the different breast carcinomas. Double immunohistochemical staining for BCAR1/p130Cas and estrogen receptor confirmed coexpression in non-malignant luminal epithelial cells and malignant breast tumor cells. The stromal cells in non-malignant tissues and tumor tissues as well as breast tumors of mesodermal origin did not stain for BCAR1/p130Cas. This immunohistochemical study demonstrates a variable expression of BCAR1/p130Cas in malignant and non-malignant breast epithelial cells, which may be of benefit for diagnostic purposes.
An Alternative Cyclin-D1 Splice Site is Not Linked to Inflammatory Bowel Disease-Associated Neoplasia
Authors: Kanaan Ziad , Eichenberger M. Robert , Young Michael , Colliver Daniel , Crawford Nigel , Cobbs Gary A. , Hein David W. , Galandiuk Susan
Published: March 2018

Background

Inflammatory bowel diseases (IBD) encompass inflammatory disorders affecting the gastrointestinal tract, primarily ulcerative colitis (UC) and Crohn's disease (CD). The risk of developing colorectal cancer (CRC) is increased in patients with IBD. The CCND1 protein is the regulatory subunit of an enzyme that inactivates the retinoblastoma protein, a tumor suppressor protein, and promotes progression through the G1-S phase of the cell cycle. The CCND1 870G-A gene polymorphism influences susceptibility to colorectal cancer. The mutant allele of CCND1 in IBD-associated neoplasia leads to a greater frequency of alternate splicing during transcription, resulting in a more stable CCND1 protein. This creates a higher concentration of CCND1, facilitating easier passage through the G1/S checkpoint, abnormal cell cycle progression, and possibly carcinogenesis.

Methods

We conducted a case-control study involving 396 individuals with IBD. IBD subgroups included CD, UC, and indeterminate colitis (IC). We studied patients with sporadic colorectal cancer (n=75) and patients without gastrointestinal disease as a control group (n=93). We extracted DNA from blood and performed polymerase chain reaction followed by high-performance liquid chromatography to screen for mutations. We confirmed the polymorphism at nucleotide A870G in exon 4. For statistical analysis, we used exact analyses of two-way contingency tables. Power calculations were done and correction for multiple testing was performed by computing the false discovery rate (FDR).

Results and discussion

Our study had a power of 75% at a 0.05 significance level. A870G SNP allele frequency in the IBD group was 44.8%, compared to 51.6% in the control population. Only the IC group showed a significant association with CCND1 splice site after correction for multiple testing (FDR=0.042). There were no differences between the other IBD groups and controls.

Conclusion

We found an association between CCND1 A870G SNP and IC group only (p=0.014, FDR=0.042). However, our data do not show an association between CCND1 A870G SNP and CD-associated or UC-associated neoplasia.
Assessment of Biomarkers for Clinical Diagnosis of Papillary Thyroid Carcinoma with Distant Metastasis
Authors: Liang Huasheng , Zhong Yuhua , Luo Zuojie , Huang Yu , Lin Huade , Luo Min , Zhan Song , Xie Kaiqing , Ma Yan , Li Qingdi Quentin
Published: March 2018

Early diagnosis and treatment of thyroid cancers are critical for better prognosis and better survival rates. The purpose of this study was to identify potential diagnostic markers for papillary thyroid carcinomas with distant metastasis. Fifty-eight papillary thyroid tumor specimens (27 papillary thyroid carcinomas with distant metastasis and 31 without metastasis) were examined, and protein expression of pituitary tumor-transforming gene (PTTG), E-cadherin, p27kip1, vascular endothelial growth factor (VEGF)-C, metalloproteinase (MMP) 2, MMP9, chemokine receptor CXCR4, and basic fibroblast growth factor (bFGF) in these tumors was assessed by immunohistochemistry. The clinicopathological variables with diagnostic significance were determined by multivariate analysis, and their diagnostic values were evaluated by ROC curve analysis. PTTG, VEGF-C, MMP2, MMP9, CXCR4, and bFGF were overexpressed in metastatic papillary thyroid carcinomas, whereas p27kip1 expression was elevated only in carcinomas lacking metastasis. Multiple-factor binary ordinal logistic regression analysis revealed that PTTG, VEGF-C, MMP2, and bFGF were independently related to biological metastatic behavior in thyroid tumors, suggesting their potential use as biomarkers. ROC curve analysis showed that among these four proteins, VEGF-C and bFGF were the best diagnostic biomarkers. A VEGF-C and bFGF cluster was the most useful factor for the differential diagnosis between metastatic and non-metastatic papillary thyroid cancers. Thus, the combined use of VEGF-C and bFGF as biomarkers may improve the diagnostic accuracy of papillary thyroid carcinoma and may be useful in multimodal screening programs for the clinical diagnosis of papillary thyroid carcinoma and early detection of papillary thyroid carcinoma with distant metastasis.
Detection of Cytokeratin 19, Human Mammaglobin, and Carcinoembryonic Antigen-Positive Circulating Tumor Cells by Three-Marker Reverse Transcription-Pcr Assay and Its Relation to Clinical Outcome in Early Breast Cancer
Authors: Chen Yan , Zou Tian Ning , Wu Zhi Ping , Zhou Yong Chun , Gu Yu Lan , Liu Xin , Jin Cong Guo , Wang Xi Cai
Published: March 2018

Aims

To investigate the diagnostic, predictive, and prognostic value of the detection of circulating tumor cells (CTCs) using a three-marker (CK19, hMAM and CEA) RT-PCR assay in patients with early breast cancer.

Patients and methods

Peripheral blood was obtained from 50 patients with early-stage breast cancer before any systemic adjuvant therapy and analyzed for the presence of CK-19, hMAM and CEA mRNA-positive CTCs using an RT-PCR assay. The specificity of the primers used was evaluated in 20 healthy individuals, 24 patients with benign breast disease, and 30 patients with metastatic breast cancer. The detection of CTCs was correlated with clinical outcome.

Results

The detection rate of three-marker-positive CTCs in the blood of patients with early breast cancer was 54.0%, significantly higher than in patients with benign breast disease and healthy blood donors (p=0.002 and p=0.000, respectively). The three-marker RT-PCR assay had 58.8% sensitivity in the parallel test and 100% specificity for CTC detection in the serial test, which was higher than the sensitivity and specificity of single-marker assays. For early breast cancer, correlation analysis between detection of three-marker-positive CTCs and clinicopathological characteristics indicated that detection of three-marker-positive CTCs was significantly correlated with elevated serum CEA levels (p=0.001). After three years of follow-up, 13 of the 27 patients with three-marker-positive CTCs in their blood had relapsed and detection of three-marker-positive CTCs was significantly associated with locoregional recurrence and/or distant metastasis (p=0.002). Detection of three-marker-positive CTCs in peripheral blood was an independent risk factor for reduced median relapse-free interval (p=0.000).

Conclusion

The three-marker RT-PCR assay can enhance the sensitivity and specificity of CTC detection compared to single-marker assay. Detection of three-marker-positive CTCs was associated with relapse and might have important predictive and prognostic implications in early breast cancer.
Evidence that Genetic Variants of Metabolic Detoxication and Cell Cycle Control Are Not Related to Gallbladder Cancer Risk in Chilean Women
Authors: Tsuchiya Yasuo , Baez Sergio , Calvo Alfonso , Pruyas Martha , Nakamura Kazutoshi , Kiyohara Chikako , Oyama Mari , Ikegami Kikuo , Yamamoto Masaharu
Published: March 2018

Background and aims

High consumption of red chili pepper has been shown to be a risk factor for gallbladder cancer (GBC) in Chilean women. However, genetic factors in addition to this and other environmental factors may also be associated with an increased risk of GBC. We aimed to examine the associations of cytochrome P450 1A1 (CYP1A1), glutathione S-transferase class mu (GSTM1), and tumor protein p53 (TP53) polymorphisms with the risk of GBC in Chilean women.

Methods

A hospital-based case-control study of 57 patients with GBC, 119 patients with gallstones, and 70 controls was conducted. The statuses of the polymorphisms CYP1A1 rs4646903, CYP1A1 rs1048943, and TP53 rs1042522 were assayed using Custom Taqman® SNP Genotyping Assays and TaqMan®SNP Genotyping Assay. GSTM1 deletion polymorphism was detected by allele-specific PCR analysis.

Results

No significant differences in the genotypic or allelic frequencies in the CYP1A1, GSTM1, and TP53 polymorphisms were found between the three groups.

Conclusion

These genetic variants were not related to an increased risk of GBC in Chilean women. Other polymorphisms, such as red-chili-pepper-related polymorphisms, may contribute to the development of GBC in Chilean women.
Serum SCCA, Cyfra 21–1, EGFR and Cyclin D1 Levels in Patients with Oral Squamous Cell Carcinoma
Authors: Feng Xiao-yu , Li Jian-hua , Li Jin-zhong , Li Hua , Han Zheng-xue , Xing Ru-dong
Published: March 2018

Objectives

To determine the concentrations of SCCA, Cyfra 21–1, EGFR and Cyclin D1 in serum of patients with oral squamous cell carcinoma, and investigate their diagnostic value and their relationship with clinical stage, histological differentiation and lymph node metastasis.

Methods

Seventy hospitalized patients with oral squamous cell carcinoma and 72 healthy individuals were included in the study. Venous blood was collected from all study participants, in the oral carcinoma patients before tumor resection. One week after surgery, venous blood was collected again from 20 patients. Serum marker levels were determined by enzyme-linked immunosorbent assay (ELISA).

Results

The serum SCCA, EGFR and Cyclin D1 concentrations were significantly higher in patients with oral squamous cell carcinoma than in healthy controls, while there was no significant difference in Cyfra 21–1 levels between patients and controls. The serum SCCA concentration decreased after surgery, but there was no significant difference in the serum Cyfra 21–1, EGFR and Cyclin D1 concentrations before and after surgery. Serum SCCA, Cyfra 21–1, EGFR and Cyclin D1 concentrations were not correlated with clinical stage, histological differentiation and lymph node metastasis. When SCCA, EGFR and Cyclin D1 were measured separately, EGFR had the highest diagnostic sensitivity and accuracy and Cyclin D1 had the highest specificity; when any two of the markers were tested in combination, the combined detection of EGFR and Cyclin D1 had the highest sensitivity, specificity and accuracy.

Conclusions

SCCA, EGFR and Cyclin D1 may prove to be useful tumor markers in oral squamous cell carcinoma. The combined determination of EGFR and Cyclin D1 may be of value in the diagnosis of oral squamous cell carcinoma. Serum SCCA may be used as an adjunct in monitoring treatment response.
Downregulation of Ap-1 Repressor Jdp2 is Associated with Tumor Metastasis and Poor Prognosis in Patients with Pancreatic Carcinoma
Authors: Yuanhong Xu , Feng Xu , Qingchang Li , Jianpeng Fan , Zhe Liu , Kejian Guo
Published: March 2018

Pancreatic carcinoma is one of the most malignant and aggressive cancers. The identification of prognostic factors is thought to be useful in directing treatment. Transcription factor Jun dimerization protein 2 (JDP2), a member of the activator protein 1 (AP-1) family, acts as an AP-1 inhibitor and has been implicated in many cellular processes including carcinogenesis. The role of JDP2 in the development of pancreatic carcinoma, however, remained elusive. In this study we examined the expression levels of JDP2 in 36 pancreatic carcinoma samples by Western blotting and found that JDP2 expression was significantly downregulated in pancreatic carcinoma samples compared with peritumoral tissues. The decrease in JDP2 expression was correlated with lymph node metastasis and distant metastasis and strongly associated with the post-surgery survival time. These results indicate a possible connection between JDP2 expression and metastasis in pancreatic carcinoma and suggest that JDP2 can serve as a biomarker to predict the prognosis of patients with this cancer.
Relation between Surgery-Induced Prolactin Increase and the Menstrual Cycle Phase at Time of Surgery in Premenopausal Breast Cancer
Authors: Barni S. , Lissoni P. , Mandelli D. , Archili C. , Real G. , Sormani A.L. , Caprotti R. , Tancini G.
Published: March 2018

It has been suggested that both the menstrual cycle phase and postoperative changes in prolactin (PRL) secretion at the time of surgery may influence the prognosis of breast cancer. The present study was carried out to evaluate the relation between menstrual cycle period and surgery-induced PRL variations. We evaluated 32 premenopausal women with operable breast carcinoma; 17 were in perimenstrual phase (days 1-6 and 21-28) and 15 were in the mid-cycle (days 7-20) period at’ the time of surgery. To investigate serum levels of PRL, venous blood samples were collected before and 7 days after surgery. Postoperative hyperprolactinemia occurred in 17/32 patients and it was statistically more frequent in patients surgically treated during the perimenstrual phase than in the mid-cycle phase (12/17 vs 5/15; p < 0.05), while no other parameter (including axillary node and estrogen receptor status) showed a significant influence on hyperprolactinemia rate. The results suggest that in premenopausal breast cancer patients surgery-induced hyperprolactinemia may be influenced by the menstrual cycle phase at the time of surgery.
Urinary Neopterin in Malignant Lymphoma
Authors: Piccinini L. , Zironi S. , Federico M. , Pini L. A. , Luppi G.
Published: March 2018

Urinary neopterin levels were studied in 96 patients with malignant lymphomas. Twenty-eight had Hodgkin's disease and 68 non-Hodgkin's lymphoma. Neopterin excretion was significantly related to the clinical stage of the disease. Mean neopterin excretion in patients with active disease (634 ± 527 μmol neopterin/mol creatinine) was significantly higher (p = 0.000) than in patients in complete remission (198 ± 105 μmol neopterin/mol creatinine). Mean neopterin levels of patients in stage III-IV were higher than for patients in stage III. These findings were the same in patients with Hodgkin's disease and those with non-Hodgkin's lymphoma (659 ± 593 - 425 ± 316 μmol neopterin/mol creatinine), regardless of the histological subtype. A significant correlation was found between neopterin excretion, ESR (r=0.31; p=0.003) and hemoglobin (r=–0.40; p=0.000). Longitudinal analysis showed a trend towards a correlation between response to therapy and neopterin excretion. These findings suggest that neopterin may be a useful prognostic marker in non-Hodgkin's lymphoma.
The Potential Value of CA125 as a Tumour Marker in Small Volume, Non-Evaluable Epithelial Ovarian Cancer
Authors: Cruickshank D.J. , Terry P.B. , Fullerton W.T.
Published: March 2018

Seventy four consecutive patients with epithelial ovarian cancer have been followed up longitudinally with serial serum CA125 for up to 48 months. From this database, the CAl25 changes in small volume disease have been evaluated.

For long term complete responders (n = l2), the mean plateau level of CA125 was 7.2 U/ml (95% confidence interval; 5.6 to 9.2 U/ml). The natural half-life of CA125 at 5.1 days (range 3.8 to 7 days) was calculated from five patients with Stage I and II disease who underwent complete surgical excision. A mean lead time of 99 days (range 14 to 255 days) was demonstrated between marker detection of disease progression and clinically apparent progressive disease in 12 out of 13 patients (92%) who relapsed after chemotherapy induced complete remission. The threshold of tumour volume detection with CA125 is unlikely to be determined by an arbitrary cut-off level. The kinetics of CA125 provide more useful information and the potential to define complete response or indeed cure with CA125 parameters requires further investigation.
Characterization of Monoclonal Antibody 436 Recognizing the ARG-PRO-ALA-PRO Sequence of the Polymorphic Epithelial Mucin (PEM) Protein Core in Breast Carcinoma Cells
Authors: Nuti M. , Turchi V. , Rughetti A. , Viacava P. , Masci A.M. , Castagna M. , Frati L.
Published: March 2018

Epithelial mucins have obtained increasing clinical relevance since they were found in the serum of cancer patients and were shown to be elevated in metastatic disease. We report here the characterization of the monoclonal antibody (MAb) 436 which recognises the protein core of the polymorphic epithelial mucin (PEM) of the human breast. MAb 436 was generated by immunizing Balb/c mice with membrane-enriched fractions prepared from metastatic lesions in the axillary lymph nodes. The antigenic determinant recognized by the MAb 436 is expressed on the surface of breast cancer cells and was measured by ELISA on all of 50 cytosol preparations of primary breast tumors. Immunohistochemistry showed 98% of primary and 100% of metastatic breast cancer lesions to be positive with the 436 antigenic determinant expressed both in the cytoplasm and at the plasma membrane level of the tumor cells. Moreover, the antigen was expressed in a homogeneous fashion (80-100% of the total number of tumor cells) in more than 60% of the tumors. Reactivity with normal tissues was rare and scattered and restricted to glandular structures particularly at the luminal border level except for the distal and collecting tubules of adult and fetal kidney, where a cytoplasmic 436 antigen distribution was observed. Other cancers proved positive but the reactivity was always variable and heterogeneous. The antigen recognized by MAb 436 appears in Western Blotting as a Mr of more than 200,000 daltons protein resolved in two bands. Epitope mapping experiments using overlapping octapeptides in the repeat unit of the PEM identified in the RPAP (Arg-Pro-Ala-Pro) sequence the binding site of the 436 antigen.

With the selective reactivity shown and the homogeneous expression of the corresponding epitope in breast cancer cells of primary and metastic lesions, the MAb 436 represents a good reagent with potential application in the diagnosis and therapy of breast cancer.
HER-2/Neu Gene in Primary and Local Metastatic Axillary Lymph Nodes in Human Breast Tumors
Authors: Tommasi S. , Giannella C. , Paradiso A. , Barletta A. , Mangia A. , Simone G. , Primavera A.T. , Albarani V. , Schittulli F. , Longo S. , De Lena M.
Published: March 2018

In order to verify whether the HER-2/neu gene is involved in the initial phases of neoplastic disease or in its progression, we evaluated the amplification and overexpression of this gene in the primary tumor and in synchronous metastatic axillary lymph nodes of 26 women with operable breast cancer.

HER-2/neu was amplified in 35% and overexpressed in 33% of the primary sites; similar percentages were found in lymph nodes. The clear correlation between the two disease sites regarding gene, mRNA and protein levels, supports the hypothesis that this gene is involved in the initial and invasive phases of neoplasia. Its actual role with respect to other biological tumor characteristics during the metastatic process should be investigated further.
External Quality Assurance of the Carcinoembryonic Antigen (CEA) Assay: Main Findings in Six Years' Experience
Authors: Zucchelli G.C. , Ferdeghini M. , Pilo A. , Clerico A. , Masini S. , Prontera C.
Published: March 2018

In 1984 we initiated a national external quality assessmnent (EQA) program (supported by the Italian National Research Council, CNR) for the CEA assay; at present, about 200 Italian laboratories are participating in the program. The laboratories assayed the quality control (QC) samples according to their routine procedures and returned the results together with the name of the method/kit they used. The collecterd results were computer-processed and reports were sent back to the participants. A significant reduction of the CVt (mean between-laboratory agreement) of the CEA assay was observed throughout the EQA survey (from 35% in 1985 to 20-25% in the last cycles). In order to better clarify the differences in variability observed in the first QC cycles against the last ones, we used the ANOVA technique to evaluate the components of variability. The improvement in between-laboratory agreement was mainly due to the reduction of the between-kit component (from 30.5% to 15.2%), rather than to the smaller decrease observed for the within-kit variability (from 18.4% to 14.0%). The results reported for QC samples from different materials showed differences in the between-lab variability and substantial changes of the kit biases, thus suggesting a different specificity of the antibodies used in the various method/kits against different families of CEA molecules.

Considerable uncertainty was also encountered in the clinical classification of low pathological samples, which seems mainly due to the variability in cut-off values used by the laboratories for the clinical assessment of the same analytical results. Our data indicate a progressive increase in the reliability of CEA determination during our study and confirm that EQA has improved the reliability of analysis carried out by the participating laboratories, thus stimulating the kit manufacturers to provide more reliable products.
The Role of Serum Carcinoembryonic Antigen (CEA) in the Management of Patients with Colorectal Carcinoma: The Experience of the Istituto Tumori of Milan
Authors: Seregni E. , Bombardieri E. , Bogni A. , Crippa F. , de Jager E. , Buraggi G.L.
Published: March 2018

CEA determination has attained an important role in the clinical management of patients with tumors of the colorectal tract. In this paper the experience of the Istituto Tumori of Milan is reviewed and the results are discussed. Three hundred and thirty-six patients were followed after curative resection of colorectal carcinoma. The follow-up period was 15 years, from January 1975 to December 1990 (global follow-up 1358 years). In the course of follow-up 136 patients developed recurrent disease. The number of CEA determinations for each patient ranged from 1 to 37 (mean 8, total 3330). CEA levels of presurgical patients were related to the clinical stage. Among patients who developed recurrences 61% showed an increase in CEA serum levels. In 200 patients with a negative follow-up we observed only 15 cases of false-positive results.
Immunological Properties of a Radioiodinated Monoclonal Antibody and Its F(ab')2μ Fragments Directed Against the Polymorphic Epithelial Mucin of Human Breast Cancer
Authors: Liberatore M. , Nuti M. , Cascialli G. , Turchi V. , Clemente M. , Rossetto G. , Colella A. CENTI , Pala A.
Published: March 2018

The purification of the IgM monoclonal antibody 436 against a breast tumor antigen from mouse ascitic fluid is reported. The purified immunoglobulin was radioiodinated and the resulting product assessed for its binding capacity and binding specificity. Purified IgM-436 served for F(ab') 2μpreparation which was tested for its antigen binding capacity. Radioiodinated IgM-436 and its F(ab')2μ retained their immunological activity which was never lower than those of the corresponding cold products.
The Diagnostic Value of Mucinous Carcinoma-Associated Antigen (MCA) Tests in Breast Carcinomas
Authors: Günes I. , Miserez A.R. , Müller-Brand J. , Maecke H.
Published: March 2018

MCA (Mucinous Carcinoma-Associated Antigen) levels of 176 breast carcinoma patients were tested postoperatively by serial determination. One hundred forty-one patients had nonprogressive disease (PD–) while 35 were in the progressive phase (PD +); in the latter the diagnosis was confirmed by means of current diagnostic procedures.

One hundred seventeen of the 141 PD– patients showed MCA levels below cutoff whereas 27 of the 35 PD + cases showed high values. The difference in the incidence of elevated MCA levels between PD–and PD + groups was statistically significant (p < 0.05). The overall diagnostic efficacy of MCA assays showed 77% sensitivity and 82% specificity.
Endocrine Effects of Human Recombinant Interleukin-3 in Cancer Patients
Authors: Lissoni P. , Rovelli F. , Tisi E. , Ardizzoia A. , Perlangeli V. , Barni S. , Tancini G.
Published: March 2018

It is known that several cytokines can exert hormonal effects. At present, no data are available about the possible influence of IL-3 on the endocrine system. In order to investigate the endocrine effects of IL-3 in humans, we have evaluated serum levels of Cortisol, β-endorphin, GH, PRL, FSH, LH, TSH and melatonin in response to intravenous injection of IL-3 at a dose of 1 mcg/kg b.w. at 6.00 p.m. The study was performed in 5 non-small cell lung cancer patients. GH increased significantly in response to IL-3. PRL showed a progressive decrease after IL-3 injection, but its variations were not statistically significant. All other hormones, including Cortisol, were not affected by IL-3. This preliminary study shows that IL-3 may exert endocrine effects in humans, which would seem at variance with previously reported results on most other cytokines.
A New Approach to Tumour Marker Assessment by Perioperative Determination in Breast and Colorectal Cancer
Authors: Gion M. , Ruggeri G. , Mione R. , Marconato R. , Casella C. , Nosadini A. , Simoncini E. , Belloli S. , dal Zennaro E. , Bruscagnin G.
Published: March 2018

Preoperative serum tumour markers are currently classified as positive or negative according to a predetermined cut-off point. In the present study we examined the dynamic variation of marker levels after radical surgery of breast and colorectal cancer. CEA and CA15.3 were measured in 93 patients with breast cancer, CEA and CA19.9 in 97 patients with colorectal carcinoma before and 30 days after radical surgery. Any variation higher than 3-fold the analytical coefficient of variation of the assay was considered significant. In patients with negative preoperative marker levels a significant decrease was noted after surgery in 15.6% of cases for CEA and 27.8% for CA15.3 in breast cancer and in 46.8% for CEA and 25.7% for CA19.9 in colorectal cancer. Using both cut-off-based and dynamic criteria, we found an overall positivity rate of 19.6% for CEA and 33.3% for CA15.3 in breast cancer; 60.0% for CEA and 37.1% for CA19.9 in colorectal cancer.

From the present findings we conclude that the dynamic study of perioperative variations of tumour markers is a sensitive method additional to cut-off-based criteria for the assessment of the phenotypic expression of the marker by the tumour.
Neuron-specific enolase (NSE) in serum. Comparison of monoclonal versus polyclonal assay based on 392 blood samples
Authors: Drivsholm L. , Osterlind K. , Cooper E.H. , Purves D.A.
Published: March 2018

Neuron-specific enolase (NSE) is the best described serum tumor marker for small cell lung cancer (SCLC). Almost all clinical studies carried out so far used assays involving polyclonal antibodies against NSE; the majority of the studies analyzed the samples by a RIA NSE kit. We evaluated a new monoclonal kit and compared it to the poly clonal kit. We analyzed 392 serum samples, 265 from patients with SCLC, 88 from non-small cell lung cancers (NSCLC) and 39 from children with neuroblastomas. We found a good correlation between the results of the two assays. When correlating NSE in SCLC as measured with the two assays with clinical data, we found the same sensitivity, prognostic impact and value in treatment monitoring. We conclude that the “new” monoclonal assay is a fully acceptable alternative to the “old” polyclonal assay.